Drug Addiction - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

DRUG ADDICTION A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES J AM...

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DRUG

ADDICTION A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES

J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS

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ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright 2003 by ICON Group International, Inc. Copyright 2003 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1

Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Drug Addiction: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-597-83895-X 1. Drug Addiction-Popular works. I. Title.

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Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.

Copyright Notice If a physician wishes to copy limited passages from this book for patient use, this right is automatically granted without written permission from ICON Group International, Inc. (ICON Group). However, all of ICON Group publications have copyrights. With exception to the above, copying our publications in whole or in part, for whatever reason, is a violation of copyright laws and can lead to penalties and fines. Should you want to copy tables, graphs, or other materials, please contact us to request permission (E-mail: [email protected]). ICON Group often grants permission for very limited reproduction of our publications for internal use, press releases, and academic research. Such reproduction requires confirmed permission from ICON Group International Inc. The disclaimer above must accompany all reproductions, in whole or in part, of this book.

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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on drug addiction. Books in this series draw from various agencies and institutions associated with the United States Department of Health and Human Services, and in particular, the Office of the Secretary of Health and Human Services (OS), the Administration for Children and Families (ACF), the Administration on Aging (AOA), the Agency for Healthcare Research and Quality (AHRQ), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Healthcare Financing Administration (HCFA), the Health Resources and Services Administration (HRSA), the Indian Health Service (IHS), the institutions of the National Institutes of Health (NIH), the Program Support Center (PSC), and the Substance Abuse and Mental Health Services Administration (SAMHSA). In addition to these sources, information gathered from the National Library of Medicine, the United States Patent Office, the European Union, and their related organizations has been invaluable in the creation of this book. Some of the work represented was financially supported by the Research and Development Committee at INSEAD. This support is gratefully acknowledged. Finally, special thanks are owed to Tiffany Freeman for her excellent editorial support.

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About the Editors James N. Parker, M.D. Dr. James N. Parker received his Bachelor of Science degree in Psychobiology from the University of California, Riverside and his M.D. from the University of California, San Diego. In addition to authoring numerous research publications, he has lectured at various academic institutions. Dr. Parker is the medical editor for health books by ICON Health Publications. Philip M. Parker, Ph.D. Philip M. Parker is the Eli Lilly Chair Professor of Innovation, Business and Society at INSEAD (Fontainebleau, France and Singapore). Dr. Parker has also been Professor at the University of California, San Diego and has taught courses at Harvard University, the Hong Kong University of Science and Technology, the Massachusetts Institute of Technology, Stanford University, and UCLA. Dr. Parker is the associate editor for ICON Health Publications.

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About ICON Health Publications To discover more about ICON Health Publications, simply check with your preferred online booksellers, including Barnes & Noble.com and Amazon.com which currently carry all of our titles. Or, feel free to contact us directly for bulk purchases or institutional discounts: ICON Group International, Inc. 4370 La Jolla Village Drive, Fourth Floor San Diego, CA 92122 USA Fax: 858-546-4341 Web site: www.icongrouponline.com/health

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Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON DRUG ADDICTION .................................................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Drug Addiction............................................................................. 6 E-Journals: PubMed Central ....................................................................................................... 66 The National Library of Medicine: PubMed ................................................................................ 67 CHAPTER 2. NUTRITION AND DRUG ADDICTION ........................................................................ 109 Overview.................................................................................................................................... 109 Finding Nutrition Studies on Drug Addiction ......................................................................... 109 Federal Resources on Nutrition ................................................................................................. 110 Additional Web Resources ......................................................................................................... 111 CHAPTER 3. ALTERNATIVE MEDICINE AND DRUG ADDICTION .................................................. 113 Overview.................................................................................................................................... 113 National Center for Complementary and Alternative Medicine................................................ 113 Additional Web Resources ......................................................................................................... 114 General References ..................................................................................................................... 114 CHAPTER 4. DISSERTATIONS ON DRUG ADDICTION .................................................................... 117 Overview.................................................................................................................................... 117 Dissertations on Drug Addiction .............................................................................................. 117 Keeping Current ........................................................................................................................ 119 CHAPTER 5. PATENTS ON DRUG ADDICTION ............................................................................... 121 Overview.................................................................................................................................... 121 Patents on Drug Addiction........................................................................................................ 121 Patent Applications on Drug Addiction.................................................................................... 133 Keeping Current ........................................................................................................................ 152 CHAPTER 6. BOOKS ON DRUG ADDICTION .................................................................................. 153 Overview.................................................................................................................................... 153 Book Summaries: Federal Agencies............................................................................................ 153 Book Summaries: Online Booksellers......................................................................................... 155 The National Library of Medicine Book Index ........................................................................... 156 Chapters on Drug Addiction ..................................................................................................... 158 CHAPTER 7. MULTIMEDIA ON DRUG ADDICTION ........................................................................ 161 Overview.................................................................................................................................... 161 Video Recordings ....................................................................................................................... 161 Audio Recordings....................................................................................................................... 163 Bibliography: Multimedia on Drug Addiction .......................................................................... 164 CHAPTER 8. PERIODICALS AND NEWS ON DRUG ADDICTION ..................................................... 165 Overview.................................................................................................................................... 165 News Services and Press Releases.............................................................................................. 165 Newsletter Articles .................................................................................................................... 167 Academic Periodicals covering Drug Addiction ........................................................................ 168 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 171 Overview.................................................................................................................................... 171 NIH Guidelines.......................................................................................................................... 171 NIH Databases........................................................................................................................... 173 Other Commercial Databases..................................................................................................... 176 APPENDIX B. PATIENT RESOURCES ............................................................................................... 177 Overview.................................................................................................................................... 177 Patient Guideline Sources.......................................................................................................... 177 Finding Associations.................................................................................................................. 179

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APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 181 Overview.................................................................................................................................... 181 Preparation................................................................................................................................. 181 Finding a Local Medical Library................................................................................................ 181 Medical Libraries in the U.S. and Canada ................................................................................. 181 ONLINE GLOSSARIES................................................................................................................ 187 Online Dictionary Directories ................................................................................................... 187 DRUG ADDICTION DICTIONARY......................................................................................... 189 INDEX .............................................................................................................................................. 257

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FORWARD In March 2001, the National Institutes of Health issued the following warning: "The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading."1 Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing. Since only the smallest fraction of information dealing with drug addiction is indexed in search engines, such as www.google.com or others, a non-systematic approach to Internet research can be not only time consuming, but also incomplete. This book was created for medical professionals, students, and members of the general public who want to know as much as possible about drug addiction, using the most advanced research tools available and spending the least amount of time doing so. In addition to offering a structured and comprehensive bibliography, the pages that follow will tell you where and how to find reliable information covering virtually all topics related to drug addiction, from the essentials to the most advanced areas of research. Public, academic, government, and peer-reviewed research studies are emphasized. Various abstracts are reproduced to give you some of the latest official information available to date on drug addiction. Abundant guidance is given on how to obtain free-of-charge primary research results via the Internet. While this book focuses on the field of medicine, when some sources provide access to non-medical information relating to drug addiction, these are noted in the text. E-book and electronic versions of this book are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). If you are using the hard copy version of this book, you can access a cited Web site by typing the provided Web address directly into your Internet browser. You may find it useful to refer to synonyms or related terms when accessing these Internet databases. NOTE: At the time of publication, the Web addresses were functional. However, some links may fail due to URL address changes, which is a common occurrence on the Internet. For readers unfamiliar with the Internet, detailed instructions are offered on how to access electronic resources. For readers unfamiliar with medical terminology, a comprehensive glossary is provided. For readers without access to Internet resources, a directory of medical libraries, that have or can locate references cited here, is given. We hope these resources will prove useful to the widest possible audience seeking information on drug addiction. The Editors

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From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.

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CHAPTER 1. STUDIES ON DRUG ADDICTION Overview In this chapter, we will show you how to locate peer-reviewed references and studies on drug addiction.

The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and drug addiction, you will need to use the advanced search options. First, go to http://chid.nih.gov/index.html. From there, select the “Detailed Search” option (or go directly to that page with the following hyperlink: http://chid.nih.gov/detail/detail.html). The trick in extracting studies is found in the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Journal Article.” At the top of the search form, select the number of records you would like to see (we recommend 100) and check the box to display “whole records.” We recommend that you type “drug addiction” (or synonyms) into the “For these words:” box. Consider using the option “anywhere in record” to make your search as broad as possible. If you want to limit the search to only a particular field, such as the title of the journal, then select this option in the “Search in these fields” drop box. The following is what you can expect from this type of search: •

Patient Screening and Medical Evaluation for Implant and Preprosthetic Surgery Source: Journal of Oral Implantology. 24(4): 222-229. 1998. Summary: Dental implant and preprosthetic surgeries aim to restore normal anatomic contours, function, comfort, aesthetics, and oral health. This article considers patient screening and medical evaluation for implant and preprosthetic surgery. The author presents a number of absolute contraindications and analyzes a series of relative contraindications for which the doctor's judgement remains the decisive factors. Absolute contraindications discussed include recent myocardial infarction, valvular prosthesis, severe renal (kidney) disorder, treatment resistant diabetes, generalized secondary osteoporosis, chronic or severe alcoholism, treatment resistant osteomalacia, radiotherapy in progress, severe hormone deficiency, drug addiction, and heavy smoking habit (more than 20 cigarettes per day). Relative contraindications discussed

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include AIDS and HIV seropositivity, prolonged use of corticosteroids, disorders of phosphocalcic metabolism, hematopoietic disorder, buccopharyngeal tumors, chemotherapy in progress, mild renal disorder, hepatopancreatic disorder, multiple endocrine disorder, psychological disorders and psychoses, unhealthy life style, smoking habits, and lack of understanding and motivation. In the latter section, the author proposes treatment patterns that could optimize certain marginal health conditions or stabilize unbalanced biological functions prior to or at the time of surgery. As life expectancy in the industrial countries is continuously increasing, a greater number of elderly patients are equipped with implant supported prosthetics. The effort must therefore be focused on keeping a regular and watchful eye on their general health and screening for possible geriatric conditions responsible for long term implant failure. 1 figure. 4 tables. 33 references. •

Chronic Hepatitis D: A Vanishing Disease? An Italian Multicenter Study Source: Hepatology. 32(4, Part 1 of 2): 824-827. October 2000. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 19106-3399. (800) 654-2452 or (407) 345-4000. Summary: Hepatitis delta virus (HDV) was responsible for a high proportion of cases of acute and chronic liver disease in Southern Europe during the 1970s. Some data suggest that by the 1990s, HDV circulation had substantially declined. This article reports on a study that assessed the prevalence of HDC infection and its clinical impact in 834 Italian hepatitis B surface antigen (HBsAg) carriers in 1997. Anti-HDV antibodies were sought in all consecutive chronic HBsAg carriers observed in 14 referral liver units throughout Italy. Risk factors for anti HDV positivity were evaluated. Anti HDV antibodies were found in 69 of 834 (8.3 percent) HBsAg positive patients. Cohabitation with an anti HDV positive subject, intravenous drug addiction, residence in the South of the country, and the presence of cirrhosis were independently associated with the presence of anti HDV antibodies. The overall prevalence of anti HDV antibodies was lower than those observed in two multicenter surveys performed in 1987 and 1992 (23 percent and 14 percent, respectively). By 1997, the percentage of anti HDV positive subjects had sharply decreased in the 30 to 50 years age group, whereas it was almost unchanged in subjects over 50 years of age. The highest prevalence of anti HDC antibodies (11.7 percent) was found in patients with cirrhosis. This prevalence was as high as 40 percent in the 1987 study. The circulation of HDV sharply decreased in Italy, by 1.5 percent per year, from 1987 to 1997. This decrease resulted mainly from the reduction in chronic HDV infections in the young, for whom high morbidity and mortality rates were recorded in the past. The authors conclude that the results anticipate the almost complete control of HDV infection in the near future. 1 figure. 5 tables. 15 references.

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Renal Disease and Psychoactive Substance Abuse and Dependence Source: American Kidney Fund Newsletter for Health Professionals. 7(1): 1-4. 1990. Summary: Psychoactive substance use disorders, more commonly referred to as alcohol and drug addiction, are important but under-diagnosed and under-treated causes of renal disease. These disorders also complicate the treatment of many patients with endstage renal disease who are undergoing chronic dialysis and/or who are being considered for transplantation. This article discusses renal disease and psychoactive substance abuse and dependence. The author explores definitions of substance dependence and abuse, misconceptions about addiction, renal complications of substance use, issues for dialysis programs, and issues for transplant programs. The

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author stresses that health providers can decrease enabling behavior that helps perpetuate addiction by confronting patients about addiction and encouraging patients to enter treatment for substance abuse. 9 references. •

Brittle Diabetes: An Update Source: Clinical Diabetes. 10(6): 83-86. November-December 1992. Summary: This article reminds physicians of some of the problems inherent in treating patients with brittle diabetes, defined broadly to include any diabetes patient with wide swings in blood glucose concentration. After a section emphasizing the importance and difficulty of the proper diagnosis of brittle diabetes, the authors focus on seven common causes of brittle diabetes: communication disorders, malingering, factitious disease, gastroparesis, insulin resistance, counterregulatory hormone insufficiency, and drug addiction. The authors note that communication disorders, the most common cause of brittle diabetes in adults, limit the ability of the patient to receive, process, or perform instructions about diabetes care that are given by the physician. The authors discuss the types of communication disorders, clues to diagnosing the role of a communication disorder in brittle diabetes, and treatment strategies.

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Effects of Nutrition on Morbidity and Mortality in Hemodialysis Patients Source: Dialysis and Transplantation. 29(10): 614, 616, 618-619. October 2000. Contact: Available from Dialysis and Transplantation, Attn.: Subscriptions. P.O. Box 10535, Riverton, NJ 08076. (800) 624-4196 or (609) 786-0871. Summary: This article reports on a recent (1999) study as it compares to a similar study by the same authors completed in 1982. In 1982, the authors evaluated the survival of 98 hemodialysis patients and found that malnutrition was the main risk factor for morbidity and mortality. In 1999, the authors evaluated 122 patients and compared them to the 1982 cohort. Most of the patients (95 percent) are African American, and the female to male ratio was similar in both groups (0.9 versus 1.1). Only 4 percent of the patients had a residual GFR (glomerular filtration rate, mean was 2.2 ml per minute). The 1999 patients were older than the 1982 cohort; a mean age of 58 years versus 49 years, respectively. Noncompliance increased from 5 percent to 15 percent; drug abuse increased from 2 to 11 percent; and dialysis dose increased 25 percent. In 1982, the membranes used for dialysis were cellulose acetate; in 1999, the membranes were made of polysulfone. The mean Hct (hematocrit) was 23 percent in 1982 and 32 percent in 1999. Serum albumin (levels of protein in the blood) levels were not statistically different, nor was the percent of patients eating less than 0.8 grams of protein per kilogram per day. Therefore, in spite of significantly higher doses of dialysis, the use of more biocompatible membranes, and higher hematocrits, malnutrition remains high in hemodialysis patients. The authors conclude that, despite aggressive nutritional support, malnutrition remains the main factor for morbidity and mortality in these patients. However, older age, noncompliance, and drug addiction also play a role. 3 tables. 9 references.

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Should Pharmacists Sell Sterile Syringes to Injection Drug Users? Source: Journal of the American Pharmaceutical Association January/February 1999;39(1):8, 10. Contact: American Pharmaceutical Association, 2215 Constitution Ave NW, Washington, DC, 20037-2985, (202) 628-4410, http://www.aphanet.org. CDC National

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Prevention Information Network, PO Box 6003, Rockville, MD, 20849-6003, (800) 4585231, http://cdcnpin.org. Summary: This journal article discusses the pros and cons of pharmacies selling sterile syringes to injection drug users. It begins with a discussion of the role injection drug use plays in the transmission of blood-borne infections such as the human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) and current laws and regulations that restrict injection drug users' (IDUs) access to sterile syringes. Surveys of pharmacists indicate that pharmacists often set conditions for syringe sales that are not stipulated by laws or regulations, while public health authorities recommend that IDUs use sterile syringes to prevent the transmission of blood-borne infections such as HIV. Pharmacists can play a critical role in decreasing blood-borne pathogens transmission among IDUs through the voluntary sale of syringes in pharmacies and the education of patients about the persistent danger of blood-borne pathogen transmission. The article expands on three actions that pharmacies can take in this area: (1) pharmacies can address the question of whether and under what circumstance pharmacists should sell syringes to IDUs; (2) the profession can provide its members increased opportunities for continuing education on the laws and regulations governing syringe sales, drug addiction, injection drug use, blood-borne pathogens transmission, and HIV prevention; and (3) pharmacists and pharmacy organizations can join health departments, community-based organizations, medical associations, and others in reviewing the laws and regulations that affect syringe sales and, by extension, the prevention of blood-borne infections. •

When AIDS Comes to Church Source: Leadership; Fall Quarter, 1989. Contact: Christianity Today, 465 Gunderson Dr, Carol Stream, IL, 60188, (773) 260-6200. Summary: This journal article recounts how a pastor from suburban Ft. Lauderdale handled ministry to a family affected by AIDS. It tells of Tom's struggle to overcome drug addiction, only to learn of his HIV infection after he joined the church. The pastor talks of dealing with his own fears and of guiding his congregation to acceptance and compassion toward Tom and his wife, Ruth.

Federally Funded Research on Drug Addiction The U.S. Government supports a variety of research studies relating to drug addiction. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.2 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to drug addiction.

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Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).

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For most of the studies, the agencies reporting into CRISP provide summaries or abstracts. As opposed to clinical trial research using patients, many federally funded studies use animals or simulated models to explore drug addiction. The following is typical of the type of information found when searching the CRISP database for drug addiction: •

Project Title: A NOVEL ANIMAL MODEL OF COCAINE ADDICTION Principal Investigator & Institution: Roberts, David C.; Physiology and Pharmacology; Wake Forest University Health Sciences Winston-Salem, Nc 27157 Timing: Fiscal Year 2001; Project Start 01-APR-2001; Project End 31-MAR-2004 Summary: Cocaine addiction in North America is a medical problem with profound social and financial cost. Approximately 2 million Americans use cocaine habitually, and those seeking treatment find it extraordinarily difficult to abstain and relapse rates are high. A medication that would help control the cravings for cocaine during the early stages of therapy would help retain patients in treatment programs. An animal model is essential for testing potentially therapeutic drugs and for evaluating the underlying neurobiology of drug abuse. This proposal will address two key features of the addictive process. The first is a progressive increase in the motivation to take cocaine and the second is the emergence of binge patterns of drug use. Cocaine selfadministration in rats will be used to model these fundamental aspects of human drug taking. A novel procedure has been developed that permits continual access to cocaine (during discrete trials) throughout the 24 dark/light cycle. Different patterns of intake (either circadian or binge-like) are engendered depending on the dose and frequency of the trials. The overall objective of this proposal is to define the critical factors that model the addictive process. Specifically we will (1) define the parameters that affect the transition from controlled (circadian) intake to binge-like, dysregulated patterns of selfadministration, (2) identify factors that lead to motivational changes across the cocaine addiction process (such as total intake, pattern to intake, and drug-free periods) and (3) characterize individual differences in the development of binge-like patterns of intake and an increased motivation to self-administer cocaine. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: A PROTEOMIC ANALYSIS OF DRUG ABUSE Principal Investigator & Institution: Jordan, Thomas W.; Victoria University of Wellington Private Bag Wellington, Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2004 Summary: (provided by applicant) This project aims to identify molecular changes that accompany chronic self-administration of cocaine. The specific aim is to use proteomic procedures to identify and quantify protein changes that might underlie the use and abuse of cocaine in reward relevant sites of the brain. The primary objective is to identify novel targets for therapeutic drug development. To this end, tissue from the brains of rats that have self-administered cocaine will be analyzed using quantitative two-dimensional electrophoresis and mass spectrometry to identify proteins whose expression or post-translational modification is altered during addiction. Regions of the brain that have been implicated in responses to cocaine will be examined. Attention will be given to synaptic plasma membrane proteins, including the dopamine transporter, that have putative roles in responses to cocaine. Approximately 1000-2000 proteins will be examined and the results will be analyzed to show addiction related change in regions of the brain that have been implicated in addictive behavior. The long term goal is to examine the potential of these proteins as novel targets for therapeutic

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interventions that may be used in treatment of addiction including relapse that is common in cocaine abusers. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: A REINFORCEMENT-BASED THERAPEUTIC WORKPLACE Principal Investigator & Institution: Silverman, Kenneth; Psychiatry and Behavioral Scis; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-MAY-2007 Summary: (provided by applicant) The Therapeutic Workplace is a novel treatment designed to address the chronic and persistent nature of drug addiction and unemployment. Under this intervention, drug abuse patients are hired and paid to work in an income-producing Therapeutic Workplace business. To promote abstinence, participants are required to provide drug-free urine samples to maintain daily access to the workplace. Applicants actively using drugs and lacking job skills participate in an initial training phase to initiate abstinence and establish job skills. If the business is financially successful, this treatment could be maintained over extended periods of time at little cost to society. This application is a competing continuation of a grant in which we developed and pilot tested a computerized Therapeutic Workplace designed to train and employ adults as data entry operators. A randomized trial is planned over 5 years to investigate the Therapeutic Workplace business as a maintenance intervention to sustain long-term abstinence and employment. Welfare recipients in methadone treatment, actively using cocaine, and at risk for contracting or spreading HIV infection will participate in an initial Therapeutic Workplace training phase. Participants (N=156) who become abstinent and skilled will be randomly assigned to a "Usual Care Control," an "Employment Only," or an "Abstinence & Employment" group. "Usual Care Control" participants will be referred to seek a job in the community. "Employment Only" participants will be offered employment for one year in a Therapeutic Workplace business, but these participants will not have to provide drug-free urine samples to work. Participants in the "Abstinence & Employment" group will be employed for one year also, but these participants will have to provide drug-free urine samples to work and earn salary. This study will provide a rigorous evaluation of the efficacy of the Therapeutic Workplace business as a long-term treatment of cocaine addiction and unemployment; determine the benefits of requiring daily evidence of abstinence to work; and provide information on the extent to which a Therapeutic Workplace business can become self-sustaining. This research could provide firm scientific foundation for the dissemination of Therapeutic Workplace businesses in the long-term treatment of cocaine addiction and unemployment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ACCUMBENS ACETYLCHOLINE IN A NEURAL CIRCUIT FOR AVERSION Principal Investigator & Institution: Hoebel, Bartley G.; Psychology; Princeton University 4 New South Building Princeton, Nj 085440036 Timing: Fiscal Year 2002; Project Start 15-SEP-1996; Project End 31-JUL-2004 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ADAPTING BEHAVIORAL MARITAL THERAPY TO TREAT DRUG ABUSE Principal Investigator & Institution: Epstein, Elizabeth E.; Associate Research Professor; Center of Alcohol Studies; Rutgers the St Univ of Nj New Brunswick Asb Iii New Brunswick, Nj 08901 Timing: Fiscal Year 2001; Project Start 01-JAN-1999; Project End 31-DEC-2002 Summary: This second revision of R01DA10835-01, originally submitted 2/96 (score was 225) then 2/97 (score was 179), is a 3 year, Stage I research plan is in response to the NIDA Behavioral Therapies Development Program. It develops a marital therapy model of treatment for drug abusing or dependent males and their female partners, by modifying a similar model currently used to treat alcohol dependence. The assessment/treatment manual will be developed by treating three cohorts of 8 couples each. Changes in the protocol based on experiences with each cohort will be incorporated into the treatment manual for the subsequent cohort. Broad objectives of the study are to begin programmatic development of a promising behavioral couples treatment for drug addiction (BCTD), and to generate a treatment manual, related materials, and descriptive data for Stage II research. Specific primary goals are: (1) to develop a feasible, manualized treatment protocol for stand-alone, outpatient cognitivebehavioral couples therapy for drug addiction; (2) to develop baseline (BL) and followup (FU) assessment batteries for both partners, to study the effects of psychopathology, substance use, and quality of the marital relationship, on response to BCTD, and (3) to generate self-report, interview, and observational data on each couple, so that we can carefully describe the sample in terms of BL and post-treatment characteristics, and marital interaction specifically related our model of change. These descriptive data will facilitate development of a treatment protocol that is applicable to wide range of drug abusing individuals, and of hypotheses related to change, that can be tested in later Stage II studies. Specific secondary goals are: (4) to develop selection and training protocols for therapists; (5) to develop a measure of therapist adherence/competence; (6) to develop a measure of treatment integrity, and (7) to evaluate the feasibility of following up this sample. Research Design and Methods: First, we will prepare a BCTD treatment manual for drug misuse, BL and FU assessment batteries, a training protocol for therapists, and a battery of treatment and therapist process measures. The assessment/treatment package will include BL assessment 24 outpatient conjoint sessions, post-treatment FU and exit interview, and a 3 month FU and exit interview. The initial version of the protocols will be developed in the first six months, by modifying existing protocols for alcohol behavioral couples therapy. During the second half of the first year, 8 couples will be recruited and the initial protocol will be piloted and revised. Eight more couples will comprise the second cohort and will be administered the revised assessment/treatment protocol during the second year of the grant. The manual will then be revised again, and the final cohort of 8 couples will pilot the "closest to final" version of the assessment/treatment/ follow-up package during the last year of the grant. Final revisions will be made based on results from the third cohort pilot, and the manual and protocols will be prepared for used in subsequent tests of the treatment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ADDICTION MEDICINE PHYSICIANS AND CARE FOR HEPATITIS C Principal Investigator & Institution: Gourevitch, Marc N.; Psychiatry and Behavioral Scis; Yeshiva University 500 W 185Th St New York, Ny 10033

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Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-MAY-2004 Summary: (provided by applicant): Drug users are heavily and disproportionately affected by hepatitis C, yet they face numerous barriers to healthcare that place them at risk for substantially lower levels of hepatitis C care than non-drug users. Because of their continuous contact with individual drug users and their knowledge of and experience with the intricacies of their healthcare, physicians practicing addiction medicine are in a unique position to facilitate drug users' access to and success with hepatitis C treatment. However, no data exists to describe the knowledge, attitudes and experience of addiction medicine physicians regarding hepatitis C care for drug users. We propose to nationwide survey of over 800 physician members of the American Society of Addiction Medicine (ASAM). Non-ASAM physicians practicing medicine in methadone maintenance treatment programs New York State will also be surveyed and compared to ASAM members to determine the generalizability of findings derived from the latter cohort. The proposed study will address the following specific aims: Aim 1: To describe the knowledge of and attitudes towards eligibility guidelines for hepatitis C treatment among physicians in addiction medicine, and determine the association between these attitudes and the physicians' provision of hepatitis C treatment to DUs, either direct or by referral; Aim 2: To determine the association between provision of HIV care by physicians in addiction medicine and the provision of hepatitis C treatment to DUs, either direct or by referral; Aim 3: To determine the association between the availability of onsite primary medical care in drug treatment programs and provision of hepatitis C treatment to DUs, either direct or by referral, by physicians in addiction medicine. The survey will focus on physicians' knowledge and attitudes surrounding treatment eligibility criteria, such as duration of abstinence from drug and alcohol use and history of depression. It will query physicians about their experience with hepatitis C treatment for drug users, either by referral or by direct management themselves, and their access to treatment resources. It will also inquire about their clinical practice setting and their professional background. The proposed study will identify strengths and weaknesses in the delivery of hepatitis C healthcare by addiction medicine physicians to drug users, and it will focus on collecting data useful for the development of interventions designed to improve drug users' access to hepatitis C treatment. Data from this study will have relevance to both drug abuse treatment policy and clinical practice. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ADDICTIVE DRUGS-PHARMACOLOGY & PHYSIOLOGY Principal Investigator & Institution: Kreek, Mary-Jeanne; Lab/Biology/Addictive Diseases; Rockefeller University New York, Ny 100216399 Timing: Fiscal Year 2003; Project Start 01-FEB-1978; Project End 31-MAR-2008 Summary: (provided by applicant): This is a competitive renewal to provide the major source of salary support for the applicant, Mary-Jeanne Kreek, M.D., as a senior Research Scientist Awardee (and also as a Principal Investigator and Scientific Director of an NIH-NIDA Treatment-Related Research Center.) This award will allow the applicant to continue to spend the majority of her time in basic laboratory-based and basic clinical research, as well as to continue to spend a significant amount of time in scientific training and mentoring in the graduate, postgraduate, and mid-career levels, as well as science education at the undergraduate, graduate and high school levels. The applicant will also continue to be active in science education, particularly as pertains to the biological basis of the addictive disease, to a more general public. The most effective treatments for the addictive diseases, including opiate addiction, cocaine addiction, alcoholism, and nicotine addiction, probably will continue to be based on a fundamental

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understanding of the biological and molecular bases of addictive diseases; the physiologic and pharmacologic effects of drugs of abuse, and of agents used for the treatment of specific addictions, and also of medical and behavioral problems which frequently coexist with specific addictions and may complicate treatment, such as HIV-1 (AIDS), hepatitis B, and especially hepatitis C. Research activities will continue to identify and study the biological correlates of addictive diseases, factors which affect treatment outcome, and primarily the molecular neurobiological basis of addiction, and the human molecular genetics of addictions. There will be four domains of Specific Aims: 1) Laboratory-based research (Projects 1, 2 and 3); 2) Basic clinical research (Project 4); 3) Human molecular genetics (Project 5); and, 4) Applied clinical research (Project 6), each related to four specific addictions: opiate (primarily heroin) addiction, cocaine addiction, alcoholism, and nicotine addiction. Three specific projects within these four Specific Aims are, e.g.: 1) Effects of chronic opiates and cocaine, withdrawal, and challenge on receptors, and gene expression of the endogenous opioid and related neurotransmitter systems; 2) Effects of opiates and cocaine on the molecular biology and expression of the stress responsive hypothalamic-pituitary-adrenal axis; 5) Human genetics research of addictions with emphasis on studies of the human molecular genetics. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ADDICTIVE DRUGS--PHARMACOLOGY AND PHYSIOLOGY Principal Investigator & Institution: Kreek, Mary J.; Lab/Biology/Addictive Diseases; Rockefeller University New York, Ny 100216399 Timing: Fiscal Year 2001; Project Start 01-FEB-1978; Project End 31-MAR-2003 Summary: (Applicant's Abstract): This is a competitive renewal to provide a major source of salary support for the applicant, Mary Jeanne Kreek, M.D., as a senior Research Scientist Awardee (and also as Principal Investigator and Scientific Director of an NIH-NIDA Treatment-Related Research Center). This award will allow the applicant to continue to spend a significant amount of time in science training and mentoring at the graduate, post-graduate level, science education at the undergraduate and high school level as well as science education of a more general public. The most effective treatments for the addictive diseases including opioid addiction, cocaine addiction, alcoholism and nicotine addiction, probably will be based on the fundamental understanding of the biological basis of addictive diseases; the physiological and pharmacological effects of drugs of abuse and of agents used for the treatment of drug addiction, and of the other medical and behavioral problems which frequently co-exist with specific addictions and may complicate treatment. Also, effective treatments and prevention may by facilitated by an understanding of the human molecular genetics underlying some cases of addictive diseases. Research activities will continue to identify and study the biological correlates of addictions, factors which affect treatment outcome and also, primarily, the molecular neurological basis of addiction. Specific projects include: Effects of Drugs of Abuse and Potential Therapeutic Agents on the Molecular Biology of Endogenous Opioids, Related Neuropeptides and their Receptors; Effects of Drugs of Abuse and Potential Therapeutic Agents on Opioid Receptor and Related Neurotransmitter Systems; Disposition; Biotransformation of Natural Synthetic Opioid Agonists, Antagonist and Related Peptides; Effects of Drugs of Abuse and Potential Therapeutic Agents on the Molecular Biology and Expression of the Stress Responsive Hypothalamic Pituitary Adrenal Axis; Effects of Cocaine on Endogenous Opioid NMDA Complex Interactions; Neuroendocrine Effects of Addictive Drugs: Role of the Endogenous Opioids and Stress Responsivity in Addictive Diseases; Effects of Drugs of

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Drug Addiction

Abuse and Potential Therapeutic Agents on the Molecular Biology and Expression of the Stress Responsive Hypothalamic Pituitary Adrenal Axis; Effectiveness of LAAM in Managing Heroin Abusing Methadone Maintained Patients. Human gene polymorphism and molecular genetics of addictions and the opioid system; and continued prospective surveillance of the medical status of patients entering methadone maintenance treatment, determining the changing patterns of hepatitis B, hepatitis C, HIV-1 infection and codependence and the impact of treatment on their natural history. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ADDRESSING NICOTINE ADDICTION IN DRUG ABUSE PATIENTS Principal Investigator & Institution: Richter, Kimber; Psychology and Sociology; University of Kansas Medical Center Msn 1039 Kansas City, Ks 66160 Timing: Fiscal Year 2001; Project Start 05-FEB-2000; Project End 31-JAN-2005 Summary: Kimber P. Richter, Ph.D., M.P.H., is a behavioral psychologist with training in public health who will use the MRSDA to develop expertise in addressing nicotine addiction among persons in drug abuse treatment, an estimated 80 percent of whom smoke. The proposal combines her behavioral background in drug abuse prevention, drug abuse treatment, and cardiovascular disease risk reduction with a new focus on smoking cessation. This plan outlines the training and research experience she will need, over the next 5 years, to develop and launch a fully independent career addressing nicotine addiction among persons in drug abuse treatment. Career Development: Activities include training in the chemistry of the nervous system, advanced biostatistics, training in addictions treatment and research, a week-long internship with a nicotine/drug addictions researcher, and an intensive bioethics course. Research Program: The goal of the proposed research program is to better understand smoking behaviors and nicotine dependence among persons in treatment for chemical dependencies, and to identify acceptable and potentially effective methods for reducing cigarette smoking in this population. Specifically, the plan involves three studies that address five research questions. Study 1 examines key issues in smoking cessation from the patient's point of view. It consists of a series of two focus groups among each of four subgroups of clients in methadone maintenance treatment (MMT) and other drug dependency programs. These 8 sessions is will identify clients' a) interest in quitting, b) barriers to quitting smoking, c) successful strategies used to quit smoking, d) strategies used to avoid illicit drug use that might be adapted for smoking cessation, and e) treatment preferences for quitting smoking. Study 2 is a descriptive study examining interactions in patterns of cigarette use and methadone maintenance. Twenty-one methadone patients will use electronic monitors to record the frequency and timing of their cigarette consumption. Data on methadone timing and dose, as well as carbon monoxide levels and psychological measures of nicotine craving and withdrawal, will be collected and analyzed to assess whether methadone dose and timing are associated with surges in cigarette consumption and smoking urges. Study 3 is a pilot study examining the feasibility and potential efficacy of a multicomponent intervention on smoking cessation. Sixty MMT patients will be randomly assigned to treatment (nicotine inhaler and motivational interviewing) or control (placebo inhaler and comparable staff contact). Primary outcomes include quit rates and avg. daily cigarette use. Pilot data will allow determination of sample sizes for a full-scale intervention trial, and will be used to assess the effects of variables such as age, gender, methadone dose on treatment effects. The research plan uses exploratory, descriptive, and intervention research to address fundamental issues of nicotine addiction. Each study stands on its own, but is designed to build on the findings of the prior study. This research may serve as a model for

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systematic research on nicotine addiction in patients with other drugs of dependence or who are in other drug abuse treatment modes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ADHERENCE THERAPY FOR OPIOID ABUSING PAIN PATIENTS Principal Investigator & Institution: Haller, Deborah L.; Associate Professor; Psychiatry; Virginia Commonwealth University Richmond, Va 232980568 Timing: Fiscal Year 2001; Project Start 15-SEP-2000; Project End 31-AUG-2004 Summary: Many pain specialists oppose the use of opioids to treat chronic non malignant pain syndrome (CPS) due to concerns about addiction and the failure of many patients to evidence functional improvements. Others advocate the use of opioids when non- pharmacologic approaches fail or when quality of life will be improved. While most providers lack the expertise to provide "integrated" care to patients with CPS and co-occurring addiction, those with proficiency in both domains believe that this co-morbidity can be managed effectively with opioids so long as special procedures for dispensing medications for monitoring for illicit drug use are implemented. With this in mind, we are proposing a Stage 1 study to develop and pilot test "Medication Adherence Therapy" (MAT). MAT is designed to enhance opioid adherence in pain patients with a history of prescription drug abuse for whom opioids are, nevertheless, clinically indicated. MAT "blends" elements of MET and CBT with specific adherence strategies including patient education, self-monitoring, and behavioral contracting. Together, these adherence strategies will comprise "Adherence Therapy" (AT), a comparison treatment which approximates best practices treatment as usual. At issue is whether adding the additional psychotherapeutic elements included in MAT (i.e., MI and CBT) improves outcomes over those for patients who receive AT only. During Phase 1 (months 1-18), we will complete drafts of the MAT and AT manuals and will pre- pilot these on 18 patients with CPS and opioid abuse (12 MAT and 6 AT). All cases will be video-taped for review by the therapy development team consisting of the PI, Co-Investigators, and consultants. Videotapes will also be used to help identify the unique aspects of MAT. Based on the results of the pre-pilot, we will revise the manuals and begin development of the adherence/competence scales. During Phase 2 (months 19-24), we will train 3 interventionists each in MAT and AT. The interventionists will be medical/rehabilitation staff who interact with these patients in medical settings as opposed to trained mental health personnel. Each interventionist will receive 2 training cases; training cases will be used to provide practice and determine therapist competence. Training will consist of didactic presentations, review of videotaped training cases, feedback, and clinical supervision. Trainees will also role-play situations they may encounter during the pilot study. During Phase 3 (months 25-42), we will conduct a pilot study comparing MAT to AT. The pilot study will in involve 30 patients with CPS and opioid abuse who are randomized to either MAT or AT. Trainees who demonstrated competence with their training cases will serve as the interventionists for the pilot study. During Phase 4 (months 42-48), the data from the pilot study will be analyzed and prepared for presentation/publication. We will estimate the effect size of the difference between MAT and AT and will then make a decision about whether MAT shows sufficient promise to warrant further testing in a State 2 study. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Drug Addiction

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Project Title: AMPHETAMINE TRANSPORTERS

SENSITIZATION:

ROLE

OF

DOPAMINE

Principal Investigator & Institution: Gulley, Joshua M.; Pharmacology; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2004 Summary: (provided by applicant): Repeated exposure to psychostimulant drugs typically leads to behavioral sensitization, which refers to enhanced motor responsiveness after administration of the same or lower doses of the drug. This phenomenon, which persists well after drug taking ceases, has been suggested to contribute to various aspects of human drug addiction, including "craving" and relapse. In the research proposed here, I will investigate the role of dopamine transporter (DAT) function in the expression of behavioral sensitization. The DAT is responsible for clearing DA from the extracellular space. Using inbred Lewis and Fischer 344 rats, which have been described as addiction-prone and addiction-resistant, respectively, I will measure DAT number and function in the striatum and nucleus accumbens using quantitative autoradiography to measure in vitro radioligand binding and in vivo highspeed chronoamperometry to measure clearance of exogenous DA. Measurements will be made in untreated rats and those withdrawn from daily intravenous injections of saline or amphetamine (AMPH). These inbred rat strains exhibit basal differences in the number of DATs expressed in striatum and nucleus accumbens, but it is not clear if this leads to differences in DAT function. I will pay particular attention to correlation between individual differences in the susceptibility to express sensitization and all of the following: DAT number in dSTR, NAc and their respective subregions, basal DAT activity in these areas, and the ability of either frequent DA application and/or systemic AMPH to regulate DAT function. These experiments will help elucidate the role of the DAT in behavioral sensitization and further our understanding of the neuroadaptations associated with repeated drug intake. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANATOMY CORE Principal Investigator & Institution: Westenbroek, Ruth E.; University of Washington Seattle, Wa 98195 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: (provided by applicant) OBJECTIVES: The projects in this Center proposal will require anatomical analysis of both gross and microscopic differences between wild type and mutant mice as related to drug addition. Gross differences and histological assays (i.e. Nissl staining, hematoxylin and eosin staining, and luxol fast blue staining) will be carried out in the laboratory of Dr. Westenbroek. The projects in this Center proposal will also require the use of confocal microscopy to determine changes in the localization and expression of various proteins in regions of the central nervous system in wild type and mutant mice as related to drug addiction. Confocal microscopy will be essential for determining whether these various proteins are expressed on the cell surface or in other cellular compartments. Two confocal microscopes are available in the W.M. Keck Imaging Facility located in the Health Sciences Building at the University of Washington. Dr. Ruth Westenbroek currently provides scientific oversight at the facility and has an extensive anatomy background and experience in preparation of tissue for immunocytochemistry. Dr. Westenbroek will be the PI on the Anatomical Core and will provide guidance in immunocytochemical procedures, proper controls, anatomical analysis, and will provide assistance in image analysis between control animals and

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experimental animals. Ms. Paulette Brunner currently provides technical support at the W.M. Keck Facility. The Imaging Center has recently acquired a new Leica TCS Spectral Confocal Microscope and Multiphoton Imaging System and Ms. Brunner will be responsible for training the individual investigators on this new system and over the long term provide assistance with image collection when necessary on both confocal microscopes located in the facility. Ms. Brunner is very adept at using image analysis software (i.e. MetaMorph, MetaFluor, NIH Image) and will assist the individual investigators in this area. In addition, Ms. Brunner will be responsible for scheduling and maintenance of the confocal microscopes, computers for image analysis and printers. The guidance and hands on help of Dr. Westenbroek and Ms. Brunner will allow the investigators quick and easy access to analysis of changes in anatomical localization associated with drug addiction. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BEHAVIORAL PHARMACOLOGY OF OPIOIDS Principal Investigator & Institution: France, Charles P.; Professor; Pharmacology; University of Texas Hlth Sci Ctr San Ant 7703 Floyd Curl Dr San Antonio, Tx 78229 Timing: Fiscal Year 2001; Project Start 10-FEB-1994; Project End 31-JAN-2004 Summary: This application is a competing continuation of a Research Scientist Development Award (RSDA) to Charles P. France, currently a Professor of Pharmacology and Experimental Therapeutics and Neuroscience at Louisiana State University (LSU) Medial Center in New Orleans. The overall objectives of research in the candidate's laboratory are to develop reliable drug discrimination procedures for studying drug dependence and withdrawal in non-human species, to use those procedures to examine the dependence potential and the therapeutic potential of a wide range of drugs, and to integrate these behavioral findings with other clinically-relevant measures of drug action. These studies also focus on the receptor mechanisms that mediate the abuse-related effects of drugs by structuring experiments around testable hypotheses that are founded in and guided by receptor theory. This combined approach, whereby behavioral procedures are used in concert with receptor theory, provides a bridge from molecular science to the clinic. During the initial period of support the breadth of research in the candidate's laboratory increased markedly to include studies on: benzodiazepine dependence and withdrawal; self- administration procedures in rats and monkeys; the effects of contingent and non-contingent cocaine administration on cognitive function (learning and memory) and on the hypothalamicpituitary-adrenal (HPA) axis; as well as endocrine and immune responses to acute and chronic drug treatment. The specific aims in this competing renewal are to evaluate opioids and GABAA modulators (e.g. benzodiazepines) for physical dependence potential, abuse liability and toxicity using drug discrimination, ventilation, antinociception, self-administration, and repeated acquisition procedures as well as schedule-controlled behavior and measures of immune and endocrine function. To augment ongoing and future behavioral studies on efficacy, the candidate plans to initiate a binding assay that is sensitive to variations in efficacy (GTPgammaS binding). Renewal of the RSDA will relieve the candidate of otherwise substantial teaching and administrative responsibilities and, thereby, allow him to fully participate in the research projects that have been initiated during the current period of support, collaborate extensively with other NIH-supported investigators at LSU Medical Center, and spend time training young scientists in his laboratory. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BIOBEHAVIORAL MECHANISMS OF DRUG REWARD AND ADDICTION Principal Investigator & Institution: Carlezon, William A.; Associate Professor of Psychiatry; Mc Lean Hospital (Belmont, Ma) Belmont, Ma 02478 Timing: Fiscal Year 2001; Project Start 01-FEB-2001; Project End 31-DEC-2004 Summary: The proposed studies will examine how cocaine exposure affects AMPA receptor subunit (GluR) expression in the nucleus accumbens shell (NASh) and basolateral amygdala (BLA). The behavioral significance of changes in GluR expression in each region will be examined using state-of-the-art molecular methods (viralmediated gene transfer) to directly modulate their expression. We will study the NASh because it mediates, at least in part, the rewarding effects of cocaine. We will study the BLA because it sends a direct glutamatergic projection to the NASh, and it is implicated in the development of cocaine sensitization. We have preliminary data showing that repeated intermittent exposure to cocaine regulates GluR expression in the BLA, and other investigators have shown cocaine regulation of GluRs in the nucleus accumbens as a whole. In Aim 1, we will examine the effects of repeated intermittent cocaine (associated with behavioral sensitization) and continuous infusion of cocaine (associated with tolerance) on GluR expression in the BLA and NASh. Tissue will be examined at numerous time points following termination of drug treatment. To examine the pharmacological specificity of cocaine effects, we will conduct parallel studies with the selective dopamine reuptake inhibitor GBR 12909. In Aim 2, we will use viral-mediated gene transfer to selectively alter expression of GluR1 and GluR2 in the BLA and NASh to examine the relevance of altered GluR expression on cocaine reward. In place conditioning experiments, we have preliminary data showing that increased expression of GluR2 in either region increases cocaine reward, whereas increased expression of GluR1 in either region decreases cocaine reward (and can make cocaine aversive). In Aim 3, we will examine whether the effects of altered GluR expression on cocaine reward involve changes in the anxiety-related effects of the drug. We have preliminary data showing, in the BLA, that increased expression of GluR1 makes cocaine more anxiety-provoking, whereas increased expression of GluR2 makes cocaine less anxietyprovoking. Together, these studies provide a framework for future studies in which we will use additional behavioral and molecular techniques to explore mechanistic links between drug-induced neuroadaptations, reward, aversion, and anxiety. Understanding mechanistic links between cocaine-induced adaptations in gene expression and adaptations in behavior may facilitate the development of novel treatments for cocaine addiction and craving. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CALCIUM SIGNALING IN REWARD CIRCUIT AND DRUG ADDICTION Principal Investigator & Institution: Morikawa, Hitoshi; Waggoner Center for Alcohol and Addiction Research; University of Texas Austin 101 E. 27Th/Po Box 7726 Austin, Tx 78712 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-MAY-2008 Summary: (provided by applicant): Dopaminergic neurons in the ventral midbrain, i.e., the ventral tegmental area and the substantia nigra pars compacta, are believed to be critically involved in the perception of reward and addiction to drugs of abuse, such as psychostimulants and opioids. The firing pattern of dopamine neurons, which is controlled by excitatory and inhibitory synaptic inputs, is significantly modulated by

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presentation of rewards and administration of drugs of abuse. Modulation of dopamine neuron firing affects dopamine release in target structures, and hence contributes to reward-driven motivated behaviors in vivo, including drug-seeking and drug-taking behaviors. It has been shown recently that repetitive stimulation of glutamatergic inputs to dopamine neurons evokes a slow inhibitory postsynaptic potential mediated by activation of metabotropic glutamate receptors (mGluRs). This hyperpolarization results from the opening of calcium-activated potassium channels following release of calcium from intracellular stores. The overall hypothesis of the proposal is that this calciummediated inhibition plays a key role in controlling the excitability of dopamine neurons and in psychostimulant-induced modulation of dopamine neuronal activity. The first aim is to determine the intracellular signaling pathway mediating the release of calcium following the activation of mGluRs. This will be accomplished by combined whole-cell patch clamp recording and confocal calcium imaging techniques using acutely prepared midbrain slices from rats. Furthermore, flash photolysis of caged compounds will be performed to examine the effects of second messengers applied directly into the cytosol on a millisecond time scale. These methods will enable detailed examination of the intracellular events that follow the activation of plasma membrane receptors. The second aim is to determine the impact of this glutamate-induced hyperpolarization on the firing pattern of dopamine neurons. An effort will be made to reproduce the firing pattern observed in vivo in an in vitro slice preparation. The third aim is to investigate how acute administration of psychostimulants interferes with the mGluR-induced inhibition to modulate the firing pattern of dopamine neurons. The information obtained will open a new avenue toward the understanding of the neural mechanism responsible for the development of drug addiction. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ADDICTION

CENTRAL

CHOLINERGIC

INVOLVEMENT

IN

COCAINE

Principal Investigator & Institution: Mark, Gregory P.; Behavioral Neuroscience; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-JUL-2006 Summary: (provided by applicant) The substantial health risk posed by the compulsive use of cocaine has prompted a serious research effort to identify the neurobiological substrates that underlie the development of addiction to this drug. Despite substantial progress, an understanding of the neurochemical systems that mediate the motivational aspects of drug seeking and craving remains incomplete. To expand this understanding, this proposal will examine the involvement of four discrete cholinergic systems in the development of compulsive cocaine intake and cocaine-seeking behaviors in rats. Experiments will focus on nicotinic acetylcholine (ACh) receptor activation in the development and expression of addictive behavior. The first specific aim is to identify the impact of escalating cocaine self-administration on the release of ACh in amygdaloid complex (AmC), ventral tegmental area (VTA), nucleus accumbens (NAc) and prefrontal cortex (PFC). Rats will be trained to press a lever to self-administer cocaine through indwelling jugular catheters. Availability of cocaine will be increased from 1 to 6 hr per day (which has been shown to escalate daily cocaine intake) and microdialysis will measure ACh release before and after escalated cocaine intake. A second experiment will examine the impact of intracerebral microinjections of nicotine or the nicotinic antagonist mecamylamine on the escalation of cocaine intake. The second aim of this proposal is to determine if nicotine injections in VTA, NAc, PFC or AmC will prime non-reinforced lever-press behavior in cocaine addicted rats. Prior to testing, rats

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Drug Addiction

will receive systemic injections of nicotine or saline before self-administering cocaine for 2 weeks. On test days, rats will be given intracerebral nicotine and non-reinforced responding will be measured as an index of cocaine craving. The third aim of this research is to determine the role of AmC, VTA, NAc and PFC ACh systems in the ability of drug-associated stimuli to control non-reinforced responding. ACh will be measured during the presentation of cocaine-associated cues along with responding elicited by a cocaine-conditioned stimulus after microinjection of nicotinic drugs into AmC, VTA, NAc and PFC. Injections of nicotinic antagonists in these four areas are expected to reduce lever-press behavior in response to presentation of second-order stimuli. It is hoped that the results of these studies will further our understanding of the involvement of central cholinergic mechanisms in cocaine-reinforced behavior and drug craving and the brain site-specific influence of nicotine on cocaine addiction and relapse. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHRONIC BRAIN IMAGING USING FLUORESCENCE ENDOSCOPY Principal Investigator & Institution: Schnitzer, Mark J.; Applied Physics; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-JUL-2005 Summary: (provided by applicant): Many forms of drug addiction lead to longstanding behavioral sensitization and to changes in neural circuits that persist well after administration of the addictive substance is terminated. Neuronal changes can involve drug-induced alterations in patterns of gene expression, increased levels of particular proteins, or morphological changes in specific neuron types. These changes likely contribute to the enduring behavioral effects of drug addiction. Understanding of such long-lasting cellular changes is important for medical efforts towards counteracting their contributions to addiction and to cognitive deficits. Unfortunately, current studies are severely hampered by the dearth of methods that can track long-term progression of cellular properties in live animals. This proposal explores an exciting new in vivo imaging technology that will enable longitudinal studies of how abused substances affect individual neurons and neuronal dendrites. The proposed research will rely on newly developed high-resolution fluorescence endoscopes that are 350-1000 um in diameter and that enable in vivo imaging of neurons and dendrites with micron-scale resolution. The first specific aim seeks to establish the ability to monitor chronically individual neurons deep in the mammalian brain over days to months. This would be powerful for studying cellular consequences of drug abuse, because specific fluorescence probes can reveal changes in neuronal morphology, gene expression, or protein distribution. The second aim seeks to demonstrate the broad utility of this methodology by using chronic endoscopic imaging to visualize long-term structural effects of fetal ethanol exposure on mouse CA1 hippocampal pyramidal cell dendrites. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: COCAINE ADDICTION--ALTERATIONS IN REWARD CIRCUITRY Principal Investigator & Institution: Breiter, Hans C.; Assistant Professor; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2001; Project Start 01-SEP-2001; Project End 31-AUG-2006 Summary: (provided by applicant) This proposal, entitled "Cocaine addiction: Mapping alterations in reward circuitry," is a request for a NIDA R01 submitted in response to the RFA "Cognitive Approaches to Addictive Processes (RFA DA-01-001). To study reward circuitry in humans, the investigators have developed multiple drug infusion protocols

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and cognitive neuroscience studies for use with functional magnetic resonance imaging (fMRI). This R01 research proposal asks two fundamental questions: (1) Does a common circuitry process reward expectancy and reward outcome information across distinct categories of reward, and (2) How does this circuitry function differently in drug naive vs. cocaine dependent subjects for distinct categories of reward? To address these questions, this proposal outlines a strategy to evaluate the function of reward circuitry with regard to expectancy and reward outcome across three distinct categories of rewarding stimuli, namely pharmacological (morphine), monetary, and social reward. It further seeks to compare the function of this circuitry across matched cohorts of drug dependent subjects and healthy volunteers. The experiments proposed have already been successfully performed in separate cohorts of healthy controls, and piloted in cocaine dependent subjects. These studies demonstrate unique patterns of activation for the nucleus accumbens, amygdala, sublenticular extended amygdala of the basal forebrain, ventral tegmentum, and orbital gyrus with regard to reward expectancy and reward outcome. Specific Aim 1 is designed to evaluate the consistency of the fMRI response with regard to reward expectancy and reward outcome within the same individuals receiving three distinct categories of reward. These rewards include a pharmacological reward in the form of low-dose morphine infusions, non-drug reward in the form of money, and social reward in the form of beautiful vs. average faces. Specific Aims 2-4 apply each of these experiments to matched cohorts of cocaine dependent subjects and healthy controls to evaluate reward circuitry differences in the processing of expectancy information and outcome information between groups. Across these experiments, it is predicted that reward circuitry function will be diminished for non-drug reward in drug-dependent subjects relative to healthy volunteers, and that this alteration will be most pronounced for expectancy systems processing probability information about rewarding stimuli. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: COCAINE DEPENDENCE: EEG SLEEP AND CYTOKINES Principal Investigator & Institution: Irwin, Michael R.; Professor; Psychiatry & Biobehav Sciences; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-MAY-2006 Summary: (provided by applicant): Sleep disturbance is a prominent complaint of cocaine dependent patients during usage, and also following withdrawal and abstinence. However, the high frequency of disordered sleep stands in sharp contrast with limited effort to fully evaluate sleep or to identify the mechanisms that account for sleep abnormalities associated with chronic cocaine abuse. Given evidence that cocaine addiction also leads to a striking increase in the risk of infectious disease, we hypothesize that the complex cytokine network is one physiological system that mediates both sleep and immune abnormalities in cocaine dependence. Basic observations demonstrate that cytokines play a key role in the regulation of sleep. Translation of cytokine-sleep mechanisms into the clinic show that sleep loss and disturbances of sleep architecture are coincident with alterations in pro-inflammatory and helper T cell type 1/type 2 (Th1/Th2) cytokines, and that cytokine abnormalities predict disordered sleep in cocaine dependent patients. Thus, the over-arching objective of this study is to evaluate sleep and the reciprocal relationships between sleep and cytokine expression in cocaine dependent patients during acute and protracted abstinence as compared to controls. Acute administration of cocaine will serve as a pharmacologic probe of cytokine-sleep regulatory processes. The specific aims of this

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Drug Addiction

study are to: 1) evaluate whether cocaine and cocaine dependence are associated with disturbances of sleep including loss of delta sleep and increases of REM sleep; 2) determine the predictive validity of proteomic measures of nocturnal pro-inflammatory, Th1, and Th2 cytokines on sleep depth in cocaine dependent subjects during acute- and protracted abstinence and following acute cocaine administration; 3) examine the consequences of disordered sleep on the expression of pro-inflammatory, Th1, and Th2 cytokines and daytime sleepiness during acute- and protracted abstinence and following acute cocaine administration. Given the prominence of sleep disturbance in cocaine dependent subjects and evidence of sleep architecture abnormalities into recovery, understanding the bi-directional relationships between cytokines and sleep in cocaine dependence has implications for answering why sleep is disordered in cocaine dependent patients and for the development of novel treatments for sleep disturbance in cocaine dependence. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: COCAINE-INDUCED METAPLASTICITY IN THE HIPPOCAMPUS Principal Investigator & Institution: Wagner, John J.; Pharmaceutical Sciences; North Dakota State University Fargo, Nd 581055756 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2008 Summary: (provided by applicant): The primary long-range objective is to elucidate and characterize the actions of drugs of abuse as they influence and modify neuronal function. One of the crucial damaging aspects of drug addiction is the persistent wanting, or craving, that remains following rehabilitation that leads to relapse and a high failure rate in attempts to treat addiction. Because craving persists long after the cessation of withdrawal, and recovery from tolerance, it is often suggested that a druginduced neural plasticity has occurred within the circuitry of the brain that sustains the potential for future triggering of drug craving. The neural underpinnings of the "craving circuitry" of the brain are largely uncharacterized. The hippocampal formation is a region of the brain involved with memory formation and is crucial for the performance of several associative learning and memory tasks. The administration of addictive substances directly into the hippocampus has been shown to support selfadministration behavior, and the activation of this brain region can prime, or reinstate, drug seeking behavior in animal models of addiction. Investigating the role of the hippocampus in drug addiction is therefore a reasonable pursuit. Electrophysiological recording techniques will be used to monitor neuronal responses from the in vitro hippocampal slice preparation. The acute and persisting effects of cocaine applied either directly to the tissue slice or systemically via in vivo injections prior to slice preparation are to be investigated. The central hypothesis of this proposal is the following: The neural adaptations resulting from exposure to drugs of abuse are likely to include modifications of normal synaptic plasticity mechanisms that are typically utilized to store information within neuronal networks. Thus an understanding of both the normal processes and the drug-induced changes are required to elucidate the long-term consequences of drug exposure. In this application, the mechanisms underlying the plasticity of synaptic plasticity (i.e. metaplasticity) in the hippocampal formation will be investigated, and the subsequent effects of exposure to cocaine on such processes will be assessed. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: COGNITIVE NOREPINEPHRINE

FLEXIBILITY,

WITHDRAWAL,

21

AND

Principal Investigator & Institution: Beversdorf, David Q.; Neurology; Ohio State University 1800 Cannon Dr, Rm 1210 Columbus, Oh 43210 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-AUG-2004 Summary: (provided by applicant) Withdrawal from opiates and cocaine causes upregulation of the noradrenergic system. My research has demonstrated a central nervous system noradrenergic modulation of cognitive flexibility in anagram problem solving. As a result, impaired cognitive flexibility due to upregulation of the noradrenergic system during opiate and cocaine withdrawal may increase maladaptive behaviors seen in withdrawal by impairing cognitive flexibility. With this proposal, we wish to explore noradrenergic modulation of cognitive flexibility in cocaine withdrawal. The long-term goal of this line of research is to guide future research into treatment of drug withdrawal based on this cognitive neuropharmacological model. Our hypothesis is that cognitive flexibility in problem solving in conditions of noradrenergic activation during cocaine withdrawal can be modified pharmacologically. Our primary specific aim is to test noradrenergic modulation of cognitive flexibility in patients withdrawing from cocaine. Initially, we will undertake a dose-response study in nonaddicted normal subjects in order to determine the optimal dose of the noradrenergic antagonist propranolol needed to modulate cognitive flexibility. We will also compare noradrenergic modulation of performance on various cognitive flexibility dependent (including anagram problem solving) and cognitive flexibility independent tasks in nonaddicted normal subjects. We will then test noradrenergic modulation of cognitive flexibility in patients withdrawing from cocaine. In normal individuals, cognitive flexibility is better after noradrenergic antagonists than after noradrenergic agonists, but no difference existed between noradrenergic antagonists and placebo. However, cocaine withdrawal upregulates the noradrenergic system sufficiently that withdrawal patients may function similarly to normal individuals receiving noradrenergic agonists. Therefore, we predict that the noradrenergic upregulation during cocaine withdrawal is sufficient that administration of noradrenergic antagonists will result in a significantly better performance on cognitive flexibility than placebo, whereas this is not observed in normal subjects. We will also compare withdrawal patients and nonaddicted normal control subjects on performance on various cognitive flexibility dependent (including anagram problem solving) and cognitive flexibility independent tasks. Future possibilities include assessment the anatomical substrate of problem solving using event-related fMRI. With better understanding of modulation of cognitive flexibility, future studies can test cocaine and opiate addicts, deriving rational pharmacotherapy for optimal treatment of drug addiction. Long-term goals include further development this model of noradrenergic modulation of cognitive flexibility and looking for potential benefits in cognitively impaired and drug-addicted patients. OSU is well equipped for these goals, including potential fMRI using the most powerful human MRI in the world, strong neuroscience and psychology programs, and an established drug addiction clinic. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: COMBINATORIAL DEPENDENCE

PHARMACOTHERAPIES

FOR

COCAINE

Principal Investigator & Institution: Cashman, John R.; Senior Scientist; Human Biomolecular Research Institute 5310 Eastgate Mall San Diego, Ca 92121 Timing: Fiscal Year 2001; Project Start 30-SEP-1997; Project End 31-JUL-2003

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Drug Addiction

Summary: (Applicant's Abstract) Cocaine overuse in the United States has resulted in enormous social and economic loss. Clinicians have attempted to use pharmacological intervention to decrease cocaine craving by blocking the affects of the "sympathetic neural storm", but the ideal pharmacotherapy has not been developed and design and synthesis of new medications designed specifically for the purpose of treating cocaine abuse is urgently needed. Because the dopamine transporter (DAT) has been identified as the relevant macromolecule for initiating cocaine self-administration, development of novel approaches to design, synthesize and procure high affinity antagonists (or partial agonists) of the DAT that do not inhibit dopamine uptake and/or that stimulate dopamine uptake would constitute an important new pharmacotherapy in the medical treatment of cocaine abuse. Such a medication could be very helpful to a cocaine addict if administered by a doctor to a patient also undergoing psychological counseling. To obtain such a human therapeutic will require the screening of large numbers of potential DAT antagonists (or partial antagonist). The long term goal of our research is to develop selective, nontoxic high affinity antagonists (or partial antagonists) of the human dopamine transporter with long duration of action that blocks the reinforcing and stimulant properties of cocaine. The proposed studies are divided into four major sections: 1) Design and synthesis of directed organic chemical combinatorial libraries and synthesis of directed pseudopeptide combinatorial libraries, 2) Evaluation of the directed combinatorial libraries as antagonists (or partial agonists) of the cDNAexpressed human hDAT as well as in uptake inhibition experiments, 3) Further define the active compounds identified in section 1 and 2, and 4) Evaluation of the selectivity of the antagonists for the hDAT relative to the norepinephrine and serotonin transporter, and examine key pharmaceutical and pharmacokinetic properties of the "optimized" compounds. The specific aims of section 2 include the kinetic evaluation of the libraries by screening for hDAT binding and dopamine uptake. The specific aims of section 4 include the large scale synthesis of the optimized drug candidates, screening against other transporter and testing the pharmaceutical properties of the most active compounds. Animal behavioral assessment may predict in vivo efficacy. The study will provide an understanding of the structural and pharmaceutical properties of hDAT antagonists. The work will lead to new insight into the preparation of human medications necessary in the cessation of cocaine abuse. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: COMPONENTS UNDERLYING OPIOID RECEPTOR TOLERANCE Principal Investigator & Institution: Chavkin, Charles; Professor of Pharmacology; University of Washington Seattle, Wa 98195 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: (provided by applicant) Opioid addiction caused by prolonged exposure to strong opioid receptor agonists follows from a series of incompletely understood molecular and cellular changes in the brain. Following the cloning of the delta opioid receptor by groups headed by Evans and Kieffer, many mechanistic details responsible for mu, delta and kappa opioid receptor desensitization in transfected cell lines have been defined. These insights complement the large literature describing behavioral measures of opioid tolerance and dependence. This project would build upon the molecular understanding of the desensitization process to explore the relationship between mu receptor desensitization and behavioral tolerance. Opioid-dependent learning mechanisms and the underlying synaptic plasticity mechanisms are thought to form a distinct, second component of opioid tolerance. The role of synaptic plasticity in cellular tolerance to opioids will also be explored. Advances in mouse genetics have

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provided powerful new tools that have been useful in defining the molecular components underlying complex behaviors. In this project, we propose to use mice having specifically engineered genetic mutations to study the role of those genes in controlling the cellular and behavioral responses to opiate drugs. Sustained exposure to opiate drugs produces adaptive changes in the nervous system that result in tolerance, dependence, and in some cases addiction. Our hypothesis is that opiate-induced synaptic plasticity forms the cellular basis of drug addiction. Ultimately, a better understanding of the consequences of prolonged opioid exposure at the cellular and molecular levels is likely to help define the changes in brain physiology responsible for opioid addiction. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CONDITIONAL MUTAGENESIS IN ADDICTION CIRCUITRY Principal Investigator & Institution: Akbarian, Schahram; Assistant Professor; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2001; Project Start 05-SEP-2000; Project End 31-MAR-2002 Summary: As a trained psychiatrist and neuroscientist, the candidate has an ongoing commitment to increase knowledge about the molecular biology of complex behavior and to improve the treatment options for substance abuse disorders and related major psychiatric illness. The candidate intends to apply innovative methods of genetic recombination and large scale gene expression screening to animal models of substance abuse and psychosis. The long-term goal of these studies is to clarify the role of nerve growth factor molecules for drug-induced neuronal plasticity and addiction behavior at different stages of postnatal and adult life and to describe, on a large scale, neurotrophin- and drug-of-abuse mediated changes in genomic expression patterns. At the core of the candidate's project is the controlled manipulation of gene expression for two neurotrophic factors that are thought to be key regulators of synaptic plasticity in the reward structures: neurotrophin-3 (NT-3) and brain derived neurotrophic factor (BDNF). These growth factors and their receptors are expressed at high levels in some parts of the reward circuitry such as the nucleus accumbens (NAc) and the monoaminergic cell groups of the mid- and hindbrain. This proposal will induce controlled deletions of NT-3 and BDNF in the developing and in the adult brain, by using the P1 phage derived Cre/lox recombination system and a tetracyclineregulatable gene expression system. The resulting functional alterations in the brain's reward circuitry will be assessed on the molecular, the cellular and the behavioral level. Comparative studies will be conducted in mice with a controlled overexpression of NT3 in the reward circuitry. Is orderly function of the reward circuitry dependent on neurotrophic factors? Are neurotrophins involved in the molecular mechanisms mediating addiction behavior and drug-related reinforcement? What are the molecular and cellular adaptations in the brain's reward systems in response to the induced changes in neurotrophin gene expression? The answer to these questions will be of major importance for a further understanding of the molecular biology of substance abuse disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CONTINUITY OF CARE FOR DRUG-ADDICTED OFFENDERS IN RI Principal Investigator & Institution: Friedmann, Peter D.; Associate Professor; Rhode Island Hospital (Providence, Ri) Providence, Ri 02903 Timing: Fiscal Year 2002; Project Start 25-SEP-2002; Project End 31-AUG-2007

24

Drug Addiction

Summary: (provided by applicant): This cooperative agreement application proposes to develop a Rhode Island Research Center to participate in NIDA's National Criminal Justice Drug Abuse Treatment Services Research System (CJ-DATS). The mission behind the CJ-DATS is to improve the public safety, drug-related, public health, health and psychosocial outcomes of drug-involved offenders. Thus, this application aims to develop research infrastructure to support rigorous, multisite studies of integrated approaches to the treatment of individuals with drug abuse or addictive disorders, including models of treatment in jail or prison and as part of community re-entry; to support research on continuity of care models integrated with re-entry programs for drug-involved offenders returning to their communities, including services for health problems such as HIV, tuberculosis, or hepatitis infections and mental health problems; and to enrich the collaborations among the criminal justice, treatment, and academic communities in Rhode Island. Our Research Center will build on the strong, existing clinical and research partnerships among the Lifespan Hospitals/Brown University investigators, the Department of Corrections and 4 community addiction treatment programs already situated in the Rhode Island prison. These 4 programs deliver a comprehensive range of treatment modalities and ancillary services. The Rhode Island Research Center offers at least 4 specific advantages to the National CJ-DATS Cooperative: (1) Investigators and treatment partners with substantial research and clinical experience regarding the organization and integration of substance abuse treatment and health services, especially continuity of care models for community reentry of inmates afflicted with health problems such as HIV, tuberculosis, or hepatitis infections, and mental health disorders; (2) Strong, existing ties among the Rhode Island partners from prior collaborative research and clinical endeavors; (3) A small state with a unified correctional system, all divisions and facilities on a single campus and an administration highly supportive of research; and (4) An accessible population of addicted persons in which we have achieved high rates of enrollment and follow-up in prior investigations. The Rhode Island Research Center would lead rigorous multisite studies that draw on our expertise in the development, delivery and evaluation of linkages to community health services, with an initial focus on hepatitis C and methadone treatment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORTICOTROPIN RELEASING FACTOR MECHANISMS AND COCAINE Principal Investigator & Institution: Gallagher, Joel P.; Pharmacology and Toxicology; University of Texas Medical Br Galveston 301 University Blvd Galveston, Tx 77555 Timing: Fiscal Year 2001; Project Start 25-APR-1999; Project End 31-MAR-2004 Summary: (applicant's abstract): Accumulating evidence suggests that the corticotropin releasing factor (CRF) neurotransmitter system may play a prominent role in the mediation of motivational aspects of drug dependence and that CRF receptors participate in the arousal-enhancing properties of psychostimulants and in behavioral sensitization. The objective of the proposed research is to define the membrane mechanism of action of the CRF neuro- transmitter system in control and after chronic cocaine administration in two limbic areas, the septum and the amygdala. This project will test the hypothesis that the effects of CRF agonists and antagonists in control neurons are mediated through different receptors in the septum and amygdala and that the altered effects of CRF after chronic cocaine are due to modulation of specific CRF receptors. In these studies, CRF, urocortin - an endogenous CRF-like peptide, CRF (9-33) - a CRF binding protein inhibitor, and peptide and non-peptide CRF receptor

Studies

25

antagonists will be analyzed using whole patch and intracellular sharp electrode recording. Electrophysiological data will be compared in naive control, saline control, and chronic cocaine animals. The following specific aims will be addressed: 1. Define the effect of CRF, urocortin, the CRF binding protein inhibitor, and CRF receptor antagonists on synaptic transmission and on membrane conductance in septal and amygdala neurons, 2. Determine receptors mediating CRF actions by analyzing the effect of the specific CRF-R1 receptor and non-specific antagonists on the agonists' responses, 3. Analyze effects of CRF, urocortin, the CRF binding protein inhibitor, and CRF receptor antagonists, on synaptic transmission and membrane conductance in the septum and amygdala in saline control and chronic cocaine treated animals, and 4. Determine the time course of the development of CRF receptor-mediated changes and the persistence of these changes. The proposed studies will contribute valuable insight into the mechanisms of CRF actions in chronic cocaine addiction and its possible motivational role in drug dependence. These results may also provide critical information regarding non-peptide and peptide antagonists of CRF as potentially effective pharmacotherapies in the treatment of chronic cocaine dependence. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RESPONSE

CORTISOL

EFFECTS

ON

HUMAN

METHAMPHETAMINE

Principal Investigator & Institution: Harris, Debra S.; Langley Porter Psychiatric Institute; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 94122 Timing: Fiscal Year 2001; Project Start 01-MAY-1999; Project End 31-DEC-2002 Summary: This proposal is for a career development award to prepare the candidate as an independent investigator in the area of the biological determinants of addiction and individual susceptibility to drug abuse, particularly endocrinological factors involved in stimulant response. The K08 award will provide financial support for human laboratory studies of drug response in the presence of manipulation of cortisol levels. Preclinical studies have linked corticosteroids and animal modes of drug addiction. The proposed experiments will provide a better understanding of the contribution of cortisol to methamphetamine addiction in human drug users. The principal mentor will be Dr. Reese Jones in whose Drug Dependence Research Center (DDRC) at Langley Porter Psychiatric Institute (LPPI) studies of human drug response, including methamphetamine studies, have been conducted for several decades. Dr. John Mendelson at the DDRC will serve as a co-mentor. For developing expertise in the area of psychoendocrinology, Dr. Victor Reus and Dr. Owen Wolkowitz, also at LPPI, will serve as co-mentors. Their expertise in the psychiatric effects of corticosteroid modulating agents will provide guidance in this area. During this period the candidate will learn methodologies in pharmacokinetic and pharmacodynamic assessment, corticosteroid manipulation, and assessment of steroid and stimulant response. Subjects will be methamphetamine users experienced in the use of the drug, without a history of serious adverse effects, and familiar with effects of the drugs. Experienced users would likely represent sensitized users, making it possible to study the role of corticosteroids in the maintenance of addiction, relevant to the target population of dependent users. Subjective, physiological, and endocrine responses to augmenting cortisol level with hydrocortisone and to lowering cortisol level with the corticosteroid synthesis inhibitor metyrapone will be studied. If lowering cortisol levels reduces the reinforcing effects of methamphetamine, antiglucocorticoid treatment could prove to be an important component of stimulant abuse treatment.

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Drug Addiction

Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DEVELOPING MEDICATION FOR TOBACCO ADDICTION: NMDA AGENTS Principal Investigator & Institution: Bisaga, Adam A.; New York State Psychiatric Institute 1051 Riverside Dr New York, Ny 10032 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-MAY-2008 Summary: (provided by applicant): Tobacco addiction is an enormous public health problem. Recent advances in understanding the effects of nicotine on the brain and behavior present an opportunity to advance medication development. Neurotransmission at NMDA receptors is involved in many of nicotine's effects and it is postulated that modulation of NMDA neurotransmission may be effective in the treatment of tobacco addiction. We propose to develop and implement human laboratory models to screen promising medications and establish whether modulation of the NMDA receptor system with memantine, a non-competitive NMDA antagonist, has beneficial effects in the treatment of tobacco addiction. For comparison we will test bupropion, an antidepressant with proven efficacy in the treatment of tobacco addiction. Inpatient laboratory studies will include paradigms designed to model several dimensions of tobacco addiction using non-treatment seeking, nicotine-dependent smokers. We will assess the effect of chronic treatment with bupropion and memantine in two paradigms that model two main components of tobacco addiction that can be a target for pharmacological modulation. In Study 1 we will model maintenance of cigarette smoking, and assess how medications affect: early tobacco withdrawal, effects of cigarettes in smoking-deprived and non-deprived smokers, reactivity to cigarette cues, and cigarette smoking under unlimited choice conditions and under operational conditions (cigarettes versus money choice). In Study 2 we will develop a laboratory model of smoking relapse induced by cigarette exposure in abstinent smokers, and will compare self-administration behavior after the exposure to the neutral or active cigarette stimulus. In Study 3, we will use a smoking relapse model to assess how medication affects extended withdrawal, the effects of cigarettes in deprived smokers, and selfadministration behavior in abstinent participants following cigarette re-exposure. At the conclusion of 5 years, we will be able to develop laboratory models for early-stage testing of new and/or existing compounds for the treatment of tobacco addiction and to further elucidate the neurobiology of nicotine dependence in humans, particularly the contribution of NMDA receptor neurotransmission. This application represents, to our knowledge, the first attempt to systematically evaluate the contribution of NMDA receptor-mediated neurotransmission on nicotine's action in humans from the perspective of medication development. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DOPAMINE TRANSPORTER AGENTS AGAINST COCAINE DEPENDENCE Principal Investigator & Institution: Dutta, Aloke K.; Associate Professor of Medicinal Chemist; Pharmaceutical Sciences; Wayne State University 656 W. Kirby Detroit, Mi 48202 Timing: Fiscal Year 2001; Project Start 30-SEP-1999; Project End 31-AUG-2004 Summary: Cocaine is a strong reinforcer which led to its wide-spread use as a major drug of abuse in U.S.A in the last two decades. The development of a medication to treat this addiction is an urgent requirement. The central mechanism of the action of cocaine

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is attributed to its binding to the dopamine (DA) transporter system in the brain. Many structurally diverse compounds that bind selectively to the DAT, have been developed with an aim to block cocaine dependence in the central nervous system (CNS), but they met with only limited success. Recently, a high affinity DAT- specific compound GBR 12909 was found to have longer duration of action, was self-administered less potently than cocaine, and could antagonize some of the cocaine action. In our structure- activity relationship (SAR) study, we have shown the development of novel piperidine analogs of GBR 12909-related potent DAT- specific compounds. Our follow-up SAR study led to the development of a second generation of compounds in this class with far more selectivity for the DAT than conventional GBR molecules. In one of our recent studies, replacement of the benzhydrylic O-atom by an N-atom is these DAT-specific compounds, led to the development of potent and more polar, new-generation N-analog molecules. Furthermore, some of our analogs showed remarkable selectivity for binding to the cocaine binding site compared to the dopamine reuptake site in the cloned human transporters binding assay. The values of their uptake to binding ratio were far greater than values of any other existing compounds. In our initial in-vivo motor action studies in mice, two of these analogs were less stimulatnt than cocaine and GBR 12909 at similar doses. In combination studies with cocaine, these compounds attenuated the locomotor stimulatory effect of cocaine efficiently. We now propose to follow up on the SAR studies of our lead compounds to develop potent and selective compounds for the DAT with high dopamine uptake to binding ratio. Selected compounds will be tested for their effects on locomotor action and drug discrimination studies to observe their ability to block cocaine action. Our goal is to develop an effective medication against cocaine addiction. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ACCUMBENS

DOPAMINE/GLUTAMATE

INTERACTIONS

IN

NUCLEUS

Principal Investigator & Institution: Wolf, Marina; Associate Professor; Neuroscience; Finch Univ of Hlth Sci/Chicago Med Sch North Chicago, Il 60064 Timing: Fiscal Year 2001; Project Start 01-JAN-2000; Project End 31-DEC-2001 Summary: (from applicant's abstract) An important new hypothesis for understanding and treating drug addiction is that it may be an inappropriate form of learning. This hypothesis is based on studies demonstrating that glutamate, a transmitter critical for learning and memory, is required for the development of neuroadaptations believed to underlie addiction and relapse. We have shown that the repeated administration of psychostimulants (amphetamine or cocaine) causes profound alterations in glutamate systems. These include alterations in AMPA receptor expression and responsiveness in the nucleus accumbens (Nac), a brain region critical for the rewarding and addictive properties of psychostimulants. Medium spiny GABA-containing neurons, which represent 95% of all neurons in the Nac, receive convergent inputs from midbrain dopamine (DA) neurons and glutamate neurons originating in cortex and limbic regions. Our long-term goal is to understand how psychostimulants, which initially target the DA transporter, ultimately produce adaptations in glutamate transmission in the Nac. This is an important question, because glutamate systems are likely to mediate the neuronal plasticity underlying the transition from drug experimentation to drug dependency. Unfortunately, we know little about chronic interactions between DA and glutamate receptors in the Nac. A logical starting point is to determine how acute DA receptor stimulation can influence glutamate transmission. This application will use postnatal Nac cultures to test the hypothesis that DA receptors modulate the

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Drug Addiction

phosphorylation of the AMPA receptor subunit GluR1. We are focusing on AMPA receptors because they are the primary mediators of excitatory transmission in medium spiny neurons and on phosphorylation as a regulatory mechanism because GluR1 phosphorylation leads to marked enhancement of AMPA receptor-mediated currents. Phosphorylation of GluR1 will be detected using phosphorylation site-specific antibodies to GluR1 developed by Dr. Richard Huganir. One selectively recognizes GluR1 phosphorylated on ser-845 [protein kinase A (PKA) site]. The other recognizes GluR1 phosphorylated on ser-831 [protein kinase C (PKC)/Ca2+ -calmodulin dependent protein kinase type II (CaMKII) site]. The first Aim is to characterize conditions regulating basal phosphorylation of GluR1 and the kinases involved in its phosphorylation. First, control cultures will be compared with cultures incubated in the absence of Ca2+, the absence of synaptic activity (TTX, bicuculline, MK-801, CNQX), the absence of inhibitory activity (bicuculline), and the absence of excitatory activity (MK801, CNQX). Second, we will use activators and inhibitors of PKA, PKC and CaMKII to determine which kinases phosphorylate GluR1 in our cultures. The second Aim is to determine if DA receptor stimulation modulates GluR1 phosphorylation. Experiments will be designed to detect both stimulatory and inhibitory effects of D1 and D2 DA receptor activation. The identity of the residue phosphorylated, combined with experiments involving selective protein kinase inhibitors, will help identify the kinases involved in DA receptor-mediated effects. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DRUG ABUSE: EPIDEMIOLOGY, TREATMENT PROCESS, & OUTCOMES Principal Investigator & Institution: Hser, Yih-Ing; Adjunct Professor; None; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2001; Project Start 01-SEP-1989; Project End 31-JUL-2004 Summary: Building upon work accomplished in the current award, the applicant will continue her professional work by conducting six convergent research studies examining drug use epidemiology and evaluating treatment interventions for drug abuse and dependence. These projects are (1) Natural history of narcotics addiction: a 33-year follow-up study, (2) Treatment utilization and effectiveness study, (3) Tobacco use and cessation study, (4) Drug treatment process study, (5) Drug abuse treatment outcome study (DATOS), and (6) Persistent effects of treatment studies (PETS). Projects 1 to 4 were initiated in the current award period and provide data for more in- depth analyzes in the renewal period. Projects 5 and 6 are ongoing national studies that will provide further data for analysis. A special emphasis is on the examination of implications of research findings pertinent to the development of improvement treatment strategies and relevant social policies. The applicant will continue her professional development applying innovative statistical methodologies to drug abuse data in support of her substantive work. The applicant's supporting institution is an organized research unit, the Neuropsychiatric Institute (NPI), within the Department of Psychiatry, School of Medicine, UCLA. Affiliated with the NPI is the UCLA Drug Abuse Research Center, which has been conducting research in drug abuse epidemiology, the natural history of narcotics addiction, treatment evaluation, and social policy over the past 20 years. In this setting, the applicant will conduct the proposed research wand will receive additional training in clinical aspects of drug abuse treatment and in the implementation of treatment services. Furthermore, the applicant's considerable psychosocial research complementing the Institute's biobehavioral perspective. The

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applicant also expects to grow professionally as Associate Director of the UCLA Drug Abuse Research Center. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DRUG ADDICTION TRANSITIONS FROM ADOLESENCE TO ADULTHOOD Principal Investigator & Institution: Clark, Duncan B.; Associate Professor; Psychiatry; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-AUG-2006 Summary: (provided by the applicant) The transition from drug use to drug addiction typically occurs between adolescence and young adulthood, highlighting the importance of this developmental period to identifying factors influencing the onset and course of substance dependence. The project's primary goal is to determine predictors of the transition from adolescent substance use to dependence in a sample of adolescents (age 12-18) who were recruited through the Pittsburgh Adolescent Alcohol Research Center from addictions treatment (n=385) and community sources (n=163) who have been assessed with an extensive battery of baseline measures. The proposed award will support collection and analysis of adult (age 25 plus/minus 1) substance use and psychosocial outcomes, complementing on-going 1-, 3-, and 5-year follow-ups of the sample. The project will address three objectives described in the RFA. First, changes in drug use patterns in the transition to addiction will be characterized using growth mixture modeling. We hypothesize that trajectory classes differing in drug dependence severity and chronicity (e.g., developmentally-limited and persistent) represent identifiable developmental phenotypes. Second, the influence of co-occurring psychopathology, particularly conduct disorder, major depression, and posttraumatic stress disorder, on drug addiction transitions will be examined. We will examine common and reciprocal influence hypotheses to explain high rates of comorbidity between substance use disorders and psychopathology. Third, behavioral, psychosocial, and environmental factors will be examined as predictors of the transition from drug use to addiction by examining influences on the course of adolescent-onset substance use and related problems through adulthood. Use of a previously ascertained and well characterized sample of clinical and community adolescents represents a cost-effective approach to the identification of developmental phenotypes of adolescent-onset substance users that has with significant implications for prevention, genetics, and addictions treatment research. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DRUG ADDICTION: DUAL 5-HT INNERVATION OF LIMBIC SYSTEM Principal Investigator & Institution: Molliver, Mark E.; Neuroscience; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2001; Project Start 05-JUL-2001; Project End 31-MAY-2004 Summary: In addition to the role of dopamine (DA) release in reward, recent evidence suggests that 5-HT released in the nucleus accumbens (NAc) may contribute to the addictive effects of stimulant drugs. Little is known about the anatomic organization of 5-HT projections to the NAc and such data are needed to understand the function of this system. In order to elucidate the role of 5-HT neurons in addiction and in drug- induced release of neuro-transmitter, this project will analyze the origin of 5-HT projections to the NAc and to other limbic structures with attention to sets of 5-HT axons that differ in

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transporter expression. Many psychostimulant drugs act via monoaminergic transporters and are differentially toxic to subsets of 5-HT and DA axons in forebrain. To identify factors that mediate the pharmacologic and toxic effects of stimulant drugs, we will study the vulnerability of 5-HT and DA axons to p- chloroamphetamine (PCA) and to methamphetamine (Meth). We have identified two separate types of 5-HT axons in the NAc, one of which densely innervates the caudal NAc shell, lacks the transporter (SERT) and is highly drug-resistant. A similar dual 5-HT innervation in prefrontal (PFC) and in entorhinal cortex will also be analyzed. (1) This project will investigate (a) the neuronal origins of 5-HT axons that innervate NAc, PFC and entorhinal cortex; (b) the expression of SERT mRNA and protein in the cell bodies of origin; and (c) whether the same 5-HT neurons send drug-resistant axon collaterals to multiple limbic target areas. (2) The NAc shell and entorhinal cortex will be analyzed by EM to establish whether these regions receive a specialized projection of varicose 5-HT axons (lacking SERT) with novel synaptic properties. The selective 5-HT neurotoxin, PCA, will be used to separate the two 5-HT axon types for ultrastructural analysis. This study should contribute to understanding the mechanisms of drug-induced 5-HT release and the role of 5-HT in addiction. We propose that the duality of 5-HT projections plays an important role in addiction, reward and affective state control. Natural, physiologic release of 5-HT resulting from impulse conduction is independent of SERT and should occur in all 5-HT axons, whereas drug-induced release requires the transporter and is more restricted. Therefore, we postulate that physiologic excitation of raphe neurons is likely to produce a different regional pattern of 5-HT release than does drug-induced release, a difference that may underlie the addictive effects of drugs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DRUG DESIGN: GLUTAMATE RECEPTOR SIGNALING Principal Investigator & Institution: Mierke, Dale F.; Associate Professor; Mol Pharm, Physiology/Biotech; Brown University Providence, Ri 02912 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2004 Summary: (provided by applicant): Recent studies provide strong evidence that glutamate receptor signaling, via both AMPA/kainate and NMDA receptors, play a mechanistic role in drug seeking responses and that addiction is a form of glutamatedependent phisticity. AMPA/kainate and NMDA receptor antagonists have potential for clinical syndromes associated with addiction to alcohol and other drugs. Although numerous subtypes of AMPA, kainate, and NMDA receptors exist, it has proven difficult to develop subtype specific antagonists because of the high homology ot their ligand binding pockets. In contrast, glutamate receptor subtypes can couple to different intracellular signaling cascades via synaptic associated proteins (SAPs). SAPs (e.g., SAP9O and SAP97) are made up of five separate domains: three PDZ domains (PDZ1, PDZ2, PDZ3), a src-homology 3 domain (SH3), and a guanyl kinase-like domain (GK). Our studies show that the PDZ domains determine the selection of receptor subtype, while intra-molecular interactions between the different domains of SAPs regulate receptor function. Here we propose to develop peptides and peptidomimetics that will disrupt the molecular interactions of specific glutamate receptors with SAP90 and SAP97 and downstream signaling proteins. We aim to structurally characterize the inter-domain interactions of SAP90 and SAP97. To accomplish this, high-resolution NMR and computer simulations will be utilized to determine the structural features of PDZ1 and SH3 while complexed with the other domains of SAP90 and SAP97 as well as fragments from the NMDA, AMPA, and kainate receptors. The high-resolution structures will provide insight into the interactions between the receptors, SAPs, and

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regulatory proteins, which are responsible for the signaling, clustering and recycling of the receptors. Incorporating the experimentally determined structural features into detailed molecular models of SAP90 and SAP97 will allow for the rational design of molecular inhibitors of these interactions. Such molecules will allow for a greater understanding of the function of SAP90 and SAP97 as well as provide a novel route for the treatment of drug addiction. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EM-TRANSMITTER INTERACTIONS OF STRIATAL OPIOID NEURONS Principal Investigator & Institution: Pickel, Virginia M.; Professor; Neurology and Neuroscience; Weill Medical College of Cornell Univ New York, Ny 10021 Timing: Fiscal Year 2003; Project Start 01-MAR-1989; Project End 31-MAR-2008 Summary: (provided by applicant): Glutamatergic cortical inputs to the nucleus accumbens (NAc) and caudate-putamen (CPu) control motivated behaviors directly influenced by reward and by addictive drugs that can produce long-term changes in synaptic efficacy. Prefrontal and anterior cingulate cortical afferents target striatal spiny GABAergic neurons containing functionally opposed opioid (enkephalin and dynorphin) peptides. These neurons and/or afferent terminals also express all known subtypes of opioid receptors as well as cannabinoid 1 (CB1) receptors activated by endogenous cannabinoids and by Delta-9-tetrahydrocannabinol (THC), the primary psychoactive substance in marijuana. Thus, the identification of pre-(axonal) and/or post- (dendritic) synaptic neuronal, or possibly glial sites for opioid and cannabinoid receptor activation is crucial for understanding the mechanisms of drug addiction. Many of these sites were established for the morphine-binding mu-opioid receptor during the current funding period by using quantitative high-resolution electron microscopic immunocytochemistry. This method will be used for determining the location of the CB1 receptor within the striatal circuitry, specifically as related to functional interactions with either the mu-opioid or ionotropic (AMPA and NMDA) glutamate receptor subunits, whose plasma membrane distributions are highly regulated by synaptic activity and are potentially altered by chronic morphine administration. Specific Aims 1-3 will test the hypothesis that CB1 receptors in both the NAc and CPu are strategically positioned for involvement in (1) modulation of glutamatergic corticostriatal transmission, (2) regulation of dendritic plasma membrane expression of both mu-opioid and ionotropic glutamate receptor subunits, and (3) differential control of the output of enkephalin and dynorphin containing projection neurons. Aims 1-3 will be conducted mainly in male rats, but also will use wild type and CB1 (-/-) mice that are specifically deficient in opiate reward. Aim 4 will test the hypotheses that in the NAc shell and CPu of rat brain, (1) chronic, intermittent morphine produces changes in the synaptic availability of AMPA (GluR1 and GluR2) and/or NMDA (NR1 and NR2) glutamate receptor subunits, and (2) these changes depend, in part, on mu-opioid and CB1 receptor distributions. Together, the results will have far reaching implications for understanding drug cross-sensitization and devising new treatment strategies for opiate addiction. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: EVALUATION OF NOVEL COCAINE MEDICATIONS Principal Investigator & Institution: Madras, Bertha K.; Professor; Psychiatry; Harvard University (Medical School) Medical School Campus Boston, Ma 02115

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Timing: Fiscal Year 2002; Project Start 30-SEP-1997; Project End 31-MAY-2006 Summary: (provided by applicant): The overall goals of this project are to develop effective medications to treat cocaine addiction while concurrently investigating the biological basis for individual primate responses to candidate medications. The dopamine transporter, a principal target of cocaine, and transport inhibitors are the central focus of the research. With molecular, biochemical, behavioral and brain imaging techniques, we will assess the therapeutic potential of dopamine transport inhibitors. The research is based on exciting leads generated over the previous project period that evolved into four aims: 1. In pursuit of a cocaine antagonist, we developed a "tropane horse", designed to react covalently with the dopamine transporter (DAT), block cocaine access to the transporter but spare dopamine transport. We will investigate this class of compounds and cocaine replacements in vitro and in behavioral paradigms to identify promising, leads. 2. In support of this goal, we will conduct PET imaging procedures to identify effective cocaine replacements and antagonists. PET imaging of the DAT with [11C]altropane will identify compounds that fully occupy the dopamine transporter (cocaine replacements) and others that block cocaine access to the DAT but do not modify extracellular dopamine levels (cocaine antagonist). 3. Monkeys display strikingly different responses to dopamine transport inhibitors that are inversely correlated with baseline levels of activity. PET imaging of the dopamine transporter and gencityping of the dopamine transporter gene will clarify the association between transporter density, activity levels, and polymorphisms in the dopamine transporter gene. 4. As pre-synaptic neuroadaption elicited by cocaine may contribute to the addictive process, the effects of chronic administration of select candidate medications on transporter density and dopamine release will be monitored by PET imaging and in post-mortem tissue. This integrated research pro-ram will further the development of candidate medications to treat cocaine addiction and provide fundamental information on the neurobiological mechanisms underlying the behavioral effects of psychostimulants. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EXPECTANCY-BASED COPING SKILLS THERAPY Principal Investigator & Institution: Jaffe, Adam J.; Psychiatry; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2001; Project Start 15-SEP-1997; Project End 31-JUL-2004 Summary: Social Learning Theory (SLT) has been a useful model for understanding substance abuse. While based on learning principles such as coping skills and relapse prevention (RP) have been promising, they have had varied results in recent empirical treatment studies involving alcohol and cocaine abuse. We have developed a modification and extension of a RP approach using expectancies as the organizing structure and as a major focus of treatment for cocaine addiction. We believe that this approach, Expectancy-based Coping Skills therapy (ECS) is likely to substantially improve treatment efficacy for the following reasons: (l) Expectancies are a central construct that holds much promise for clinical research involving the assessment, etiology, and treatment of cocaine addiction; (2) Cocaine- related expectancies are readily measured using a validated, multifactorial, self-report instrument developed by the principal investigator of this study (Cocaine Expectancy Questionnaire, CEQ) and represent a domain that is amenable to change with talking therapy; and (3) An extensive pilot study conducted by the principal investigator and this research group strongly supports the feasibility, acceptability, and efficacy of manualized ECS therapy for the treatment of cocaine addiction. For these reasons we believe that expectancies

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have profound implications for treatment and that expectancy-based treatment warrants further evaluation and development. Because prior to our current pilot work, expectancies had received minimal cinical and empirical treatment emphasis, their implications for treatment need to be explored in a systematic fashion. Instruments such as the CEQ, combined with our manualized intervention of ECS, make it possible to assess and use expectations about cocaine in a clearly specified treatment that can be reliably delivered, monitored, and evaluated. This study proposes to conduct a randomized clinical trial with 168 ambulatory cocaine dependent participants to evaluate whether ECS therapy improves treatment efficacy substantially in comparison to two other manualized approaches: Rp and addiction counseling, a reference control condition. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FOS, JUN AND CONTROL OF SYNAPTIC PLASTICITY Principal Investigator & Institution: Ramaswami, Mani; Associate Professor; Molecular and Cellular Biology; University of Arizona P O Box 3308 Tucson, Az 857223308 Timing: Fiscal Year 2003; Project Start 15-APR-2003; Project End 31-JAN-2008 Summary: (provided by applicant): Drug addiction, long-term memory and other lasting behavioral changes derive from plasticity of underlying neural circuits, driven by activity-regulated gene expression. Recent behavioral analyses demonstrate critical roles for two transcription factors, CREB and AP1 (usually a dimer of Fos and Jun) in regulating cocaine addiction. Induction of FosB, a dominant-negative Fos isoform, in rodent nucleus accumbens causes long-term behavioral sensitization and craving for cocaine; in contrast, induction of CREB reduces drug-reward by inducing adaptation to higher levels of cocaine. Despite the obvious importance of AP1 and CREB for behavioral plasticity, little is known about the mechanism of their action. Our recent observations are consistent with the unexpected, important hypothesis that AP1 acts upstream of CREB at the top of the hierarchy of known plasticity-associated transcription factors. While testing this hypotheses, this proposal aims to: a) more completely elaborate cellular functions of AP1; and b) identify molecular mechanisms that operate upstream and downstream of AP1. In the short term, the work will provide a description of cellular biological consequences of AP1 manipulations, and outline the hierarchies and relationships among regulatory proteins, like AP1, CREB and MAP kinases that initiate plasticity processes. In the longer term, effector molecules that mediate the processes of synaptic change will be identified and their functions analyzed. Drosophila melanogaster is an excellent model organism for these analyses. The commonality of underlying mechanisms involved in plasticity regulation in mammals and insects is indicated by the functional conservation of almost all known regulators of plasticity in both phyla. However, the rate of progress of the proposed analyses in Drosophila is much faster, facilitated not only by its short generation time and facility for genetics, but also by novel resources from Drosophila genome projects, microarray technologies and newly developed procedures for gene disruption, perturbation and replacement in vivo. The proposed experiments address an area of fundamental importance in synaptic remodeling events that underlie behavioral change. The work is particularly significant because it addresses the function of Fos and Jun, two critical regulators of drug addiction. In addition, by identifying activity-regulated neuronal proteins the program may contribute new, molecular markers of plasticity processes that underlie addiction. Finally, results from these experiments may identify and validate new molecules to target for pharmacological therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: FROM DRUG USE TO ADDICTION: UNEARTHING THE SWITCHES Principal Investigator & Institution: Gutstein, Howard B.; Anesthesiology/Crit Care; University of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-MAY-2006 Summary: (provided by applicant): A critical issue for the neurobiology of drug addiction is what changes are responsible for the transition from non-dependent drug use to addiction. The goal of the present proposal from a new investigator is to begin to explore the neurobiological mechanisms responsible for drug escalation and define the molecular mechanisms responsible for mediating the change from drug use to addiction. To achieve this goal, we will test the following hypotheses: 1) Sufficient exposure to heroin and cocaine leads to changes in specific elements of the extended amygdala to produce elevations in hedonic set point that in turn leads to progressive elevation in drug intake. A subhypothesis is that the neurobiological basis of this transition to drug escalation reflects the development of drug addiction; 2) These neurobiological changes involve cellular effects at the translational and post translational levels that alter protein expression levels and function; 3) The transition to addiction does not occur as a result of one discrete neurochemical change; rather, a series of layered changes developing over the course of the drug escalation process; and 4) These changes represent the "switches" responsible for the transition from drug use to addiction, and are similar even for different classes of abused drugs. To test these hypotheses, we propose studies with the following Specific Aims: 1) To compare and contrast changes in protein expression and modification associated with excessive levels of heroin intake with those associated with escalated cocaine intake; 2) To define the time course of changes in protein expression and modification during the development of heroin and cocaine escalation; and 3) To define persistent changes in protein expression and modification associated with abstinence and with relapse upon reexposure to heroin or cocaine. Our proposed combination of cutting-edge behavioral, neuroanatomical, and proteomic approaches will permit the identification of important molecular substrates of the transition from casual drug use to addiction. It is hoped that these findings will eventually lead to improved treatments for these devastating conditions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENES AND PROTEINS LEADING TO ADDICTION Principal Investigator & Institution: Friedman, Theodore C.; Assistant Professor; Internal Medicine; Charles R. Drew University of Med & Sci 1621 E 120Th St Los Angeles, Ca 90059 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2007 Summary: (provided by applicant): Drug addiction is a complex state that results from compulsive drug intake, in which both neurotransmitter and hormonal systems are affected. The state is comprised of tolerance, sensitization, dependence and reward that lead to drug seeking and compulsive use. Many brain substances are altered with chronic drug use and are likely to be involved in the state of drug addiction. Therefore, the main goal of this proposal is to identify and characterize genes and gene products in specific brain regions in mice that are altered as the organism is exposed to acute and chronic opiates. We hypothesize that opiate use leads to altered neurohormonal levels mediated by changes in the processing enzymes that control the ratio of active hormone to prohormone. Two prohormone convertases, PC1 and PC2, are believed to be primarily responsible for the activation of many pro-neurohormones, e.g., PC1 generates

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ACTH and PC2 generates the endogenous opiate, b-endorphin, from the precursor, proopiomelanocortin (POMC). The regulation of PC1/PC2 is linked to the cAMP/cAMP response element binding protein (CREB)/cAMP response element (CRE) system. Agents such as opiates that alter CREB levels can be expected to change the activity of these prohormone processing enzymes and affect the biosynthesis of addictionmediating hormones with major biochemical and behavioral consequences to the organism. By affecting CREmediated gene transcription, opiates also likely modulate other genes and gene products that have not been investigated due to the lack of technology and information available. In this grant application, we propose to conduct a series of interconnecting experiments to test the hypothesis that acute and chronic morphine exposure regulates CRE-mediated gene expression in discrete brain regions. The specific aims are designed to test this hypothesis by: 1) determining the brain regions expressing CRE-responsive genes following morphine exposure; 2) monitoring the levels of the prohormone processing enzymes, PC1 and PC2, as well as bioactive peptide hormones in these regions; and 3) determining novel or uncharacterized genes/proteins regulated by various paradigms of morphine exposure in CREresponsive mouse brain regions. The focus of this proposal will be to use two new technologies, ProteinChip Array (SELDI-TOF Mass Spectrophotometry) and Gene Chip Array, to characterize and identify genes and proteins involved in opiate use. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC DISSECTION OF GLUTAMATE RECEPTOR FUNCTION Principal Investigator & Institution: Heinemann, Stephen F.; Professor; Salk Institute for Biological Studies 10010 N Torrey Pines Rd San Diego, Ca 92037 Timing: Fiscal Year 2001; Project Start 01-JUL-1990; Project End 31-MAY-2003 Summary: Most theories of nervous system function depend heavily on the properties of the synapse and for this reason the synapse has been a focus of neuroscience research for many decades. The synapse is also the focus of medical and pharmaceutical research because in general the drugs that have proven useful for the treatment of mental illness and neurological disease act on various aspects of synaptic function, i.e. transmitter uptake and metabolism, ion channels and receptors. It is also likely that synaptic changes underlie the long term or permanent changes that take place in memory formation and learning. Recently there are suggestions that similar long term changes in synaptic transmission take place as part of the mechanism of many neurological diseases such as epilepsy, drug addiction and long term intractable pain. Long term alterations in synaptic function may explain the symptoms of withdrawal experienced by addicts when drug administration is terminated. Inappropriate activation of glutamate receptors is thought to contribute to the nerve cell death which occurs after brain injury due to stroke, epilepsy, head trauma and perhaps other neurological diseases such as ALS, Parkinson's and Alzheimer's disease. Little is known about the function of the kainate glutamate receptor subtype which is a major focus of this grant application made possible by the recent cloning of the kainate receptor genes. The structure of the glutamate binding site will be studied. A search for glutamate receptor modulatory and accessory proteins will be undertaken using a new molecular genetic approach. The calcium permeability and function of the glutamate receptors are regulated by a novel mechanism of RNA editing which will be studied and altered in mutant mice. The role of kainate receptors will be studied making use of a battery of mutant mice that we have engineered to alter the kainate receptor system and synaptic transmission. Results from these studies will provide insight into the role that specific glutamate receptor subtypes play in the nervous system. This should make it possible

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by using recombinant DNA technology to develop new drugs and therapies to treat epilepsy, pain, stroke, mental illness, degenerative diseases and drug addiction. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GHB: EFFECTS, WITHDRAWAL AND TREATMENT Principal Investigator & Institution: Miotto, Karen A.; Associate Clinical Professor; None; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2007 Summary: (provided by applicant): Career Goals: The candidate is a psychiatrist whose goal is to expand her research and academic activities in the field of addiction medicine. Her immediate career goal is to obtain the training and experience necessary for becoming an independent investigator. Her professional goal is to become an academic resource in the field of addiction with a focus on evaluation of medications. Research Career Development Plan: The candidate proposes to obtain a Master of Science (M.S.) in Clinical Research Design and Statistical Analysis (CRDSA) from the University of Michigan School of Public Health. This program is designed specifically for physicians and other health care professionals involved in clinical research. In addition to this coursework, the applicant's career development plan draws on the resources of a large, well established addiction research group, the Integrated Substance Abuse Program (ISAP) at UCLA, and includes a program of supervision by experts in their respective fields in the qualitative and quantitative aspects of study design and methodology. Description of the research projects: The proposed research plan is designed to objectively describe signs and symptoms of GHB withdrawal, identify predictors of withdrawal severity and treatment response, and develop and validate treatment guidelines for GHB withdrawal. There has been a sharp rise in the number of GHB related emergency room visits in the United States over the past few years, yet little is known about effective treatment of GHB withdrawal and dependence. The signs and symptoms of GHB withdrawal begin one to six hours after last use, and may escalate rapidly and unpredictably to delirium, agitation, and psychosis. Given the rapid, progressive and serious nature of GHB withdrawal symptoms, there is a crucial need to develop improved treatments. There has been little systematic study of the signs and symptoms of withdrawal, and controlled studies on the effectiveness of treatment of these symptoms are lacking. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HIGH THROUGHOUT PHENOTYPIC SCREEN: DRUG EFFECTS ON HOMEN Principal Investigator & Institution: Liang, Yiqing; Clever Systems, Inc. 1334 Stokley Way Vienna, Va 22182 Timing: Fiscal Year 2003; Project Start 30-SEP-2001; Project End 31-JUL-2005 Summary: (provided by applicant): We propose to develop a completely functioning prototype system for rapid and automated high-throughput phenotypic screening: drug effects on home-cage behavior in mice or rats. The purposes of the project are to develop technologies and tools that can automatically measure different behaviors in mice to reliably predict drug-induced changes in home-cage and locomotor behaviors, or measure behavioral responsivity to drugs of abuse or potential therapeutic agents. The main advantage of the methods for this proposal is that it will enable investigators to perform very complex and sophisticated analysis of home cage an locomotor behaviors

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that are almost impossible with today's technologies, and to conduct large scale screening tests to examine the effects of a wide variety of different drugs of abuse in mutant mice or rats. This technology will improve the quality, and alleviate the burden, of observing mouse behavior and achieve more objective and constant analysis. Once all the specific aims are accomplished, the developed methods will be able to facilitate and enhance research in animal models of addiction that use behavioral, neurobiological, pharmacological, and genetic approaches, and may serve the foundation of the Nation's investment in understanding the causes, consequences, and treatment of drug addiction. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HIGH-FIELD FUNCTIONAL MRI OF HUMAN EUPHORIA Principal Investigator & Institution: Cowan, Ronald L.; Psychiatry; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-AUG-2004 Summary: (provided by applicant): Drug abuse and addiction pose major health problems to individuals worldwide. The brain biology of drug addiction is thought to involve a variety of brain structures that evolved to have a role in natural rewards, such as finding food or having sex. Drugs of abuse are used in part because they make an individual "high" or euphoric when they are taken. Much of the evidence learned thus far about drug addiction suggests that regions of the brain, including the ventral tegmental area which uses the neurotransmitter dopamine, and the nucleus accumbens have a major role in reward and the experience of euphoria. Additional evidence indicates that humans reliably develop a high voltage electroencephalographic (EEG) waveform in the alpha band during the experience of euphoria. We propose to use the functional magnetic resonance imaging (fMRI) blood oxygen level dependent (BOLD) method to study the regional changes in brain activity during the experience of euphoria in humans. Human volunteers will be screened for medical or psychiatric problems that prevent them from participating in the study. Subjects will then be given a dose of dextroamphetamine, and the ongoing activity in their brain will be studied with fMRI BOLD. Subjects will be asked to indicate when they feel euphoric, and we will use statistical analysis to determine which brain regions seem to produce the euphoria, and how they are interconnected to other brain regions. In the future, we plan to combine this method with other methods, including EEG, so that we might begin to develop a detailed understanding of the temporal and spatial changes in brain activity during the euphoric experience. Additionally, we plan to investigate how different drugs of abuse, and some medications that might interfere with the effects of drugs of abuse, affect the human reward system. Eventually, we believe that a better understanding of the brain structures that allow us to get high, and become addicted, will lead to improved awareness and treatment for substance abuse. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HOMELESS PERSONS' USE OF ADDICTION TREATMENT SERVICES Principal Investigator & Institution: Kertesz, Stefan G.; Medicine; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 03-DEC-2002; Project End 31-AUG-2007 Summary: (provided by applicant): Stefan G. Kertesz, M.D. is an academic physician in general internal medicine with five years of clinical experience caring for homeless

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persons addicted to drugs and alcohol, and drug abuse research training experience. As part of his K23 career development award, he will seek to identify factors associated with addiction treatment utilization and addiction outcomes among homeless persons who abuse drugs and/or alcohol (Aim 1). Given the heterogeneity of the homeless population, in particular the ways in which the duration of homelessness can vary from a few nights to many years, the proposed research also seeks to determine whether factors associated with addiction treatment utilization differ according to the persistence of homelessness (Aim 2). The research program will use two existing datasets to address these aims. In Part 1, data from the 1996 National Survey of Homeless Assistance Providers and Clients will permit evaluation of factors associated with treatment utilization in a nationally representative cross-sectional survey of homeless persons. In Part 2, data from a completed 2-year prospective follow-up study of 470 homeless and housed persons addicted to drugs and/or alcohol will permit evaluation of factors associated with sustained treatment utilization, and evaluation of the relationship between treatment utilization and addiction outcomes. The value of treatment itself has been documented in the context of clinical trials. The importance of this proposed research lies in its potential to assist policymakers and treatment planners who wish to understand how to improve actual treatment access and treatment utilization by homeless persons who are addicted to drugs and/or alcohol. Career development activities for this career development award include the research itself, mentoring by individuals with extensive research experience in addiction and homelessness, and coursework to develop methodological expertise pertinent to the use of large and complex datasets, content expertise in the areas of addiction, addiction treatment theory, housing policy and homeless sociology, and research ethics. Completion of the proposed work will prepare Dr. Kertesz to independently investigate the treatment of drug and alcohol abuse in the homeless. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMPORTANCE OF SLEEP & GENOTYPE IN DRUG ABUSE STUDIES Principal Investigator & Institution: Dugovic, Christine; None; Northwestern University Office of Sponsored Programs Chicago, Il 60611 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-AUG-2004 Summary: (provided by applicant): It has been well established that both genetic background and the environment can have pronounced effects on how mice respond to drugs of abuse, including both psychostimulants and the opiates. In particular, different strains of mice respond differentially to drug treatment, and acut7e sleep deprivation alters the response to a number of drugs of abuse. However, essentially nothing is known about how the genetic background affects the response to drugs of abuse in animals with disrupted sleep. Examining the effects of sleep disruption on the response to drugs of abuse in mice with different genetic backgrounds is particularly important since one of the hallmarks of substance abuse in humans is disrupted sleep. Poor sleep, whether due to genetic or environmental causes, may in itself predispose one to abuse and drug addiction. One of the overall objectives of the proposed studies is to determine if the effects of acute sleep deprivation on the response to drugs of abuse in mice is dependent on genetic background. Since very little is known about the effects of chronic sleep loss on the response to drugs of abuse, a second overall objective will address this question and determine if the genetic background influences the effects of chronic partial sleep deprivation on the response to drugs of abuse. Six different strains of mice will be used to test hypotheses. that genetic differences in either sensitivity or sensitization of the locomotor response to either cocaine or morphine are affected by

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either acute or chronic partial sleep deprivation. The completion of the proposed studies is expected to not only lead to a better understanding of how genetic differences predispose mice to be more or less responsive to cocaine and/or morphine under both baseline and sleep deprivation conditions, but also will provide new insights for optimizing the genetic animal models to be used for ultimately elucidating the genetic, neurochemical and biochemical mechanisms underlying the actions of drugs of abuse. The use of these genetic animal models is expected to lead to new genetic and pharmacological strategies for the treatment of drug abuse and addiction. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INCUBATION OF CRAVING: NEURAL SUBSTRATES Principal Investigator & Institution: Grimm, Jeffrey W.; Psychology; Western Washington University 516 High St Bellingham, Wa 98225 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2006 Summary: (provided by applicant): The limiting factor in the treatment of drug addiction is the high rate of relapse seen in addicts, despite costly treatment interventions. Craving for the drug long after the initiation of abstinence is argued to be a primary contributor to this recidivism. Relapse is often preceded by subjective reports of intense craving for the drug. Such craving can be induced in an individual by the presentation of stimuli previously associated with their drug taking experiences. Cueinduced craving is modeled in procedures using rats wherein rats will press a lever for the presentation of a stimulus complex (a tone + light) previously associated with their drug taking. We have recently demonstrated (Nature, 412:141-2, 2001.) that responding for a stimulus previously associated with cocaine self-injections increases progressively over the course of withdrawal from self-administration (13-fold increase by day 60 of withdrawal). We have labeled the phenomenon an "incubation of craving". We have also recently observed the incubation of craving effect in rats responding for a stimulus previously associated with orally self-administered sucrose. The experiments outlined in this proposal will explore the neuroanatomical substrates of the incubation of craving effect in both cocaine- and sucrose-experienced animals. The basolateral amygdala and the nucleus accumbens will be examined in this regard using a procedure of reversible inactivation of each structure prior to testing at the different withdrawal time points. All experiments in this proposal are designed to allow full participation of undergraduate and master's level students in an area of research usually reserved for Ph.D. students and post-doctoral researchers. These experiments provide an initial examination of the incubation of craving effect and will influence the direction of a future RO1 proposal from my laboratory. Information gained from this project will provide direction for behavioral therapy and medications-based therapy for craving and relapse. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: INDIVIDUAL DIFFERENCES IN CHOICE STUDY PREDICT DRUG USE Principal Investigator & Institution: Heyman, Gene M.; Associate Professor; Mc Lean Hospital (Belmont, Ma) Belmont, Ma 02478 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2005 Summary: (provided by applicant): The long-term goal of this application is to explain individual differences in susceptibility to addictive drugs. The hypothesis that guides the research is that individual differences in decision making contribute to individual differences in drug use. The specific aims of the research are to answer the following

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questions: Do individual differences in decision making predict smoking cessation? Do differences in decision making help explain the high correlations between substance dependence and other psychiatric disorders? And to what extent are differences in decision making correlated with differences in impulsivity and cognition? The studies use a computer-based procedure in which choices earn money. The salient features of the task are that current choices alter the consequences of future choices, and that one option is best from the perspective of the current trial (the "local" solution), whereas the other option is best from the perspective of two or more trials (the "global" solution). According to some theories, these conditions are similar to the situation facing a drug user. From a local perspective, drug use may be the best choice, but from a global perspective, alternatives to drug use are usually the better choice. The first set of studies tested drug clinic patients. Choice behavior was correlated with drug use history. Preference for the local solution in the experimental procedure predicted long-term illicit drug use and the persistence of smoking. Drug clinic and control groups differed in terms of education and IQ, but these two measures were not as strongly correlated with the pattern of choices as was drug history. The proposed studies will test the generality of the initial results and test hypotheses concerning the psychological factors that influence decision-making. The findings will help clinicians target behaviors that are instrumental in the persistence of drug use. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INNOVATIVE PHARMACOTHERAPY

APPROACHES

FOR

COCAINE

Principal Investigator & Institution: Pettinati, Helen M.; Director; Psychiatry; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2001; Project Start 30-SEP-1999; Project End 31-AUG-2004 Summary: This application is for a Medication Development Unit (MDU) which will complement our existing program of research in finding effective treatments for drug addiction. The tight integration of this MDU within the general umbrella of the Penn/VA Center for Studies of Addiction, allows us to propose a substantial amount of research (two large scale clinical trials, a laboratory study, and pilot projects) with minimal new resources. Specifically, the theme of this center focuses on the use of innovative strategies to find effective pharrnacotherapies to treat cocaine dependence. The core facilities Include a data management unit, significant computer support including a wide area network to facilitate Center communication, human labs, and a urine testing lab. This Center proposal includes a core and three projects plus a series of pilot studies on GABAergic agents. The core will have general administrative functions and help with the overall scientific direction, data management, common clinical services, subject recruitment, pharmacy services, laboratory functions, and coordination of the individual projects. In addition, the core will conduct pilot studies of promising pharmacological agents for cocaine dependence related to enhancing GABAergic activity, creating new directions for clinical trials. Project l investigates the use of amantadine and propranolol, alone or in combination, in subjects in the early stages of their recovery who have recently had a positive urine for cocaine and a high score on the Cocaine Selective Severity Assessment. Our preliminary data suggest that pharmacotherapy is particularly helpful for this subgroup of patients. Project 2 will test the use of naltrexone and disulfiram, alone and in combination, in the treatment of cocaine dependence complicated by alcohol dependence. This study attempts to replicate and extend recent findings that disulfiram reduces both cocaine and alcohol use in cocaine- alcohol dependent patients. In addition, it extends our earlier pilot study

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of naltrexone on alcohol abusing cocaine dependent subjects. The combination of these two compounds may be particularly helpful in enhancing treatment retention and reducing cocaine and alcohol use. Project 3 evaluates the effects of various medications on cue reactivity and the predictive validity of cue reactivity on clinical outcome. By taking subjects randomized from Project 1, 2 and the core pilot projects, subjects will be administered cue screening prior to receiving study medications, and again about 4 weeks into the clinical trial while on study medications. In addition to testing specific medications, the Center will utilize an integrated series of projects to improve our understanding of cocaine treatment as it relates to stabilization and detoxification as treatment goals versus reducing the number and intensity of cocaine relapses. In addition we will investigate the use of cue reactivity as it predicts treatment outcome and as a possible screening tool for new medications. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INTRACELLULAR MECHANISMS OF DRUG REWARD AND ADDICTION Principal Investigator & Institution: Self, David W.; Assistant Professor; Psychiatry; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2001; Project Start 01-SEP-1996; Project End 31-JUL-2002 Summary: (Applicant's Abstract) All of the reward-related dopamine and opiate receptors are coupled to the cAMP second messenger system, which is up-regulated in the nucleus accumbens (NAc) following chronic drug exposure. Recently, studies from our laboratory have suggested that the NAc-cAMP system modulates drug reinforcement mechanisms. These studies directly tested the role of inhibitory G proteins and cAMP-dependent protein kinase (PKA) in drug reinforcement by infusing agents that modulate these intracellular proteins into the NAc of rats self-administering cocaine or heroin. In addition, our studies also have suggested that PKA in the NAc is involved in drug craving, and relapse of drug-seeking behavior, since NAc infusions of PKA modulators reinstate drug-seeking behavior following extinction from drug selfadministration. The present studies will further characterize the intracellular mechanisms of drug reinforcement and addiction. Firstly, the role of excitatory G (Gs) proteins, specific subunits of PKA, and cAMP Response Element Binding (CREB) proteins (a major substrate of PKA), in drug reinforcement and addiction will be studied by infusing agents that modulate these proteins into the NAc of rats during drug selfadministration tests. Parallel biochemical experiments will study (and verify) the modulation of intracellular proteins by the NAc infusions. Similarly, intra-accumbens infusions will be used to study the role of PKA in both the positive and the negative motivational aspects of drug addiction and withdrawal by using the conditioned place preference paradigm. Another major focus of this application will study the pharmacological, anatomical, and intracellular substrates of drug craving and relapse by using a drug reinstatement paradigm. With the reinstatement paradigm, we recently found that Dl dopamine receptor agonists will suppress, while D2 receptor agonists will induce, drug-seeking behavior in rats. Thus, Dl and D2 agonists will be used as probes to identify the anatomical loci that mediate these opposing effects on relapse of drugseeking behavior. The intracellular substrates of drug craving will be studied by infusing PKA modulators into the specific brain sites that mediate the Dl and D2 receptor effects on reinstatement of drug-seeking behavior. Finally, the neural mechanisms through which conditioned cues trigger drug craving will be studied in a cue reinstatement paradigm. The studies in this grant will continue to provide a

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Drug Addiction

mechanistic link between the molecular, cellular, and behavioral aspects of drug abuse, and will seek to identify potential targets for pharmacotherapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IV COCAINE ABUSE TREATMENT: A LABORATORY MODEL Principal Investigator & Institution: Foltin, Richard W.; Professor of Neuroscience; Anatomy and Cell Biology; Columbia University Health Sciences New York, Ny 10032 Timing: Fiscal Year 2002; Project Start 01-JAN-1990; Project End 31-MAY-2007 Summary: (provided by applicant): This protocol continues implementation of a laboratory model to evaluate medications potentially useful in the treatment of cocaine abuse, investigating problems relevant to understanding and reducing uncontrolled cocaine use. Psychiatric comorbidities are pervasive in the cocaine-dependent population, and are significant in the population seen in community treatment centers. However, these comorbidities are rarely addressed in either clinical trials or laboratory settings. While it has been hypothesized that treatment for cocaine dependence could be improved by targeting cocaine users with specific psychiatric comorbidities, this has not been systematically evaluated. We will examine the relationship between psychiatric comorbidity and potential medications for cocaine dependence using two approaches. First, we will compare the subjective and reinforcing effects of cocaine under controlled laboratory conditions, in groups of abstinent cocaine abusers with Major Depressive Disorders (MDD), Attention Deficit/Hyperactivity Disorder (ADHD) or no psychiatric comorbidity. If cocaine use in individuals with comorbid disorders is related to their comorbid. disorder, then the behavioral effects of cocaine should vary across the groups being studied. Second, we will compare responses to cocaine under three separate conditions: maintenance on 1) gabapentin, 2) venlafaxine, and 3) the combination of the two medications. The laboratory, setting of the current proposal offers a unique opportunity to test the hypothesis that individuals with comorbid MDD or ADHD respond differently to cocaine than those without a comorbid psychiatric disorder, and that treating the MDD or ADHD alone will not sufficiently reduce the response to cocaine. Treating the comorbid disorder or decreasing the behavioral effects of cocaine will be necessary but not sufficient pharmacotherapy for individuals with comorbid disorders. A combination of the gabapentin for cocaine and venlafaxine for depressive symptoms will have a synergistic effect in these individuals. The laboratory is an ideal setting in which to carry out this research, allowing us to carefully monitor participants and collect maximal data with the fewest number of participants. The proposed research offers a unique opportunity to evaluate medications in cocaine-dependent individuals with MDD, ADHD or no comorbid disorder, and will provide important information about differential responses of these groups to cocaine and to gabapentin and venlafaxine, alone and in combination. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MECHANISM OF SENSITIZATION TO COCAINE Principal Investigator & Institution: Angulo, Jesus A.; Hunter College 695 Park Ave New York, Ny 10021 Timing: Fiscal Year 2001; Project Start 01-APR-2001; Project End 31-MAR-2002 Summary: Although a large body of elegant work has developed on cellular and molecular aspects of drug abuse with the neurotransmitter dopamine at its core, the neuropeptides represent an area that has not been studied in relation to drug addiction. Neuropeptides can exert direct and/or indirect effects on the output of the

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dopaminergic network of the mammalian brain. The present project will focus on the role played by the neuropeptide substance P (and neurokinin A) on the development and/or expression of sensitized locomotor and neurochemical responses to cocaine. We hypothesize that these tachykinin peptides serve homeostatic functions within the basal ganglia to prevent excessive locomotor output in rodents sensitized to cocaine. The first and second specific aims will assess the effect of highly selective non-peptide neurokinin receptor antagonists on the development of progressive and enduring locomotor sensitization to cocaine. The third specific aim will examine the effect of these highly selective antagonists on the sensitized pattern of dopamine and glutamate release in dopaminergic terminal field areas of the caudate-putamen and the nucleus accumbens as well as in dopaminergic cell body areas of the midbrain substantia nigra compacta and the ventral tegmental area. The neurokinin receptor antagonists will be infused intracerebrally through the microdialysis probe. The fourth specific aim provides tissue peptide levels for substrate P and neurokinin A from rats sensitized to cocaine under progressive and enduring treatments. The data from this aim complements neuropeptide and receptor mRNA levels obtained from animals in aims I and II. These studies will provide strong behavioral and neurochemical evidence supporting a role for tachykinin peptides in sensitized responses to cocaine. An understanding of the neurobiology of sensitization to cocaine is relevant to the management of addiction in humans because sensitization is implicated as a mechanism sustaining drug-seeking behavior in humans addicted to cocaine and other drugs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MEDICATION DEPENDENCE

DEVELOPMENT

FOR

METHAMPHETAMINE

Principal Investigator & Institution: Johnson, Bankole A.; Wurzbach Distinguished Professor and Dep; Psychiatry; University of Texas Hlth Sci Ctr San Ant 7703 Floyd Curl Dr San Antonio, Tx 78229 Timing: Fiscal Year 2001; Project Start 30-SEP-2000; Project End 31-MAY-2004 Summary: (Applicant's Abstract) Our promising research in healthy human volunteers has provided preliminary evidence that isradipine, a dihydropyridine-class calcium channel antagonist (DCCCA), significantly reduces the rewarding (including euphoric) effects of methamphetamine mediating its abuse potential. This proposal aims to determine if these anti-rewarding effects of isradipine will generalize to methamphetamine dependent individuals during drug-taking, thereby laying the foundation for the programmatic development of DCCCA in future clinical trials as treatment agents for methamphetamine dependence. Using state-of-the-art measures of human liability assessment, we plan to conduct two placebo-controlled, double-blind studies using a counter-balanced (for sequence and ordinal position) cross-over design in which we will examine the behavioral and physiological effects of dmethamphetamine both alone and in combination with isradipine. Subjects will be forty-two non treatment-seeking methamphetamine dependent men and women. Experiment #1, a proof-of-concept analysis, will test the hypothesis that acute isradipine pretreatment reduces methamphetamine-induced changes in subjective mood and other measures of human abuse liability. Secondarily, we will determine, if and by how much, d-methamphetamine-induced changes in cognitive, psychomotor, and physiological function, are altered by isradipine in non-fatigued subjects during drug-taking. Experiment #2 addresses issues of potential clinical effectiveness and utility by testing the hypothesis that repeated isradipine administration will: a) antagonize dmethamphetamine's rewarding effects, and b) prove to be clinically tolerable by

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Drug Addiction

decreasing d-methamphetamine's pressor effects while producing no cognitive or psychomotor deterioration. Establishing isradipine's effectiveness and tolerability in the human laboratory lays a solid foundation for its use in future clinical trials for the treatment of methamphetamine dependence. This study supports NIDA's mission to develop effective medications for the treatment of methamphetamine dependence, and to understand the pharmaco-behavioral processes associated with psychostimulant use. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MIDARP AT HUNTER COLLEGE Principal Investigator & Institution: Barr, Gordon A.; Professor of Psychology; Psychology; Hunter College 695 Park Ave New York, Ny 10021 Timing: Fiscal Year 2001; Project Start 30-SEP-1999; Project End 31-AUG-2004 Summary: Hunter College of the City University of New York has a traditionally high (greater than 50 percent) minority population. It is our goal to develop a program at Hunter that draws on existing strengths to broaden and encourage drug abuse research at Hunter. This program for studies on drug abuse will encompass research on the molecular, cellular, and behavioral level in response to different drugs of abuse. It will include active research faculty, graduate and undergraduate research students, and technical support personnel in the Psychology and Biology Departments, who share an interest in understanding addiction as a brain disease or who want to move their research efforts in that direction. The aims of proposal are to enhance the research infrastructure of Hunter to facilitate our efforts in drug abuse research, develop individual projects within our departments within this area of research, and to stimulate the interest of other faculty and our students, both at the undergraduate and graduate levels, in research on drug abuse. An integral goal of this center is to facilitate the career development of minority undergraduate and graduate students who will become the independent scientists of the future. The specific projects proposed include: 1) Mechanism of sensitization to methamphetamine; 2) Neurobiology of drug addiction and impulsive behavior; 3) Interactions between stress and psychostimulant drugs in behavioral sensitivity and memory; and 4) Effects of the estrous cycle and gender differences in cocaine-induced alterations in the CNS. The PI, who is not submitting a research project is an established drug abuse research and will serve as advisor on these projects and mentor to the junior scientists. Three of the five of us are Hispanic scientists and the two non- minority scientists have a long history of training minority scholars and are part of the administration of the COR, MARC and MBRS grants. Three of the five work in areas consistent with the NIDA mission and the other two are moving in that direction. Finally, two of us are senior scientists with over 25 years of research experience each and will serve as mentors to the more junior faculty of this group, especially the two faculty who have joined Hunter this year. The mechanisms for this mentoring are built into the collaborations that we have and the program itself. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MOLECULAR BASES OF ADDICTIVE MEMORIES Principal Investigator & Institution: Alberini, Cristina; Physiology and Biophysics; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-JUL-2005 Summary: (provided by applicant): Drugs of abuse, such as morphine, cause longlasting changes that underlie behaviors associated with drug addiction. It has been proposed that these changes are similar to those underlying memory formation. In

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agreement, many compounds that impair memory formation and inhibit memoryassociated molecular pathway also attenuate drug tolerance and dependence. Newly formed memories are initially labile and require protein synthesis in order to be consolidated into a long-term memory. Furthermore, when a consolidated memory is recalled, it again becomes labile and requires protein synthesis in order to be maintained. The requirement for protein synthesis of addictive memories is virtually unknown. Here we propose to address several fundamental questions that will target the protein synthesis-dependent processes of addictive memory and other addictive behaviors. The results of these experiments will lay a foundation for further studies, which will examine molecules, pathways and pharmacological intervention in addiction. These investigations may produce significant breakthroughs that could help in the development of new therapies for drug addiction. The Aims of this project are: 1) To determine the temporal and anatomical specificity of protein synthesis requirement in addictive contextual associations. 2) To determine the behavioral specificity of the requirement for protein synthesis in addiction. 3) To determine whether the requirement for protein synthesis is a general mechanism underlying addictive memories. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR DETERMINANTS OF COMPULSIVE COCAINETAKING Principal Investigator & Institution: Xu, Ming; Assistant Professor; Cell Biol, Neurobiol/Anatomy; University of Cincinnati 2624 Clifton Ave Cincinnati, Oh 45221 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-JUL-2006 Summary: (provided by the applicant) Drug addiction is a chronic relapsing disease with psychological and social factors. Compulsive drug-taking is the central feature of drug addiction. Understanding the molecular mechanisms underlying the transition between controlled drug use and the loss of control over drug-taking is crucial for developing methods for the prevention and treatment of drug addiction. The neurobiological mechanisms underlying the development of uncontrolled drug-taking behaviors are associated primarily with the brain mesocorticolimbic dopamine (DA) pathway. Moreover, changes in gene expression are thought to mediate, in part, the neuroadaptive responses to the development of cocaine-taking behaviors. However, the molecular determinants and their temporal and spatial involvement in the transition from initial drug use to compulsive drug-taking behaviors remain unidentified. Based on work from our own laboratory and from others, we hypothesize that DA D1 and D3 receptors and c-Fos play important roles in the transition between controlled cocaine use and escalated cocaine intake. We propose to generate novel mouse models in which the expression of D1, D3 receptor or c-fos genes can be temporally controlled in D1 receptor-expressing neurons respectively. We propose then to test the above hypothesis by turning off the expression of D1, D3 receptor or c-fos genes in these mice during the escalation or abstinence phases and then measuring cocaine intake in an escalating cocaine self-administration paradigm. Finally, we propose to identify c-Fos-regulated target genes that are involved in the transition between controlled cocaine use to escalated cocaine intake. Successful completion of the proposed work will provide valuable information for the temporal and spatial requirement of DA D1 and D3 receptors and c-Fos in the development of compulsive drug-taking behaviors. Identification of c-Fos-regulated molecular changes involved in the transition to escalated cocaine intake will pave the way for testing the physiological significance of these changes in cocaine-taking behaviors in the future. The combined use of genetically engineered mouse models with proper behavioral and molecular biological analyses has

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Drug Addiction

tremendous potential to provide novel insights into mechanisms underlying the development of drug addiction and new strategies for the treatment of drug abuse. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOUSE BEHAVIOR MODELS OF COCAINE ADDICTION Principal Investigator & Institution: White, Francis; Professor and Chairman; Cellular & Molecular Pharm; Finch Univ of Hlth Sci/Chicago Med Sch North Chicago, Il 60064 Timing: Fiscal Year 2001; Project Start 01-APR-2001; Project End 31-MAR-2004 Summary: (provided by applicant): The introduction of gene targeting to the study of brain function has rapidly advanced our knowledge of how various neurotransmitters, receptors and effectors are involved in basic aspects of brain function. However, there are few sophisticated behavioral models that can be used to establish the roles of various gene products in the addiction process. We propose to develop three distinct behavior models to apply to the study of drug addiction and to extend such models specifically for use in genetically altered mice. We also propose to begin an extensive series of studies to determine the feasibility of forward genetic approaches to identify genes involved in cocaine addiction. The first model utilizes a novel signaled switching task from a schedule that reinforces high-rate responding to a schedule that reinforces lowrate responding. An FR-8 evaluates behavioral activation whereas the DRL-90 evaluates working memory, response inhibition and impulsivity. The second model is one that assesses aspects of behavior indicative of withdrawal from repeated cocaine exposure. We have found that "binge-type" administration of cocaine for several consecutive days leads not only to locomotor sensitization upon cocaine challenge, but also to profound nocturnal hypoactivity during the first several days of cocaine abstinence. The third model will utilize cocaine self-administration coupled to a variant of the extinction/reinstatement model of drug seeking behavior. In addition to the successful use of transgenic approaches to identify how genes are related to particular functions, the use of forward genetics (proceeding from phenotype to gene) has also been tremendously useful. To use this approach one must have a rapid high throughput screen for mutations of interest. We propose to test the possibility of using two rapid high throughput screens as possible determinants of mutations altering sensitivity to cocaine. The development of these models should allow phenotypic characterization of behaviors related to drug taking and drug seeking and provide novel tests for various transgenic mice. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MOUSE GENETICS CORE Principal Investigator & Institution: Burton, Kimberly A.; University of Washington Seattle, Wa 98195 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: (provided by applicant) OBJECTIVES: The Mouse Genetics Core (MGC) will produce knockout, mutant, and transgenic mice for each of the investigators as described in their project proposals. The advantages of combining forces in a Core for this activity are obvious since the technical expertise required to manipulate DNA constructs, select for homologous recombination in ES cells, and produce chimeric mice is considerable. In addition, the cost of running a mouse colony for blastocyst injection are high and the maintenance of specific Cre recombinase expressing lines in a central Core greatly reduces the cost to individual investigators and provides ready access to a valuable resource. The Core will assist all investigators by providing advice and direct

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technical help with DNA construction, ES cell culture, electroporation, selection, and screening. The MGC will take on the responsibility of training individuals from the participating labs in all aspects of mouse genetics and this training will occur in the MGC laboratory. This hands on guidance will assure success and encourage investigators to utilize these powerful new approaches to study drug addiction. Although it might be somewhat more efficient to simply make the mutant mice in the MGC without the participation of project investigators this was deemed unlikely to enhance the training environment that we are trying to maintain as an academic entity. We expect the graduate student and postdoctoral fellows trained in our Center to be future leaders in the use of mouse genetic approaches to study drug addiction. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MU OPIOID RECEPTOR GENE IN HEROIN ADDICTS Principal Investigator & Institution: Yu, Lei; Professor; Cell Biol, Neurobiol/Anatomy; University of Cincinnati 2624 Clifton Ave Cincinnati, Oh 45221 Timing: Fiscal Year 2001; Project Start 30-SEP-1994; Project End 31-JUL-2004 Summary: Addiction to heroin is a major social problem, affecting over a million people in the United States. In the body and brain, heroin is hydrolyzed to morphine, which acts at the mu opioid receptor and results in a euphoric effect, thus conferring the reinforcing properties of the drug and contributing to addiction. Drug addiction is a complex process, thought to result from the interaction of social, environmental, and biological factors including a genetic component. In our original proposal, we hypothesized that genetic polymorphisms might exist in the mu opioid receptor and alter receptor function, contributing to variation in individual susceptibility to heroin abuse. During the current funding period we have observed five different single nucleiotide polymorphisms (SNPs); two of these SNPs were relatively common (10.5 percent and 6.6 percent allelic frequency), and both showed differential distributions among ethnic groups. One appeared to exert a protective effect against opioid addiction in one of the ethnic groups; it also altered beta-endorphin binding affinity and agonist potency. The other common variant occurred with a significantly higher frequency in former heroin addicts, suggesting a genetic predisposition for opioid dependence. In this competing renewal application, we propose to extend our study of the clinical and functional significance of genetic variation in the human mu opioid receptor. We will examine a larger number of study subjects, and determine the allele distribution in former heroin addicts and controls among different ethnic groups. We will also examine their impact on receptor modulation of neuronal Ca2+ channels and inhibition of adenylyl cyclase activity. Furthermore, we will determine the effects of the mu receptor polymorphisms on the cellular responses to chronic morphine treatment, since the primary problems that develop during heroin addiction come from prolonged exposure to the opioid drug. Results from the proposed study in this renewal application will provide valuable information in two areas: First of all, by studying the effects of sequence variants on the cellular function of the mu receptor, we will understand how genetic polymorphisms impact on receptor activity and neuronal excitability. Furthermore, by determining distribution of these genetic variations between opioiddependent individuals and normal controls, we will start to appreciate the role of genetic polymorphism is predisposition for or protection against opioid dependence. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MUCOADHESIVE BUPRENORPHINE FOR OPIOID ADDICTION THERAPY Principal Investigator & Institution: Das, Sudip K.; Pharmaceutical Science; Idaho State University Pocatello, Id 83201 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2004 Summary: (provided by applicant): The long-term objective of this proposal is to develop a mucoadhesive formulation of buprenorphine suitable for sublingual delivery for the treatment of opioid type drug addiction Major drawbacks of currently available dosage forms are related to poor compliance and suboptimal bioavailability of the drug. Buprenorphine undergoes extensive first pass metabolism, therefore salivary washout and involuntary wallowing of the conventional immediate release sublingual tablet would lead to drug loss and inconsistent bioavailability. The use of a mucoadhesive dosage form could address these problems by localizing the drug in the sublingual region, providing sustained release, maximizing compliance by being easy to administer with reduced dose frequency, as well as reducing the potential of drug diversion by the addicted patient. The specific aims of this proposal include the formulation of dosage forms of buprenorphine with mucoadhesive polymers and other excipients using a statistical design, followed by in vitro screening of physicochemical characteristics, mucoadhesive strength and drug release rate, and the in vivo evaluation of the pharmacokinetics of buprenorphine from select formulations in a rabbit animal model. In view of the growing concern with drug abuse and the difficulty to counteract drug related social problems, it is critical to improve the bioavailability, therapeutic value and compliance of drugs already proven to be safe and effective in the treatment of drug addiction, and this can be successfully achieved by utilizing specialized drug delivery systems as the one proposed in this project. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MULTIPLE MEMORY SYSTEMS IN ACTION SELECTION Principal Investigator & Institution: Berke, Joshua D.; Research Assitant Professor; Psychology; Boston University Charles River Campus 881 Commonwealth Avenue Boston, Ma 02215 Timing: Fiscal Year 2001; Project Start 01-AUG-2001; Project End 31-JUL-2006 Summary: The proposed research program examines how multiple neural circuits involved in learning contribute to making a decision, and how this process may be subverted by addictive drugs. Several current models suggest that the abnormal engagement of normal learning mechanisms contributes to drug addiction. In particular, it has been argued that repeated drug-enhanced release of dopamine in the striatum produces unusually strong learned habits of drug-seeking and drug- taking. Such habits are hard to suppress, resulting in a progressive narrowing of behavioral repertoire, and greatly diminished control over drug intake. To better understand this process, we shall examine neural coding mechanisms involved in habit formation and inhibition, in striatum, hippocampus and medial frontal cortex. We shall also investigate how neural representations are altered when habits are artificially strengthened by the psychomotor stimulant drug amphetamine. Our approach has two essential features. Firstly we apply electrophysiological methods to tasks whose behavioral and neuroanatomical characteristics are relatively well understood. Secondly we perform comparisons between closely related situations, aiming to isolate aspects of neural representations that are specifically associated with distinct cognitive demands. Rats will perform two radial maze tasks that are identical in the stimuli presented to the

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animal, differing only in the strategies required to obtain rewards. In the 'win-stay' task (visual stimulus- response) the rat has to choose the arm that is illuminated, regardless of its recent history of choices. Learning this task has been shown to require the striatum, and can be enhanced by intra-striatal injections of amphetamine. In the other task ('win-shift'), the rat has to avoid the most- recently-visited arm, and the visual cue is irrelevant. This is a spatial working-memory task, that requires intact hippocampal function. Shifting between the visually-cued and spatial strategies requires suppression of the learned habit, and has been shown to involve the rat medial frontal cortex. By examining neural representations associated with acquisition of a visual stimulusresponse habit, with drug enhancement of a habit, and with suppression of a habit, we aim to gain convergent data on how habits are encoded, and how excessively strong habits may contribute to addiction. At the same time we aim to provide a behavioral model of drug-induced loss of behavioral flexibility, that could be used by investigators testing novel drug abuse therapies. A fuller understanding of neural representations in frontal- striatal circuits, and how they are affected by dopamine, would also greatly contribute to our understanding of schizophrenia, obsessive-compulsive disorder, Tourette's syndrome, and Parkinson's Disease, as well as drug abuse. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NE AND COCAINE SENSITIZATION Principal Investigator & Institution: Jimenez-Rivera, Carlos A.; Universidad Central Del Caribe Bayamon, Pr 009606032 Timing: Fiscal Year 2002; Project Start 01-AUG-1994; Project End 31-DEC-2005 Summary: Repeated exposure to cocaine administration results in a progressive and enduring enhancement in the motor stimulant effect induced by subsequent drug challenge. This phenomenon, is termed behavioral sensitization and forms part of the basic pathological mechanisms involved in drug addiction. The present proposal is aimed at studying the NE modulatory effects on the cellular mechanisms of cocaine actions in the VTA during the development of cocaine sensitization. Initial experiments will investigate if NE transmission mediates cocaine enhancement of dopaminergic VTA cell activity in response to prefrontal cortex stimulation. Experiments will include systemic and iontophoretic administration of NE antagonists. Comparisons between cocaine sensitized and saline control rats will be made. The hypothesis to test is that cocaine sensitization will produce an increase in NE modulation of glutamate-excitation in the VTA induced by prefrontal cortex. stimulation. Additional studies will investigate if NE mediates the enhanced glutamate-induced VTA excitation observed with cocaine sensitization. Iontophoretic glutamate liberation together with NE agonists and antagonists' administration will be employed to assess whether the development of sensitization involves an enhancement of NE modulation of glutamate tone in the VTA. A third experiment will determine if NE modulation of VTA synaptic properties is enhanced by the development of cocaine sensitization. Whole cell patch recording techniques in in vitro slices will be employed. The hypothesis to test is that cocaine sensitization will provide and increase in spike frequency adaptation, after hyperpolarization and after hyperpolarization currents in the VTA, which will render this area more excitable and prone to develop behavioral sensitization. Finally, the last objective is to determine the contribution of NE transmission in the expression of cocaine sensitization. The completion of these experiments will provide important information on whether a dysfunction of NE modulatory properties is an important factor in the development and expression of cocaine sensitization. A clear understanding of NE changes in the above condition will increase our knowledge of the

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specific role of the noradrenergic system in cocaine addictive processes. and might provide possible avenues for therapeutic pharmacological interventions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NETWORK BUPRENORPHINE

THERAPY

DEVELOPMENT,

STAGE

II

WITH

Principal Investigator & Institution: Galanter, Marc; Professor; Nathan S. Kline Institute for Psych Res Psychiatric Research Orangeburg, Ny 10962 Timing: Fiscal Year 2001; Project Start 01-APR-1999; Project End 31-MAR-2003 Summary: (Applicant's Abstract) This is a Stage II psychosocial development study, combined with medication. It ensues from our Stage I study titled "Development of Network Therapy for Cocaine Abuse" (PA-92110). Only a minority of heroin addicts are enrolled in addiction treatment, and it is therefore important to develop approaches to care that will attract the larger, unserved population. Network Therapy, a comprehensive intensive, standardized, psychosocial treatment in combination with a pharmacotherapy regimen may offer one such option, and may also be appropriate for certain patients in a private medical office setting. The objective of the present study is to ascertain the relative effectiveness of Network Therapy and a less intensive level of behavioral intervention, when each is paired with an identical regimen of buprenorphine treatment. The treatments are carried out by physicians experienced in the substance abuse field in conventional medical office settings. The subjects are 200 heroin addicts seeking treatment in an outpatient office practice medical setting. The subjects will be randomly assigned to a behavioral treatment condition consisting of (a) a limited regimen of medication management (MM) or (b) network therapy, consisting of sessions that include support from family and friends in a structured program of relapse prevention. All patients will be in treatment for 26 weeks. They will undergo induction onto buprenorphine during the first week and be maintained on a fixed daily dose of 16 mg administered in tablet form for 20 weeks, after which the drug will be discontinued over five weeks. Outcome will be evaluated on the basis of length of time in treatment, use of heroin or secondary drugs, changes in HIV risk behavior, and psychiatric and psychosocial function. In addition, social support for abstinence will be evaluated to determine its predictive effect on treatment outcome. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NEUROBIOLOGY OF DRUGS OF ABUSE Principal Investigator & Institution: Graybiel, Ann M.; Professor; Brain and Cognitive Sciences; Massachusetts Institute of Technology Cambridge, Ma 02139 Timing: Fiscal Year 2001; Project Start 01-MAY-1993; Project End 31-JUL-2002 Summary: (Applicant's Abstract) Chronic exposure to psychomotor stimulants produces long-term changes in behavior including addiction and sensitized responses to further drug exposure. There is a great need to understand the changes in the central nervous system that occur with repeated drug exposure. A large body of evidence has implicated the striatum (caudoputamen and nucleus accumbens) in these brain effects, together with the midbrain dopamine systems that innervate the striatum. An interesting recent series of studies has demonstrated that exposure to psychomotor stimulants can produce striking effects on the expression of a series of immediate early genes (IEGs) that code for transcription factors. These experimental data are interesting because changes in transcription factor expression could have long-term effects on neuronal function. We propose a series of interrelated experiments to study these changes in

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expression. We propose to test specific hypotheses under three Aims. In Aim 1, we propose to test the hypothesis that chronic intermittent exposure to cocaine and amphetamine leads to long-term changes in the inducibility of IEGs in the striatum and that these involve down-regulation of IEG expression in the matrix relative to the striosome (patch) compartment. This hypothesis is based directly on preliminary experiments showing increased patchiness in striatal IEG expression following chronic intermittent exposure. To test for long-term effects, IEG expression after prolonged withdrawal periods will also be examined. In Aim 2, we will test the hypothesis that changes in dopamine receptor sensitivity occur with chronic exposure, that glutamate receptor function also is important for changes in IEG expression, and that IEG expression after cocaine and amphetamine treatment will show cross-sensitization. Finally, in Aim 3 we will test the hypothesis that drug-selective IEG expression patterns induced in the striatum by acute cocaine and amphetamine will be present in the squirrel monkey striatum, with amphetamine inducing a striosome-predominant pattern relative to cocaine. Taken together, these experiments will provide critical new data on the systems-level molecular change occurring in the striatum in response to chronic psychomotor stimulant exposure, on the duration of these changes, and on the receptor systems involved in producing these changes. In addition, these experiments will provide new and much-needed data on molecular responses to these drugs in acutely treated non human primates, a critical bridge toward understanding their effects in humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NEURO-COGNITIVE ASPECTS OF OPIATE ABUSE & ANTISOCIAL BEHAVIOR Principal Investigator & Institution: Vassileva, Jasmin L.; Psychiatry; University of Illinois at Chicago 1737 West Polk Street Chicago, Il 60612 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-AUG-2005 Summary: (provided by applicant): Rates of heroin addiction are increasing worldwide with concomitant legal and health costs, including increased risk of HIV and hepatitis C viral transmission. However, at present it is difficult to impossible to study the consequences of "pure" heroin use since the majority of addicts are polysubstancedependent. Further, co-morbid conditions, such as Antisocial Personality Disorder (APD) and psychopathy, additionally complicate the clinical picture and daily function of heroin-dependent persons. Study of the effect of drugs of abuse on the brain and the development of addiction are particularly difficult, due to difficulty in isolating drug effects on cognition from dysfunction associated with co-morbid conditions. We propose to develop a program of studies with the long-term goals of investigating neurocognitive aspects of brain function in drug addicts with and without a diagnosis of ASPD / psychopathy. This program will be developed in Bulgaria, a low-middle income country in Southeastern Europe with significantly high prevalence of heroin addiction. Bulgaria's geographical position make it a key country on the "Balkan Drug Route", one of the main routes for international drug traffic from South-West Asia to Western Europe, through which approximately 80% of the heroin currently used in Western Europe passes. Consequently, heroin is easily available in the country, and in fact heroin addiction has become one of the most significant health and legal problems. Patterns of heroin addiction in Bulgaria are unique in that polysubstance dependence is uncommon. Consequently study of Bulgarian addicts provides a unique opportunity to evaluate neurocognitive and psychiatric consequences of relatively "pure" heroin use. In addition, the nature of the Bulgarian legal system facilitates the opportunity to study

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heroin dependent subjects both with and without APD because all detainees arrested for drug-related charges undergo mandated medical and psychiatric evaluation prior to disposition of their cases. We have partnered with physicians and mental health professionals in Sofia who have access to a large population of pre-trial detainees, a large majority of whom have been detained for drug-related crimes. Research on addiction and its neuro-cognitive consequences is minimal in Bulgaria, despite a significant need to address these concerns. In the proposed project the PI, her colleagues the University of Illinois-Chicago, and at the Clinic of Forensic Psychiatry and Psychology at the State University Hospital of Neurology and Psychiatry in Sofia, Bulgaria, will initiate the development of resources for studies of neuro-cognitive function in heroin addicts with and without APD/psychopathy, and without polysubstance dependence. This preliminary work will culminate in a pilot study of neuro-cognition in heroin addicts with and without ASPD/psychopathy and an R01 application based on these pilot findings and other hypotheses developed in the course of the two years. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NEURONAL SUBSTRATES OF COCAINE REWARD Principal Investigator & Institution: Koob, George F.; Director; Scripps Research Institute 10550 N Torrey Pines Rd La Jolla, Ca 920371000 Timing: Fiscal Year 2001; Project Start 25-APR-1987; Project End 31-MAR-2004 Summary: (Adapted From The Applicant's Abstract): A critical issue for the understanding of drug addiction is what neurobiological mechanisms are responsible for the transition from non-dependent drug use to addiction. This is a competing renewal application to continue to study the neural mechanisms of cocaine reinforcement that lead to compulsive drug seeking behavior. Work during the previous funding period has established that neurochemical mechanisms within specific subregions of a basal forebrain circuit termed the extended amygdala may be involved in the acute reinforcing effects of cocaine and reward system dysfunction associated with chronic administration of cocaine. Within this neural circuitry, evidence was generated for a role in cocaine dependence of specific dopaminergic and serotonergic receptors subtypes as well as interactions with the glutamate system and the brain stress neurotransmitter corticotrophin releasing factor. In addition, during the previous funding period, a model of the transition to compulsive drug seeking was developed where rats allowed more prolonged daily access to cocaine (6 hours) escalate their cocaine intake over time whereas rats that were allowed more limited exposure (1 hour) showed stable, non escalating cocaine intake. This escalation in drug intake was accompanied by a shift of the cocaine dose effect function upwards such that the animals were taking more cocaine at each dose. In addition, animals with a history of drug escalation more readily escalated drug intake upon re-exposure to cocaine. It is hypothesized that this escalation in cocaine intake results from a change in reward set point that reflects changes in neural activity within the extended amygdala and its connections. The purpose of the proposed studies is to further characterize escalation of cocaine intake with more prolonged access (Specific Aim 1), and to explore the neuroanatomical substrates for escalation of cocaine intake (Specific Aim 2). In addition, the proposed studies are designed to explore the neuropharmacological mechanisms involved in escalation of cocaine intake (Specific Aim 3). Finally, drawing on the results of Specific Aims 2 and 3, the role of specific neuropharmacological mechanisms within the extended amgydala in escalation of cocaine intake will be explored (Specific Aim 4). These experiments will provide critical information on the brain changes that

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accompany the transition from the stable drug intake of limited access to the escalated intake of more prolonged access. Such information is essential for the development of new treatments for drug addiction as well as for the development of strategies to identify vulnerability to the development of addiction. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NIDA CLINICAL TRIALS NETWORK - NYC EAST SIDE NODE Principal Investigator & Institution: Rotrosen, John P.; Professor; Psychiatry; New York University School of Medicine 550 1St Ave New York, Ny 10016 Timing: Fiscal Year 2001; Project Start 20-FEB-2000; Project End 31-JAN-2005 Summary: The mission of the to-be-established NIDA National Drug Abuse Clinical Trials Network (CTN) is to improve the quality of drug abuse treatment nationally by (1) accelerating the pace of treatment research, testing findings from small controlled studies in real-life treatment settings, and (2) accelerating community-treatmentprogram implementation of new treatment technologies via dissemination and training. Specific CTN objectives include conducting studies in the areas of pharmacological, behavioral and practice research in a range of treatment settings and clinical populations; conducting studies on how best to translate science-based findings into clinical practice; encouraging collaboration between community treatment facilities and academic researchers; and assessing the health and systems impact of the implementation of new treatment modalities. The New York City East Side (NYC-ES) Node will contribute the following to this overall mission: (1) leadership in addiction research, training and treatment, (2) broad clinical trials expertise and extensive clinical capacity, (3) a state-of the-art clinical trials data management system and expertise, (4) leadership in dissemination and evaluation of addiction treatment training material, and (5) unique capacity to contribute to the network in the following areas (a) health services and health outcomes research, (b) genetics and pharmacogenetics related to vulnerability to drug addiction, (c) central data management. The NYC-ES Node is a consortium of academic and clinical investigators/providers who have a longstanding track record of fruitful collaboration in research, training, and clinical service delivery for the addictive disorders. The Community-based Treatment Programs (CTPs) are characterized by programmatic and treatment-model diversity, and provide access to an overall clinical population of more than 10,000 patients with extensive diagnostic, ethnic and gender diversity. Regional Research and Training Center (RRTC) components include (1) the Rockefeller University Laboratory for the Study of Addictive Disease and its Cornell-affiliated programs, (2) the NYU School of Medicine Division of Alcoholism and Drug Abuse; (3) a group of NYU and Nathan Kline Institute investigators with extensive large scale clinical trials experience; and (4) the Epidemiology and Health Services Research Laboratory at the Nathan Kline Institute. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NON-ADDICTING CANNABINOID MEDICATIONS Principal Investigator & Institution: Malan, Thomas P.; Anesthesiology; University of Arizona P O Box 3308 Tucson, Az 857223308 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-MAY-2006 Summary: (provided by applicant): As a physician, I see many patients with medical conditions for which adequate therapy is not available. CB2 cannabinoid receptorselective agonist medications may prove useful in treating some of these disease states. One is moderate-to-severe pain, where the use of opioid medications, the most effective

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therapy, is often limited due to concerns over addiction. In addition, opioids prescribed as analgesics are subject to diversion and abuse. We have shown that CB2 receptorselective agonists produce strong antinociceptive effects in animal models, suggesting that they may be useful as analgesic medications for humans. Unlike cannabinoids with agonist activity at CB1 receptors, CB2 receptor-selective agonists are predicted not to produce the rewarding properties associated with drug abuse, since CB2 receptors are not found in the CNS. By reducing the need for opioids, CB2 receptor-selective medications would diminish the problem of addiction with its severe individual and social costs. CB2 receptor-selective agonists, however, are likely to have important medical applications beyond analgesia. In this proposal, we hypothesize that CB2 receptor-selective agonists will be useful in the treatment of the prevalent and challenging problems of urinary incontinence; irritable bowel syndrome, inflammatory bowel disease and visceral hypersensitivity; and opioid resistant neuropathic pain. Our goal is to combine state-of-the-art chemistry and biology to develop CB2 receptorselective agonists as medications. Aim one will test the hypothesis that CB2 receptorselective agonists will have therapeutically desirable properties beyond analgesic effects. We will explore the activity of CB2 receptor-selective agonists in experimental models relevant to urinary incontinence; inflammatory bowel disease and other conditions associated with sensitization or increased activity of C-fibers. We will also test the hypothesis that CB2 receptor-selective agonists will not produce a withdrawal syndrome or provide reward. Aim two will use a lead optimization strategy to improve the medicinal properties of AM1241, our structural lead compound. This will be accomplished by a structure-activity relationship study involving the systematic manipulation of each of the molecule's pharmacophoric groups using drug design principles. Novel compounds will be evaluated for their affinity at and selectivity for CB2 cannabinoid receptors in vitro and for desired properties in vivo. The successful completion of these aims will provide physicians a therapeutic option that may provide relief for patients with difficult medical conditions and decrease the use of opioids, minimizing opportunities for abuse. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TREATMENT

PARENT-CHILD

INTERACTIONS

DURING

ADDICTION

Principal Investigator & Institution: Wilson, Jeffrey J.; Psychiatry; Columbia University Health Sciences New York, Ny 10032 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2007 Summary: (Provided by Applicant) The goal of this K-23 award is to provide the applicant, a psychiatrist with advanced training in both child/adolescent and addiction psychiatry, with the advanced training needed to develop a paradigm to study and treat the transmission of addictive vulnerability (AV) among high-risk families. Preceptors and consultants for this award have been selected with the long-range intent of designing interventions to reduce AV through the treatment of parental addiction, child externalizing behavior (CXB), and the improved identification of communication problems within these families. Formal education in therapeutic interventions (including behavioral, psychoeducational and psychopharmacological approaches) and statistical methods complement this training. Among families with addicted parents, CXB may mediate the transmission of AV. Hence early identification and effective treatment of CXB may also reduce AV. Although parental substance abuse has multiple deleterious effects on children, little is known regarding the needs of these children and their families once their parents are treated for addiction. CXB is closely linked to

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coercive patterns of interaction between parents and their children, and these interactions may adversely effect both children and parents. A one-year prospective study of 100 families with a parent-proband in methadone maintenance treatment and their 6-9 year old children has been designed to better identify the treatment needs of these families. Parental substance use will be prospectively assessed as a predictor of child externalizing behavior, considering parent-child interactions as mediators or moderators of this relationship. The role of additional parent (e.g., comorbid psychopathology, gender, exposure, ethnicity, SES) and child (baseline externalizing behavior, comobid psychopathology, language ability) factors will also be considered in this developmental model of addictive vulnerability. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PROCESSES

PATHWAYS

TO

LONG-TERM

ABSTINENCE:SELF-HELP

Principal Investigator & Institution: Laudet, Alexandre; National Development & Res Institutes Research Institutes, Inc. New York, Ny 10010 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-MAY-2007 Summary: (provided by applicant): Participation in substance abuse treatment has consistently proven effective in reducing substance use. However, treatment gains are often not maintained; relapse may occur rapidly after treatment ends and relapse risk remains high for several years. Affiliation with self-help groups (SH) been shown to extend treatment effects. Treatment and SH study findings bear on predictors of shortterm abstinence; it is not known whether these findings can be generalized to long-term abstinence. Moreover, SH affiliation studies have typically used treatment samples of alcoholics (often-white men) in Alcoholics Anonymous (AA). Little is known about the effects of SH affiliation among other groups of individuals, especially illicit polysubstance users who may attend Narcotics Anonymous rather than or in addition to AA. Illicit drug users differ from alcohol-dependent persons in critical ways that bear on long-term prognosis and the NA membership differs from AA. Even less is known about the change processes underlying the benefits of SH. The investigation of predictors of long-term abstinence will contribute to enhancing the likelihood of breaking the relapsing cycle of addiction by informing treatment, especially relapse prevention programs, and a longitudinal study of SH affiliation and its underlying processes will inform referral patterns for drug users, elucidate the critical ingredients of affiliation driving therapeutic benefits of SH, a widely used recovery resource, and provide valuable information about the dynamic process of change implicated in the resolution of addiction. This application proposes a longitudinal community-based naturalistic investigation of the predictors of long-term abstinence from illicit drugs with special focus on SH affiliation and underlying change processes. The sample will be a cohort of abstinent individuals (N = 300) stratified by length of abstinence at recruitment (3- to 18-month and 18- to 36months); subjects will be followed-up for 3 years. The aims are: 1. To determine whether predictors of short-term abstinence can be generalized to long-term abstinence. 2. To study longitudinal patterns of affiliation with self-help among illicit drug users. 3. To examine the relationship between these patterns and the maintenance of long-term abstinence. [Aims 2 and 3 would constitute the 1st. long-term, longitudinal investigation of self-help among illicit drug users not recruited in a treatment setting]. 4. To elucidate the processes underlying the demonstrated benefits of affiliation with self-help among drug user by testing a conceptual model (Figure 1) building on and integrating previous findings. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PHARMACOGENETICS OF METHADONE Principal Investigator & Institution: Devane, C L.; Professor; Medicine; Medical University of South Carolina 171 Ashley Ave Charleston, Sc 29425 Timing: Fiscal Year 2001; Project Start 05-APR-2001; Project End 31-MAR-2004 Summary: (Verbatim from the Applicant's Abstract): Methadone is used as a maintenance treatment for opiate addiction and is the standard of care in the management of the pregnant opiate-addicted woman. Maternal methadone dose at delivery and the severity of neonatal withdrawal are closely related. Thus, methadone dose is a critical factor determining both maternal health and birth outcome. Most dosage regimens for methadone are empirical, titrating dose against withdrawal symptoms and, where appropriate, on the history of opiate use. Despite the use of methadone for nearly 50 years, details of its pharmacokinetics are surprisingly incomplete. A linear relationship has been reported between methadone dose and drug concentration in plasma but drug dose explains less than 50 percent of the variability. Methadone is marketed as a mixture (50:50) of 2 enantiomers called (R)-methadone and (S)-methadone, but (R)methadone accounts for nearly all of the opioid effects of the racemic dose. The disposition of methadone appears to be stereoselective and under genetic and environmental control. The pharmacogenetic contribution to methadone's disposition has received little study. Accordingly, a three-year dual-site, collaborative ROl study is proposed to define the major pharmacogenetic variables that influence the disposition of methadone in women. The major determinants to be studied include 1) gender, 2) ethnic origin (Africian-American vs. Caucasian background), 3) enantioselective metabolism; 4) plasma protein binding of methadone's enantiomers, 5) genetically determined phenotype of alpha1-acid glycoprotein (AGP), 5) the cortisol ratio as a surrogate marker of cytochrome P-450 (CYP) 3A4 activity, and 6) genotype of CYP2D6. A rigorous pharmacokinetic study of methadone disposition will be completed in healthy volunteer women and the results compared to healthy men. Correlations will be sought between the pharmacokinetics of methadone's enantiomers and effect measures shown in our preliminary data to be highly related (pupillary constriction, oral temperature, blood glucose concentration). Demographic and pharmacokinetic data will be obtained from 600 women (240 in Charleston and 360 in Cincinnati) receiving methadone maintenance. A population pharmacokinetic model will be constructed and tested to predict plasma concentrations of active (R)-methadone before and during pregnancy. The goals of this research are to describe the major pharmacogenetic factors which influence methadone concentration in women, and through pharmacokinetic analyses, to form a clearer understanding of the dose-concentration-effect relationship of methadone in a special population at risk, the pregnant opiate-addicted woman. This study will form the basis for subsequent studies which should provide a more rational basis for dosing of methadone in pregnant addicts. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PHYSIOLOGY TRANSMISSION

OF

MIDBRAIN

DENDRITIC

DOPAMINE

Principal Investigator & Institution: Beckstead, Michael J.; None; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-AUG-2005 Summary: (provided by applicant): Dopamine cells in the ventral midbrain serve a role in a number of critical functions, including motor processes, focused attention, reward and incentive learning. It is not surprising then that the same cells participate as neural

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substrates of human diseases such as drug addiction, Parkinson's disease, and likely schizophrenia and attention deficit hyperactivity disorder. Dopamine cells exert their main effects distally through projections to brain regions involved in decision making, movement, and emotion. Small amounts of dopamine are also released dendritically near the midbrain nuclei of the ventral tegmental area (VTA) and substantia nigra (SN). Recently it was discovered that this dendritic release may occur through reversal of the dopamine transporter, a widely-distributed membrane-bound protein responsible for the majority of free dopamine uptake from the extracellular space. Dopamine released by this mechanism can activate D2 dopamine receptors on the dopamine cell bodies, inhibiting firing, and thus the release of dopamine in distal brain regions implicated in behavioral processes. While the existence of dopamine transporters and D2 receptors in the VTA and SN suggest a physiological role for dendritic release, the precise synaptic mechanisms have yet to be investigated. This proposal addresses this issue by investigating the mechanisms of dendrodendritic transmission in the VTA. Whole-cell patch clamp electrophysiological technique will be used to record from dopamine neurons in rat midbrain slices. Of particular interest is the elucidation of the role of metabotropic glutamate receptors in the dopamine-induced inhibition of dopamine cell firing. Amphetamine, a drug of abuse known to act on dopaminergic cells, will also be used to attempt to gain and understanding of the importance and role of the dendritic release of dopamine. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PROGRAMMATIC RESEARCH ON FAMILIES AND ADDICTION Principal Investigator & Institution: O'farrell, Timothy J.; Associate Chief of Psychology; Psychiatry; Harvard University (Medical School) Medical School Campus Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-JAN-1997; Project End 31-MAY-2007 Summary: (provided by applicant): The overall aim of the proposed Research Career Award is to free the candidate from clinical and administrative duties so that he may devote nearly full-time to continue and develop further his programmatic research on family treatment and family processes among individuals with alcoholism and other drug problems. Family-involved treatments for alcohol and drug problems have substantial evidence for their effectiveness as documented in recent reviews. Family processes affect and are affected by the course and treatment outcome of addictions, and processes within families troubled by addiction are linked to some of our most urgent societal problems. This application has two specific aims: (1) the aims for research on family treatment are to conduct a randomized clinical trial evaluating behavioral family counseling and naltrexone with opioid dependent patients and to complete work currently in progress; and (2) the aims for research on family processes are to describe the natural history and to explore explanations of male-to-female violence among female alcoholics and their male partners and to complete work currently in progress on domestic violence among male alcoholic patients. Career development activities will include (1) consultation from leading experts about adding a focus on the functioning of children to the candidate's couple/family treatment outcome research and to his longitudinal research on domestic violence; and (2) a course on the responsible conduct of research. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PURIFICATION AND MASS SPECTROMETRY OF OPIOID RECEPTORS Principal Investigator & Institution: Howells, Richard D.; Associate Professor; Biochem and Molecular Biology; Univ of Med/Dent Nj Newark Newark, Nj 07103 Timing: Fiscal Year 2003; Project Start 15-JUL-1997; Project End 31-JAN-2008 Summary: (provided by applicant): Drug addiction is a major medical problem in the United States. Opioid addiction is associated with a variety of behaviors that are detrimental to both the individual and society. While much has been learned about opioid pharmacology and signal transduction over the last three decades, the molecular mechanisms that are responsible for opioid tolerance and dependence due to chronic opioid drug use are complex and much remains to be learned. Acute administration of opioids triggers intracellular signal transduction, initiated by receptor-mediated heterotrimeric G protein activation. Effectors include adenylyl cyclase, potassium and calcium ion channels, and MAP kinase, all of which contribute to the pharmacological effects of opioids. Agonist efficacy diminishes rapidly when multiple doses are given over a short period of time. This homologous desensitization is due to uncoupling of the receptor from the G protein, due to receptor phosphorylation by G protein-coupled receptor kinases (GRKs). Arrestin binds preferentially to GRK phosphorylated receptors and precludes further activation of G proteins. Chronic administration of opioid agonists results in receptor down regulation, involving proteolysis of the receptor protein and a concomitant decrease in the number of functional receptors. It is highly probable that agonist-induced down regulation of opioid receptors contributes to opioid tolerance. The PI has provided compelling evidence that the ubiquitin/proteasome system is involved in basal turnover and agonist-induced down regulation of opioid receptors. Pulse-chase analysis revealed that agonist treatment accelerates proteolysis of the receptor. Preincubation with proteasome inhibitors, but not other protease inhibitors, blocked agonist-induced receptor down regulation. Immunoprecipitation of opioid receptors revealed that opioid receptors are polyubiquitinated prior to degradation. This research proposal will focus on the purification of opioid receptors and analysis of post-translational modification using mass spectrometry. Sites of phosphorylation and ubiquitination of opioid receptors will be mapped by mas spectrometric analysis and site-directed mutagenesis. The hypothesis that inhibition of agonist-induced down regulation with proteasome inhibitors will attenuate the developments of tolerance will be tested. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ROLES OF ORBITOFRONTAL CORTEX IN COCAINE ABUSE BY FMRI Principal Investigator & Institution: Li, Shi-Jiang W.; Biophysics; Medical College of Wisconsin Po Box26509 Milwaukee, Wi 532264801 Timing: Fiscal Year 2002; Project Start 30-SEP-1996; Project End 31-MAR-2007 Summary: (provided by applicant) Cocaine addiction is often considered a disease of drive and compulsion. Based on this concept, reward/pleasure per se cannot completely account for compulsive drug intake. The goal of this proposal is to study the neural systems subserving reward and compulsive drug taking in cocaine addiction, and to study the neural circuitry responsible for compulsive drug taking behaviors triggered by both drug-related cues and cocaine itself. Ultimately, our understanding of drug addiction will require the elucidation of how these neuronal circuits interact and contribute to relapse and drug seeking. Therefore, knowledge of the neural mechanisms

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underlying drug rewarding and cravings should lead to the development of more effective treatment strategies. Our central hypothesis is that both cue-and cocaineelicited cravings that drive further drug taking commonly activate the orbitofrontal cortex (OFC) and associated cortical and subcortical structures. Once the OFC is activated, the result is an intense drive to get the drug (sometimes perceived as craving), and leads to compulsive drug taking (consciously perceived as loss of control). This hypothesis is supported by many findings from positron emission tomography (PET) and functional MRI (fMRI studies. Nevertheless, the issue of how rewards or cravings result in compulsive drug abuse remains primarily unsolved. There are many factors that contribute to this gap in our knowledge. One roadblock has been the difficulty of simultaneously measuring cue- or cocaine-induced neuronal activity in the region of the OFC and in the region of the nucleus accumbens (NAc). Therefore, tofill this methodology gap, we will develop a customized fMRI-BOLD (blood oxygenation level dependent) acquisition method as proposed in Specific Aim 1. To test our central hypothesis, three sub-hypotheses have been formulated. Specific Aim 2 will test the hypothesis that cue-induced craving associated with comulsive behaviors and relapse is related to activations involving the hippocampus (Hipp)/Amygdala (Amy) to OFC pathways. Specific Aim 3 will test the hypothesis that cocaine-induced craving associated with cocaine binge is related to activations through the dopaminergic mesocorticolimbic (MCL) to OFC pathways. Specific Aim 4 will test that the combination of cue- and cocaine-elicited cravings, similar to the actual context of cocaine experience, will greatly enhance OFC activations and induce intense drive to take the drug. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SERVICE OUTREACH TO HOMELESS DRUG USERS Principal Investigator & Institution: Magura, Stephen; Acting Executive Director; National Development & Res Institutes Research Institutes, Inc. New York, Ny 10010 Timing: Fiscal Year 2001; Project Start 25-SEP-1996; Project End 31-MAY-2003 Summary: This a competing continuation for the grant, "Service Outreach to Homeless Drug Users at HIV Risk." The parent grant surveyed soup kitchen guests, finding very high rates of cocaine/crack (75%) and substantial rates of heroin/opiate use (20%). However, drug treatment utilization was low; in particular, very few (10% of the primary cocaine/crack users were in treatment or attending 12-step groups. An efficacy trial of an enhanced case management model successfully delivered a variety of entitlements, health and social services to subjects, but resistance to drug treatment was high. To respond to this situation, this application proposes: 1) To implement a Motivation Enhancement for Recovery (MER) group intervention as a means to increase participation of street cocaine/crack users in formal treatment and other credible interventions for drug addiction. 2) To conduct an efficacy trial of a comprehensive model (Service Outreach and Recovery-SOAR) designed to increase participation of street cocaine crack users in treatment and other credible interventions for drug addiction. Subjects will be randomized voluntary into two conditions: 1. SOAR ModelCase Management Team (CMT), Motivational Enhancement for Recovery (MER), and Incentivized Options for Recovery (IOR) (n=120). 2. Case Management Team (CMT) only (n=120). The options for Recovery will be traditional formal treatment modalities (outpatient, residential/TC, inpatient rehabilitation, detoxification); traditional 12-step meetings (Narcotics Anonymous [NA]), alternative 12 step meetings (Recoveries Anonymous [RA]), and a low threshold, harm reduction group therapy (Education and Skills for Recovery); the latter two options will be offered directly by the study. Subjects

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Drug Addiction

will receive accelerated incentives of modest amounts to participate in their selected Option for Recovery for us to three months. The primary outcome variables are entry into treatment or other intervention for drug addiction; length of retention in treatment or other intervention; and substance use at 6 and 12 month follow-ups. 3) To determine the client characteristics and service process variables which predict entry to and retention in treatment/interventions for drug addiction, as well as other differences in outcomes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SUGAR ADDICTION IN RATS: LINKS TO DRUGS OF ABUSE Principal Investigator & Institution: Avena, Nicole M.; Psychology; Princeton University 4 New South Building Princeton, Nj 085440036 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-AUG-2007 Summary: (provided by applicant): The objectives and aims of this research proposal are to investigate the neural and behavioral correlates of sugar and drug addictions. The recent increased awareness of eating disorders and obesity in our country has led many to speculate about the addictive properties of food, and how this addiction may be related to the over-eating epidemic our society is currently facing. Recent research in rodents has indicated that sugar bingeing can lead to dependency that shares some behavioral and neurochemical similarities with drug dependency (Colantuoni et al., 2001; Colantuoni et al., 2002). This proposal plans to elaborate on these findings, by behaviorally investigating sugar craving, sensitization and cross-sensitization with other known drugs of abuse. Moreover, this research will examine neurochemical similarities between sugar and drug addiction in the nucleus accumbens. By further elucidating a possible link between food and drugs, new pharmacological and behavioral treatments may be developed to treat eating disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SYMPTOM BASED TRANSITIONS IN ADDICTION IN MALE TWINS Principal Investigator & Institution: Bucholz, Kathleen K.; Research Professor; Psychiatry; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-AUG-2004 Summary: (provided by applicant) Support is requested for 3 years to conduct secondary analyses of transitions in drug addiction, using data from the NIDA-funded Harvard Drug Study (HDS), in which 8169 members of the Vietnam Era Twin Registry (VETR) (a large general population sample of male same-sex twins who served in the military during the Vietnam era) were interviewed by telephone with a structured psychiatric diagnostic interview. Covered in the interview were DSM-III-R lifetime criteria for dependence and abuse on 5 illicit and 2 licit drug classes, as well as other psychiatric disorders. The availability of ages of onset and offset for each drug-class specific symptom of addiction in these data make them uniquely suitable for a method of studying transitions to drug addiction that we have already used successfully with alcohol symptom data. The twin structure of the data permits study of the effect of genetic factors on occurrence and transitions to addiction on specific drugs. Specifically we will: 1) explore the nosology of drug-class specific addictions and investigate the role of genetic factors in the classifications, using latent structure techniques like latent class analysis; 2) investigate transitions in addiction in both epidemiologic and genetic frameworks, using a) a more conventional approach that relies on drug use patterns

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(e.g. initiation, regular and problem use), as well as b) a novel approach based on person-years of addiction symptoms, developing a method for incorporating symptom offsets; 3) study factors (including use of other substances, psychiatric comorbidity, social characteristics, family history) that may promote, accelerate, or inhibit transitions; and 4) conduct, wherever possible, cross-study analyses using other sources of data, especially data from the Vietnam Era Study (VES), National Comorbidity Survey (NCS), National Longitudinal Alcohol Epidemiology Survey (NLAES), and the Collaborative Study on the Genetics of Alcoholism (COGA), in order to test the replicability of the findings. We expect our proposed analyses will contribute to an understanding of transitions in addiction to specific types of drugs. Ultimately, our research may suggest certain points in transitions in specific drug addictions that might be amenable to preventive interventions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THE ROLE OF CDK5 IN ADDICTION Principal Investigator & Institution: Bibb, James A.; Psychiatry; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-MAR-2008 Summary: (provided by applicant): Many drugs of abuse target dopaminergic neurotransmission in the striatum. It is important to biochemically characterize intracellular signal transduction both in post-synaptic dopaminoceptive neurons of striatum and in pre-synaptic dopaminergic neurons of the midbrain in order to provide clearer information about how numerous, interacting signaling cascades are altered by drug addiction. Previously, we have shown that the neuronal protein kinase, Cdk5 (cyclin-dependent kinase-5), is an important regulator of dopaminergic neurotransmission. Furthermore, we have shown that Cdk5 and its neuron-specific activating cofactor, p35, are targets of chronic cocaine exposure. More recently, we have found that chronic cocaine-induced effects on neuronal synaptic morphology in the nucleus accumbens, the ventral portion of the striatum, which is particularly important for cocaine's behavioral effects, are under the control of Cdk5. We now propose to further characterize the role of Cdk5 in striatal brain function and determine its role in the processes that contribute to the addictive state. Toward this goal, we will investigate the ability of Cdk5 to regulate the activity of a striatal post-synaptic target (protein phosphatase inhibitor-1), and a pre-synaptic target tyrosine hydroxylase). In addition, we will search, using a proteomic approach, for additional proteins that mediate Cdk5dependent processes in the striatum that contribute to cocaine action. The goal of this work is to identify new targets and therefore new biomolecular mechanisms underlying drug addiction. This information may also serve as the basis for the development of novel treatments for this disorder. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: THERAPEUTIC COCAINE VACCINE Principal Investigator & Institution: Kosten, Thomas; Psychiatry; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2000; Project Start 01-MAY-1997; Project End 31-DEC-2003 Summary: APPLICANT'S ABSTRACT: Cocaine abuse is a major medical concern in the United States, with 2.1 million people estimated to be dependent on cocaine. No pharmacotherapies have been shown to be clinically effective and there is an urgent need for novel therapeutic approaches. This application requests funding for the

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evaluation of a cocaine vaccine for the treatment of cocaine addiction. The vaccine induces anti-cocaine antibodies which bind to cocaine in the circulation and inhibit its entry into the brain. As a result, the pharmacologic effect of the drug is reduced and it is anticipated that the patient will receive reduced gratification from the use of cocaine. The therapy is intended to help prevent relapse as part of a comprehensive treatment program. The safety and immunogenicity of the cocaine vaccine in humans will be evaluated in a Phase I clinical trial. Subsequent clinical studies will evaluate the safety and efficacy of the vaccine-induced antibody cocaine addiction. The Panel was favorably impressed by all components of the proposal and concluded that the development of a cocaine vaccine is an innovative response to the intent of the SPIRCAP RFA and is strongly supported by preliminary studies in animal models. In addition, the Panel was very favorably impressed by the qualifications of the proposed researchers, especially the program PI and the Project Leader (PL) for Projects 3a and 3b. The Panel found only minor weaknesses in this program. However, they recommended deletion of specific studies in project 2 because of inadequate justification and a reduction in work scope for projects 3b and 4 along with the recommendation to pool the collected data to enhance the efficacy of these two projects. In line with the above recommendation the Panel recommended reduced funding for the Administrative Core and for Projects 2, 3b and 4. The Panel expressed concern about the protection of Human Subjects. The Panel felt strongly that these issues needed to be addressed prior to the initiation of any human subjects trails. This application proposes four years of support for the evaluation of a vaccine to treat cocaine addiction. The vaccine reduces the gratifying affects of cocaine and is designed to help prevent relapse in drug abuse treatment programs. The applicant proposes a project composed of five components that would increase the safety and efficacy of the cocaine vaccine. These components are as follows: Administrative Core -- Barbara S. Fox, Principal Investigator Project 1: Immunogenicity of Cocaine Vaccine in Human Subjects -- Barbara S. Fox, Project Leader Project 2: Evaluation of Cocaine Vaccine in Rat Models of Cocaine Addiction - - Kathleen M. Kantak, Project Leader Project 3a: Active Immunization to Develop Antibodies to Cocaine -- Thomas R. Kosten, Project Leader Project 3b: Immunological Agents for Cocaine Abuse -- Thomas R. Kosten, Project Leader Project 4: Use of a Laboratory Model with Human Research Subjects -- Marian W. Fischman, Project Leader Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TRANSITION TO COCAINE ABUSE IN MONKEY:ROLE OF DOPAMINE Principal Investigator & Institution: Nader, Michael A.; Professor; Physiology and Pharmacology; Wake Forest University Health Sciences Winston-Salem, Nc 27157 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-AUG-2006 Summary: (provided by the applicant) The goal of this research is to broaden our understanding of the neural and behavioral mechanisms that mediate the transition from recreational cocaine use to cocaine addiction. More specifically, this application proposes a series of studies using models of cocaine self-administration in monkeys, with the brain imaging procedure positron emission tomography (PET), in an effort to better understand the consequences of long-term cocaine use and cocaine abstinence on dopamine (DA) receptor function. In PET studies with monkeys self-administering cocaine, we have observed 20 percent reductions in D2 binding potentials throughout 1 year of cocaine use. We also found that baseline D2 receptor levels correlated with rates of cocaine self-administration, suggesting that D2 receptor levels were associated with "vulnerability." These studies are the first to use a within-subjects design and PET

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imaging to examine long-term changes in the brains of monkeys self-administering cocaine and during abstinence. The studies proposed in this application are designed to extend our understanding of DA receptor function and compulsive cocaine seeking in male rhesus monkeys (M. mulatta) self-administering cocaine, in an effort to identify a transition "switch" for addiction. Specifically, we propose to study how the DA system, in particular D1, D2 and DA transporters (DAT): 1) is differentially influenced by pattern of cocaine use, comparing cocaine-maintained responding under a second-order schedule to a binge pattern of self-administration; 2) recovers during abstinence and how lifetime cocaine intake modifies the rate of recovery; and 3) is correlated with cocaine seeking in a model of craving that does not involve extinction of cocainemaintained responding. We hypothesize that the "switch" is a functional interaction between D1, and D2 receptors with cocaine-induced increases in extracellular DA via DAT. Combining PET imaging with our monkey models of cocaine abuse, we will be able to characterize DA receptor function, as it pertains to cocaine seeking, over long periods of time. A better understanding of the neuroadaptation of the DA neurotransmitter system correlated with behavioral outcomes of cocaine use and abstinence will lead to a better understanding of the mechanisms that mediate the transition from drug use to addiction. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TRANSITIONAL STATES IN DRUG ADDICTION Principal Investigator & Institution: Howell, Leonard L.; Research Associate Professor; Psychiatry and Behavioral Scis; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-MAY-2008 Summary: (provided by applicant): The progression of drug addiction in humans typically involves a transition from casual, recreational drug use to compulsive drug use that leads to serious adverse consequences. Hence, the frequency and pattern of drug use changes as a function of drug history. The proposed studies will utilize i.v. drug self-administration protocols in rhesus monkeys to identify critical behavioral endpoints indicative of transitional states in drug addiction. Efforts will focus on the importance of response-contingent drug history and drug-related environmental stimuli. Subjects will be exposed to a limited-access condition designed to incorporate features of recreational drug use in humans, followed by a binge period with increased duration of access and marked elevations in drug intake. Changes in the pattern and frequency of drug intake during the limited-access and binge conditions will be a major focus (Specific Aim 1). Reinstatement of drug-seeking behavior by cocaine priming injections and drug-paired stimuli will provide another objective behavioral measure indicative of transitional states in drug use (Specific Aim 2). Parallel studies will utilize in vivo microdialysis in awake subjects to characterize functional changes in monoamine neurochemistry associated with the behavioral changes observed (Specific Aim 3). In addition, positron emission tomography will document the pattern of drug-induced brain activation at different transitional states observed in behavioral and neurochemical studies (Specific Aim 4). Brain tissue obtained at different transitional states will be assayed for gene expression profiles and protein products, providing relevant molecular markers to complement in vivo functional measures in a nonhuman primate model of drug use (Specific Aim 5). These integrated efforts, including behavioral and mechanistic approaches, will provide a comprehensive analysis to elucidate transitional states in cocaine addiction. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: VIRTUAL REALITY CUE EXPOSURE FOR DRUG ADDICTION: SMOKING Principal Investigator & Institution: Bordnick, Patrick S.; Virtually Better, Inc. 2450 Lawrenceville Hwy, Ste 101 Decatur, Ga 30033 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-MAR-2004 Summary: (provided by investigator): This study will develop and test the feasibility of virtual reality cue exposure (VRCE) for drug addiction: Smoking. Traditional cue exposure has involved bringing persons into an austere laboratory environment and using photos, video, or paraphernalia to elicit reactions. While traditional approaches result in reactions, generalization of this type of cue exposure into treatment programs remains in question. Virtual reality exposure (VRE) combines computer graphics with sensory input devices including: tracking devices, visual head mounted displays (HMD), and directional audio designed to immerse a participant in a computer generated virtual environment. VRCE for drug addiction would combine the elements of VR with specific drug cues, environments, drug related social interactions, and other associated stimuli in the safe, confidential and controlled lab or office setting. VRCE combining video images and exposure to complex cues can expand traditional cueexposure (reactivity) approaches and offer distinct advantages over traditional approaches. This project will focus on the development of a VRCE combining both computer generated and video images depicting smoking cues (e.g. cigarette packages, ash trays, burning cigarette) and smoking social interactions (e.g. being offered a cigarette in a social context). The feasibility of VRCE will be tested in a clinical pilot study with cigarette smokers. Twenty nicotine dependent smokers will be exposed to both VR neutral stimuli and VR drug stimuli. Physiological arousal and self-reported craving will be compared between the VR neutral and VR drug stimuli. The aim of this project is to develop and pilot test VRCE for nicotine dependent cigarette smokers. The long-term goal is to develop and test the VRCE, and develop affordable turnkey, VRCE systems that will be commercially available to substance abuse programs, individual therapists, hospitals, and drug addiction researchers for nicotine and other drugs of abuse. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: VOCATIONAL TRAINING FOR DRUG DEPENDENT WOMEN Principal Investigator & Institution: Randall, Carrie L.; Professor; Medical University of South Carolina 171 Ashley Ave Charleston, Sc 29425 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-AUG-2007 Summary: (provided by applicant): Unemployment in individuals recovering from drug addiction may be a risk factor for relapse. Presumably, employment provides an individual with an activity that is inconsistent with drug use, increases financial independence, provides a source of social support unrelated to substance use, and improves self-esteem. These benefits may be especially helpful to women recovering from addiction, as often these women rely on financial support from either the government (welfare) or from a male partner who may not be supportive of her sobriety. The goal of the present proposal is to improve the employment status of women who are in addiction recovery. The project also seeks to examine the relationship between substance dependence and employment in women, an area that has been relatively unstudied. Two different vocational training programs will be compared. Women who have completed an intensive, outpatient, drug treatment program will be randomized to one of these two programs. One is a specialized, gender-

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specific, 12-week program called Innovative Alternatives for Women (IAW). The other approach is a gender-neutral, 4-session program called Job Seekers Workshop that teaches job-seeking skills and which may be more likely used within an addiction treatment program. Participants will be assessed at 2 months and 5 months following completion of the program to which they were randomized. Main outcome variables are (1) whether she is employed full time, (2) whether she is employed full time in a job that provides health benefits, and (3) percent days abstinent from substances of abuse. It is expected that IAW, because of its focus on issues relevant specifically to women, and because of its technical skills training, will be superior to JSVV in producing graduates who have better outcomes in all three domains. This study represents a first step toward addressing the relationship between employment and relapse in drug recovering women. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: VULNERABILITY INTERVENTIONS

TO

DRUG

ABUSE--EXPERIMENTAL

Principal Investigator & Institution: Carroll, Marilyn E.; Professor of Psychiatry and Neuroscience; Psychiatry; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2001; Project Start 01-JUL-1983; Project End 31-AUG-2006 Summary: (provided by applicant): The overall objective of this project is to study factors that predict vulnerability to drug addiction such as sex, hormonal status and prior experience with other addictive behaviors. This work is based on the hypothesis that nondrug substances and events such as preferred foods and exercise may act as rewards that are interchangeable with drugs, and individuals that show high levels of behavior maintained by nondrug events may be more susceptible than others to drug abuse. Sex and hormonal conditions are also important determinants of the rewarding effects of drugs and other substances. Several phases of the addiction process will be modeled: 1) acquisition/vulnerability, 2) maintenance (regulation/reinforcing efficacy progressive ratio schedule) and 3) reinstatement/relapse. Using these models, behavioral and pharmacological methods for preventing and treating drug abuse will also be tested. Rats will be prepared with indwelling venous catheters, and they will be trained to self-administer infusions of cocaine or heroin. To determine the effects of sex and hormonal status, males vs. females will be compared during the three phases. The effect of ovarian hormones will be examined by comparing intact female rats with and without ovariectomy (OVX) and with OVX and estrogen replacement with estradiol benzoate (EB). To determine whether individual differences in other addictive behavior predicts vulnerability to drug abuse, in Experiment 1 groups of rats will be screened for high or low levels of wheel running, sucrose intake other drug self-administration, and their rate and success of acquisition of drug self-administration, maintenance and reinstatement will be compared. Experiment 2 will compare rats that were selectively bred (in another laboratory) for sweet preference on acquisition, maintenance and reinstatement. Experiment 3 will focus on sex and hormonal differences in acquisition, maintenance and reinstatement. Experiment 4 will examine the effect of nondrug reinforcers (sucrose, wheel-running) as a treatment for drug abuse in males and females during the 3 phases of addiction, and Experiment 5 will follow a similar approach with males, females, the 3 phases of addiction using potential treatment medications, baclofen (a GABAB agonist) and bremazocine, (a kappa opioid receptor agonist). It is hoped that the outcome of these experiments will identify vulnerability factors that have not yet been adequately considered, compare those factors at various phases of

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addiction, and compare behavioral and pharmacological treatments in groups varying in vulnerability to provide useful information on treatment approaches that selectively reduce drug-seeking behavior. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: VULNERABILITY TO THE REINFORCING EFFECTS OF OPIOIDS Principal Investigator & Institution: Morgan, Drake; Physiology and Pharmacology; Wake Forest University Health Sciences Winston-Salem, Nc 27157 Timing: Fiscal Year 2001; Project Start 01-APR-2001; Project End 31-MAR-2006 Summary: (provided by applicant) Current estimates suggest that there are 600,000 people in need of treatment for heroin addiction. Unfortunately, there is very little scientific data regarding vulnerability to heroin abuse. This makes it extraordinarily difficult to study the biological substrates responsible for the findings that some people exposed to heroin progress to a compulsive and uncontrolled use of the drug, whereas others use heroin several times, and then stop using it. This question is impossible to experimentally evaluate in humans because of the obvious ethical issues involved in exposing drug-naive people to heroin. If animal models are to be used to understand this phenomenon, then appropriate self-administration methods that allow for a differential sensitivity to be expressed need to be developed. Furthermore, if a procedure that screens for this eventual "vulnerability" was used, then biological studies can be conducted in essentially drug-naive animals, allowing the determination of the mechanisms that produce this differential reaction to drugs of abuse. This proposal is designed to investigate the relationship between sensitivity to the analgesic effects of opioids and various measures of the reinforcing effects of opioids (primarily heroin). Once this relationship is established, animals can be screened for "vulnerability" to drug addiction, and extensive neurobiological and biochemical analyses can be conducted in drug-naive animals. In particular, the following questions will be answered over the course of this award: 1. What is the relationship between sensitivity to the analgesic effects and the reinforcing effects of opioids? 2. What are the differences in the localization, characteristics, or coupling efficiency of the opioid system across subgroups (i.e. "vulnerable" or "resistant") of animals? 3. What are the differences in the expression of various genetic markers and proteins in the brain pathways relevant to opioid reinforcement across these subgroups of animals? This series of experiments will provide extensive training for the candidate in the neurobiology and biochemistry of drug abuse, to complement the behavioral background already established. In the end, this research will identify neurobiological, biochemical and genetic determinants of susceptibility to heroin use. An improved understanding of the individual risk of drug addiction will lead to the development of better prevention and treatment strategies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

E-Journals: PubMed Central3 PubMed Central (PMC) is a digital archive of life sciences journal literature developed and managed by the National Center for Biotechnology Information (NCBI) at the U.S. National

3

Adapted from the National Library of Medicine: http://www.pubmedcentral.nih.gov/about/intro.html.

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Library of Medicine (NLM).4 Access to this growing archive of e-journals is free and unrestricted.5 To search, go to http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Pmc, and type “drug addiction” (or synonyms) into the search box. This search gives you access to full-text articles. The following is a sample of items found for drug addiction in the PubMed Central database: •

D is for drug addiction --- and disability. by Berger PB.; 2001 May 29; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=81106

The National Library of Medicine: PubMed One of the quickest and most comprehensive ways to find academic studies in both English and other languages is to use PubMed, maintained by the National Library of Medicine.6 The advantage of PubMed over previously mentioned sources is that it covers a greater number of domestic and foreign references. It is also free to use. If the publisher has a Web site that offers full text of its journals, PubMed will provide links to that site, as well as to sites offering other related data. User registration, a subscription fee, or some other type of fee may be required to access the full text of articles in some journals. To generate your own bibliography of studies dealing with drug addiction, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “drug addiction” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for drug addiction (hyperlinks lead to article summaries): •

A behavioral/systems approach to the neuroscience of drug addiction. Author(s): White FJ. Source: The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. 2002 May 1; 22(9): 3303-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11978803&dopt=Abstract

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A behaviorally-oriented treatment program for drug addiction: a preliminary report. Author(s): Copemann CD, Shaw PL. Source: American Journal of Public Health. 1976 March; 66(3): 286-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1259066&dopt=Abstract

4

With PubMed Central, NCBI is taking the lead in preservation and maintenance of open access to electronic literature, just as NLM has done for decades with printed biomedical literature. PubMed Central aims to become a world-class library of the digital age. 5 The value of PubMed Central, in addition to its role as an archive, lies in the availability of data from diverse sources stored in a common format in a single repository. Many journals already have online publishing operations, and there is a growing tendency to publish material online only, to the exclusion of print. 6 PubMed was developed by the National Center for Biotechnology Information (NCBI) at the National Library of Medicine (NLM) at the National Institutes of Health (NIH). The PubMed database was developed in conjunction with publishers of biomedical literature as a search tool for accessing literature citations and linking to full-text journal articles at Web sites of participating publishers. Publishers that participate in PubMed supply NLM with their citations electronically prior to or at the time of publication.

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A case history of drug addiction and a T.L.C. system for the separation and identification of some drugs of addiction in sub-microgramme amounts. Author(s): Harrison AJ, Cook A. Source: J Forensic Sci Soc. 1969 December; 9(3): 165-7. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=5383496&dopt=Abstract

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A conceptual framework for explaining drug addiction. Author(s): Heather N. Source: Journal of Psychopharmacology (Oxford, England). 1998; 12(1): 3-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9584962&dopt=Abstract

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A lawyer's view of the alcoholism and Drug Addiction Act 1966. Author(s): Williams DA. Source: N Z Med J. 1969 January; 69(440): 1-4. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=5250390&dopt=Abstract

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A neurochemical basis for alcohol and other drug addiction. Author(s): Miller NS, Gold MS. Source: J Psychoactive Drugs. 1993 April-June; 25(2): 121-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8377079&dopt=Abstract

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A new program to combat drug addiction in New York City. Author(s): Ramirez E. Source: The British Journal of Addiction to Alcohol and Other Drugs. 1968 September; 63(1): 89-103. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=5245951&dopt=Abstract

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A placental evaluation of drug addiction in pregnancy. Author(s): Freese UE. Source: J Reprod Med. 1978 June; 20(6): 307-15. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=671410&dopt=Abstract

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A psychoanalytical theory of 'drug addiction': unconscious fantasies of homosexuality, compulsions and masturbation within the context of traumatogenic processes. Author(s): Hopper E. Source: The International Journal of Psycho-Analysis. 1995 December; 76 ( Pt 6): 1121-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8789164&dopt=Abstract

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A psychologist's approach to drug addiction. Author(s): Kaldegg A. Source: The British Journal of Addiction to Alcohol and Other Drugs. 1968 September; 63(1): 71-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=5245947&dopt=Abstract

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A solid front: unity, timing, goal oriented counseling break drug addiction cycle. Author(s): Westman WC. Source: Journal of Rehabilitation. 1974 May-June; 40(3): 15-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4449107&dopt=Abstract

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A study of drug addiction at the Eastern District Hospital, Glasgow. Author(s): Bennie EH. Source: The British Journal of Addiction to Alcohol and Other Drugs. 1970 December; 65(4): 341-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=5280065&dopt=Abstract

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A study of the relationship between child abuse and drug addiction in 178 patients: preliminary results. Author(s): Cohen FS, Densen-Gerber J. Source: Child Abuse & Neglect. 1982; 6(4): 383-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6892324&dopt=Abstract

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A therapeutic framework of drug addiction. Author(s): Mayer J, Samaraweera AB, Myerson DJ. Source: The International Journal of Social Psychiatry. 1972 Summer; 18(2): 114-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4650916&dopt=Abstract

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A token economy treatment of drug addiction. Author(s): Eriksson JH, Gotestam KG, Melin L, Ost LG. Source: Behaviour Research and Therapy. 1975 June; 13(2-3): 113-25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1164366&dopt=Abstract

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ABC of drug addiction. Author(s): Tylden E. Source: Community Health (Bristol). 1969 September-October; 1(2): 68-83. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=5406785&dopt=Abstract

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Abdominal complications of drug addiction: radiologic features. Author(s): Balthazar EJ, Lefleur R. Source: Semin Roentgenol. 1983 July; 18(3): 213-20. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6137065&dopt=Abstract

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Abdominal pain and drug addiction. Author(s): Stuebe D. Source: Aust Fam Physician. 1999 January; 28(1): 15. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9988907&dopt=Abstract

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Accepting drug addiction in America. Author(s): Cimons M. Source: Nature Medicine. 1998 January; 4(1): 8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9427588&dopt=Abstract

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Accidental intra-arterial injection of amphetamine: an unusual hazard of drug addiction. Case report. Author(s): Birkhahn HJ, Heifetz M. Source: British Journal of Anaesthesia. 1973 July; 45(7): 761-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4730172&dopt=Abstract

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Acute poisonings in the course of drug addiction: chemicotoxicological diagnostics. Author(s): Wiernikowski A, Soltycka M, Kosecka-Grzybek E, Groszek B, Brodkiewicz A. Source: Przegl Lek. 1996; 53(4): 334-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8711186&dopt=Abstract

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Adaptive modulations of brain membrane lipid fluidity in drug addiction and denervation supersensitivity. Author(s): Heron DS, Shinitzky M, Zamir N, Samuel D. Source: Biochemical Pharmacology. 1982 July 15; 31(14): 2435-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6889866&dopt=Abstract

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Addiction and the laboratory. The work of the National Research Council's Committee on Drug Addiction, 1928-1939. Author(s): Acker CJ. Source: Isis; an International Review Devoted to the History of Science and Its Cultural Influences. 1995 June; 86(2): 167-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7558752&dopt=Abstract

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Advances in the treatment of drug addiction. Author(s): Wilson CW. Source: The Practitioner. 1972 October; 209(252): 536-43. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4562348&dopt=Abstract

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AIDS and drug addiction needle exchange schemes. Author(s): Loza N. Source: Journal of the Royal Society of Medicine. 1989 February; 82(2): 123. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2926760&dopt=Abstract

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AIDS and drug addiction needle exchange schemes: a step in the dark. Author(s): Farid BT. Source: Journal of the Royal Society of Medicine. 1988 July; 81(7): 375-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3411582&dopt=Abstract

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Alcohol and drug addiction in northern Nigeria. Author(s): Ifabumuyi OI. Source: Acta Psychiatrica Scandinavica. 1986 May; 73(5): 479-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3751654&dopt=Abstract

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Alcohol use following treatment for drug addiction. A four-year follow-up. Author(s): Simpson DD, Lloyd MR. Source: J Stud Alcohol. 1981 March; 42(3): 323-35. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7278276&dopt=Abstract

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Alcoholism and drug addiction in the 'nineties: an American in London. Author(s): Crellin JK. Source: British Journal of Addiction. 1980 June; 75(2): 153-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6992820&dopt=Abstract

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Alcoholism And Drug Addiction Research Foundation of Ontario: research goals and plans. Author(s): Rankin JG. Source: Annals of the New York Academy of Sciences. 1976; 273: 87-97. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1072406&dopt=Abstract

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Alcoholism and drug addiction. Author(s): David M. Source: N Z Nurs J. 1968 February; 61(2): 5-6. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=5238553&dopt=Abstract

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Alcoholism, drug abuse and drug addiction: a study of nursing education. Author(s): Burkhalter P. Source: The Journal of Nursing Education. 1975 April; 14(2): 30-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=236362&dopt=Abstract

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Alcoholism, drug addiction, and mental illness: the use of rehabilitative remedies in arbitration. Author(s): Marmo M. Source: Labor Law Journal. 1981 August; 32(8): 491-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10317130&dopt=Abstract

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An ethopharmacological approach to the development of drug addiction. Author(s): Wolffgramm J. Source: Neuroscience and Biobehavioral Reviews. 1991 Winter; 15(4): 515-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1792014&dopt=Abstract

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Anger and drug addiction. Author(s): De Moja CA, Spielberger CD. Source: Psychological Reports. 1997 August; 81(1): 152-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9293203&dopt=Abstract

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Anthropological research. Its relevance to the treatment of alcoholism and drug addiction. Author(s): Strug DL. Source: J Stud Alcohol. 1981 September; 42(9): 819-21. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7311544&dopt=Abstract

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Applying laboratory research: drug anticipation and the treatment of drug addiction. Author(s): Siegel S, Ramos BM. Source: Experimental and Clinical Psychopharmacology. 2002 August; 10(3): 162-83. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12233979&dopt=Abstract

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Are we winning the war against drug addiction? Author(s): Klumpp TG. Source: Med Times. 1974 September; 102(9): 39-46. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4850632&dopt=Abstract

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Assessment of drug addiction. The experience of the Medico Legal Institute of Oporto. Author(s): da Costa JP, de Sousa MJ, Magalhaes T, Ribeiro C, Grams AC, Ramon J, Rangel R. Source: Med Law. 2000; 19(2): 309-19. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10994216&dopt=Abstract

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Attitudes toward death and dying on a drug addiction unit. Author(s): Gertler R, Ferneau E, Raynes A. Source: Int J Addict. 1973; 8(2): 265-72. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4753823&dopt=Abstract

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Bacterial resistance due to antimicrobial drug addiction among physicians. Time for a cure! Author(s): Abramson JS, Givner LB. Source: Archives of Family Medicine. 1999 January-February; 8(1): 79-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9932076&dopt=Abstract

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Beating abuse. Glutamate may hold a key to drug addiction. Author(s): Powledge TM. Source: Scientific American. 2002 January; 286(1): 20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11799610&dopt=Abstract

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Behavioral health issue brief: co-occurring mental illness and drug addiction treatment: overview and bibliography: year end report - 2002. Author(s): Colker AC, Crean E. Source: Issue Brief Health Policy Track Serv. 2002 December 31; : 1-10. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12809142&dopt=Abstract

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Behavioral health issue brief: pharmacotherapy treatment of alcoholism and drug addiction: overview and bibliography: year end report-2002. Author(s): Colker AC. Source: Issue Brief Health Policy Track Serv. 2002 December 31; : 1-6. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12875273&dopt=Abstract

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Behavioral treatment of drug addiction: a review and analysis. Author(s): Droppa DC. Source: Int J Addict. 1973; 8(1): 143-61. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4576684&dopt=Abstract

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Bio-clinical prevalence or non-prevalence of drug addiction over psychiatric symptomatology. Author(s): Macher JP, Crocq MA, Duval F, Minot R, Rogue P, Koehl C, Hirth C, Gindein J, Fleck F. Source: Med Law. 1992; 11(1-2): 11-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1522768&dopt=Abstract

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Biofeedback application to drug addiction in the University of Colorado drug rehabilitation program. Author(s): Brinkman DN. Source: Int J Addict. 1978 July; 13(5): 817-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=363627&dopt=Abstract

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Body image and drug addiction. Author(s): Gainotti MA. Source: Percept Mot Skills. 1999 February; 88(1): 21-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10214628&dopt=Abstract

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Bone scintigraphy in drug addiction. Author(s): Lopez-Majano V, Miskew D, Sansi P. Source: European Journal of Nuclear Medicine. 1981 January; 6(1): 17-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7202420&dopt=Abstract

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Brain regions and drug addiction. Author(s): Harlan RE, Garcia MM. Source: Science. 1999 May 14; 284(5417): 1124-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10366343&dopt=Abstract

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Bridging the Gap: addressing alcohol and drug addiction from a community health perspective. Author(s): Turner NH. Source: American Journal of Public Health. 1995 June; 85(6): 870-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7762730&dopt=Abstract

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Can alcoholism and other drug addiction problems be treated away or is the current treatment binge doing more harm than good? Author(s): Peele S. Source: J Psychoactive Drugs. 1988 October-December; 20(4): 375-83. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3244058&dopt=Abstract

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Candida albicans spondylodiscitis and vertebral osteomyelitis in patients with intravenous heroin drug addiction. Report of 3 new cases. Author(s): Lafont A, Olive A, Gelman M, Roca-Burniols J, Cots R, Carbonell J. Source: The Journal of Rheumatology. 1994 May; 21(5): 953-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8064741&dopt=Abstract

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Cardiac glycoside toxicity. An unusual manifestation of drug addiction. Author(s): Kennedy M. Source: The Medical Journal of Australia. 1981 December 12-26; 2(12-13): 686, 688-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7199612&dopt=Abstract

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Case studies in bioethics. Drug treatment or drug addiction? Can a physician differentiate between a true sickle cell crisis and iatrogenic aroctic addiction? Author(s): Murray RF Jr, Soble A. Source: The Hastings Center Report. 1974 June; 4(3): 10-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4457502&dopt=Abstract

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Case studies: profiles of women recovering from drug addiction. Author(s): Miller SM. Source: Journal of Drug Education. 1995; 25(2): 139-48. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7658294&dopt=Abstract

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Cellular mechanisms of striatum-dependent behavioral plasticity and drug addiction. Author(s): Fasano S, Brambilla R. Source: Current Molecular Medicine. 2002 November; 2(7): 649-65. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12420804&dopt=Abstract

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Centres for treatment of drug addiction. Advantages of special centres. Author(s): Bewley TH. Source: British Medical Journal. 1967 May 20; 2(550): 498-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6023971&dopt=Abstract

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Centres for treatment of drug addiction. Importance of research. Author(s): Connell PH. Source: British Medical Journal. 1967 May 20; 2(550): 499-500. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6023972&dopt=Abstract

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Centres for treatment of drug addiction. Integrated approach. Author(s): Owens J. Source: British Medical Journal. 1967 May 20; 2(550): 501-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6023974&dopt=Abstract

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Centres for treatment of drug addiction. Treatment in the community. Author(s): Chapple PA. Source: British Medical Journal. 1967 May 20; 2(550): 500-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6023973&dopt=Abstract

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Characteristics of a population undergoing treatment for drug addiction in a therapeutic community setting in Spain. Author(s): Hinojal Fonseca R, Martinez JJ, Rodriguez-Hevia AJ. Source: Bull Narc. 1988; 40(1): 67-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3219457&dopt=Abstract

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Chemical dependency treatment: the integration of the alcoholism and drug addiction/use treatment systems. Author(s): Rawson RA. Source: Int J Addict. 1990-91; 25(12A): 1515-36. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1966837&dopt=Abstract

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Chronic depression and drug addiction treated by stereotactic surgery. Author(s): Knight G. Source: Nurs Times. 1969 May 8; 65(19): 583-6. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4888937&dopt=Abstract

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Circuits, drugs, and drug addiction. Author(s): Koob GF. Source: Adv Pharmacol. 1998; 42: 978-82. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9328061&dopt=Abstract

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Clinical aspects of drug addiction. Author(s): Connell PH. Source: Journal of the Royal College of Physicians of London. 1970 April; 4(3): 254-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4939972&dopt=Abstract

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Clinical impact of drug addiction in alcoholics. Author(s): Jiang JJ, Dubois F, Driss F, Carnot F, Thepot V, Pol S, Berthelot P, Brechot C, Nalpas B. Source: Alcohol and Alcoholism (Oxford, Oxfordshire). 1995 January; 30(1): 55-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7538299&dopt=Abstract

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Comparison of clients assigned to in-patient and out-patient treatment for alcoholism and drug addiction. Author(s): Skinner HA. Source: The British Journal of Psychiatry; the Journal of Mental Science. 1981 April; 138: 312-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7272632&dopt=Abstract

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Complementary therapy to fight drug addiction. Author(s): Southall D. Source: Nurs Times. 1997 August 13-19; 93(33): 48-9. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9335881&dopt=Abstract

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Compulsory education: a cause of drug addiction. Author(s): Berger H. Source: Med Times. 1969 December; 97(12): 178-82. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=5366133&dopt=Abstract

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Conference to look at ways of using scarce skills to combat drug addiction. Author(s): Chudley P. Source: Nursing Standard : Official Newspaper of the Royal College of Nursing. 1984 August 23; (361): 12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6566004&dopt=Abstract

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Correlation between disease and community: is drug addiction a problem of fringe groups? Author(s): Baumgarten R. Source: Forensic Science International. 1993 November; 62(1-2): 67-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8300037&dopt=Abstract

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Current thoughts about the mechanism of drug addiction and the possibility of development of new drugs in its treatment. Author(s): De DP. Source: J Indian Med Assoc. 1994 July; 92(7): 239-40. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7963608&dopt=Abstract

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Cusp and butterfly catastrophe modeling of two opponent process models: drug addiction and work performance. Author(s): Guastello SJ. Source: Behavioral Science. 1984 October; 29(4): 258-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6517835&dopt=Abstract

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Cutaneous stigmata of drug addiction. Author(s): Fellner MJ, Weinstein LH. Source: International Journal of Dermatology. 1979 May; 18(4): 305-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=457326&dopt=Abstract

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Death caused by drug addiction: a review of the experiences in Hamburg and the situation in the Federal Republic of Germany in comparison with the literature. Author(s): Janssen W, Trubner K, Puschel K. Source: Forensic Science International. 1989 December; 43(3): 223-37. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2693287&dopt=Abstract

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Depression and drug addiction. Author(s): Robbins PR. Source: The Psychiatric Quarterly. 1974; 48(3): 374-86. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4156882&dopt=Abstract

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Drug addiction among physicians. Author(s): Berman JI. Source: Jama : the Journal of the American Medical Association. 1977 March 14; 237(11): 1076. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=576433&dopt=Abstract

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Drug addiction among physicians. The Virginia experience. Author(s): Green RC Jr, Carroll GJ, Buxton WD. Source: Jama : the Journal of the American Medical Association. 1976 September 20; 236(12): 1372-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=989093&dopt=Abstract

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Drug addiction and AIDS in France in 1987. Author(s): Olievenstein C. Source: Nida Res Monogr. 1988; 80: 114-8. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3136337&dopt=Abstract

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Drug addiction and AIDS. Author(s): Cargnel A, Orlando G, Zehender G, Zanetti AR. Source: Antibiot Chemother. 1991; 43: 45-54. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1883224&dopt=Abstract

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Drug addiction and AIDS: highlights of the 1st European Congress. Author(s): Loimer N. Source: Aids Care. 1992; 4(1): 111-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1348632&dopt=Abstract

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Drug addiction and crime. Author(s): Hammersley R. Source: British Journal of Addiction. 1988 April; 83(4): 445-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3395727&dopt=Abstract

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Drug addiction and drug abuse in Korea. Author(s): Myung CW. Source: Med J Malaysia. 1974 December; 29(2): 135-6. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4282401&dopt=Abstract

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Drug addiction and fear of AIDS. Author(s): Pristera R, Casini M, Perino F, Degiorgis A. Source: Lancet. 1987 January 17; 1(8525): 160. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2879993&dopt=Abstract

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Drug addiction and mother/child welfare. Rights, laws, and discretionary decisionmaking. Author(s): Garcia SA. Source: The Journal of Legal Medicine. 1992 June; 13(2): 129-203. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1640162&dopt=Abstract

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Drug addiction and parental rearing style: a controlled study. Author(s): Emmelkamp PM, Heeres H. Source: Int J Addict. 1988 February; 23(2): 207-16. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3366496&dopt=Abstract

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Drug addiction and pregnancy: a different perspective. Author(s): Custo GM, Saitto C, Minozzi M. Source: Acta Eur Fertil. 1988 March-April; 19(2): 105-6. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3223193&dopt=Abstract

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Drug addiction and pregnancy: policy crossroads. Author(s): Chavkin W. Source: American Journal of Public Health. 1990 April; 80(4): 483-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2180329&dopt=Abstract

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Drug addiction and viral hepatitis in the dental patient. Studies on various aspects of providing dental care for drug addicts and their consequences for patients and dental personnel. Author(s): Scheutz F. Source: Dan Med Bull. 1986 October; 33(5): 228-49. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3536337&dopt=Abstract

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Drug addiction in America: challenges and opportunities. Author(s): Koop CE. Source: Military Medicine. 2003 May; 168(5): Viii-Xvi. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12775166&dopt=Abstract

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Drug addiction in Poland and criminalistic traces. Author(s): Kala M, Borkowski T. Source: Forensic Science International. 1990 May-June; 46(1-2): 129-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2210540&dopt=Abstract

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Drug addiction in pregnancy and the neonate. Author(s): Blinick G, Wallach RC, Jerez E, Ackerman BD. Source: American Journal of Obstetrics and Gynecology. 1976 May 15; 125(2): 135-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1266895&dopt=Abstract

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Drug addiction in pregnancy. Author(s): Fraser AC. Source: Lancet. 1976 October 23; 2(7991): 896-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=62125&dopt=Abstract

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Drug addiction in pregnancy: the interface of science, emotion, and social policy. Author(s): Harrison M. Source: Journal of Substance Abuse Treatment. 1991; 8(4): 261-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1787551&dopt=Abstract

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Drug addiction in the Federal Republic of Germany: problems and responses. Author(s): Wille R. Source: British Journal of Addiction. 1987 August; 82(8): 849-56. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3479169&dopt=Abstract

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Drug addiction of health professionals. Author(s): Canfield TM. Source: Aorn Journal. 1976 October; 24(4): 665-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1049523&dopt=Abstract

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Drug addiction, pregnancy, and childbirth: legal issues for the medical and social services communities. Author(s): Connolly WB Jr, Marshall AB. Source: Clin Perinatol. 1991 March; 18(1): 147-86. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2040115&dopt=Abstract

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Drug addiction, relapse, and the amygdala. Author(s): See RE, Fuchs RA, Ledford CC, McLaughlin J. Source: Annals of the New York Academy of Sciences. 2003 April; 985: 294-307. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12724166&dopt=Abstract

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Drug addiction. Author(s): Boyd P. Source: Midwife Health Visit Community Nurse. 1976 December; 12(12): 390-4. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1050631&dopt=Abstract

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Drug addiction. Author(s): Cami J, Farre M. Source: The New England Journal of Medicine. 2003 September 4; 349(10): 975-86. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12954747&dopt=Abstract

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Drug addiction. Author(s): Sandosham AA. Source: Med J Malaysia. 1976 June; 30(4): 249. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=979723&dopt=Abstract

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Drug addiction: causes and prevention. Author(s): Bhatia MS. Source: The Nursing Journal of India. 1988 December; 79(12): 330-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3241748&dopt=Abstract

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Drug addiction: helping to make the break. Author(s): Briggs L, Deering D. Source: N Z Nurs J. 1986 December; 79(12): 18-9. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3468441&dopt=Abstract

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Drug addiction: I. A theoretical framework for behavior therapy. Author(s): Copemann CD. Source: Psychological Reports. 1975 December; 37(3 Pt 1): 947-58. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=704&dopt=Abstract

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Drug addiction: II. an aversive counterconditioning technique for treatment. Author(s): Copemann CD. Source: Psychological Reports. 1976 June; 38(3 Pt 2): 1271-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=778888&dopt=Abstract

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Drug addiction: its effects on mother and baby. Author(s): Lindo M. Source: Midwifery. 1987 June; 3(2): 82-91. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3302618&dopt=Abstract

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Drug addiction: stars fall. Author(s): Potts SG, Glatt MM. Source: Lancet. 1990 December 1; 336(8727): 1385. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1978196&dopt=Abstract

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Drug addiction--current trends. Author(s): Low Wah Yun, Yusof K. Source: Med J Malaysia. 1988 March; 43(1): 34-9. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3244317&dopt=Abstract

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Drug addiction--myth or reality? Author(s): Schlicht J. Source: Public Health. 1973 September; 87(6): 249-56. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4787976&dopt=Abstract

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Drug addicts attending specialised institutions: towards a drug addiction data bank? Author(s): Facy F, Rosch D, Angel P, Touzeau D, Cordonnier JP, Petit F. Source: Drug and Alcohol Dependence. 1991 January; 27(1): 43-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2029859&dopt=Abstract

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Dual diagnoses: psychiatric syndromes in alcoholism and drug addiction. Author(s): Miller NS, Gold MS. Source: American Family Physician. 1991 June; 43(6): 2071-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2042549&dopt=Abstract

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Economic impact of drug addiction. Author(s): Wilson OW. Source: Imj Ill Med J. 1966 October; 130(4): 522-3. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4380658&dopt=Abstract

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Editorial: Personality and social factors in drug addiction. Author(s): Carstairs GM. Source: J Med Liban. 1972; 25(5): 409-14. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4669962&dopt=Abstract

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Editorial: Problem of drug addiction in Lebanon. Author(s): Puzantian VR. Source: J Med Liban. 1973; 26(3): 211-3. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4759644&dopt=Abstract

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Educating educators about alcoholism and drug addiction: the role of employee assistance programmes. Author(s): Van den Bergh N. Source: Med Law. 1990; 9(1): 713-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2118214&dopt=Abstract

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Effect of chronic maternal drug addiction on placental drug metabolism. Author(s): Ostrea EM Jr, Porter T, Balun J, Wardell JN, Bottoms S. Source: Dev Pharmacol Ther. 1989; 12(1): 42-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2721332&dopt=Abstract

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Effects of maternal drug addiction on the fetus. Author(s): Gilbody JS. Source: Adverse Drug Reactions and Toxicological Reviews. 1991 Summer; 10(2): 77-88. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1932463&dopt=Abstract

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Effects of neuro-electric therapy (N.E.T.) in drug addiction: interim report. Author(s): Patterson MA. Source: Bull Narc. 1976 October-December; 28(4): 55-62. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1087892&dopt=Abstract

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Efforts to reduce perinatal mortality, HIV, and drug addiction: surveys of the states. Author(s): Chavkin W, Breitbart V, Wise P. Source: J Am Med Womens Assoc. 1995 September-October; 50(5): 164-6. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7499705&dopt=Abstract

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Endocrine complications of AIDS and drug addiction. Author(s): Brown LS Jr, Singer F, Killian P. Source: Endocrinology and Metabolism Clinics of North America. 1991 September; 20(3): 655-73. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1935923&dopt=Abstract

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Enkephalin, drug addiction and acupuncture. Author(s): Chen GS. Source: The American Journal of Chinese Medicine. 1977 Spring; 5(1): 25-30. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=15449&dopt=Abstract

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Environmental theory of drug addiction. Author(s): DeFeudis FV. Source: General Pharmacology. 1978; 9(5): 303-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=359405&dopt=Abstract

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Epidemiological studies of female prisoners. II: Biological, psychological, and social correlates of drug addiction. Author(s): Climent CE, Raynes A, Rollins A, Plutchik R. Source: Int J Addict. 1974; 9(2): 345-50. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4430527&dopt=Abstract

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Establishment of a new drug addiction program. Author(s): McIsaac WM. Source: Psychopharmacology Bulletin. 1966 December; 3(4): 40-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=5981122&dopt=Abstract

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Ethical and legal dilemmas of Jerusalem treatment model for drug addiction. Author(s): Fish N, Shufman E, Barel Y. Source: International Journal of Law and Psychiatry. 1990; 13(1-2): 155-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2210929&dopt=Abstract

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Excision of tricuspid valve with later replacement in endocarditis of drug addiction. Author(s): Wright JS, Glennie JS. Source: Thorax. 1978 August; 33(4): 518-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=694808&dopt=Abstract

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Experience in the treatment of drug addiction by electro-acupuncture. Author(s): Wen HL, Teo SW. Source: Xianggang Hu Li Za Zhi. 1975 November; 19: 33-5. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1082838&dopt=Abstract

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Factors in the development of drug addiction. Author(s): Boehm H, Amboy P. Source: J Med Soc N J. 1973 January; 70(1): 23-6. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4509780&dopt=Abstract

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Fatal outcome in drug addiction. Author(s): Tunving K. Source: Acta Psychiatrica Scandinavica. 1988 May; 77(5): 551-66. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3407425&dopt=Abstract

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Feigning dystonia to feed an unusual drug addiction. Author(s): Dooris B, Reid C. Source: Journal of Accident & Emergency Medicine. 2000 July; 17(4): 311. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10921835&dopt=Abstract

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Fight to develop drug addiction therapy. Author(s): Birmingham K. Source: Nature Medicine. 1998 April; 4(4): 377. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9546770&dopt=Abstract

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Fungal endocarditis secondary to drug addiction. Recent concepts in diagnosis and therapy. Author(s): Harris PD, Yeoh CB, Breault J, Meltzer J, Katz S. Source: The Journal of Thoracic and Cardiovascular Surgery. 1972 June; 63(6): 980-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=5028688&dopt=Abstract

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GABA(B) receptor agonists for the treatment of drug addiction: a review of recent findings. Author(s): Cousins MS, Roberts DC, de Wit H. Source: Drug and Alcohol Dependence. 2002 February 1; 65(3): 209-20. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11841892&dopt=Abstract

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Gender differences in drug addiction and treatment: implications for social work intervention with substance-abusing women. Author(s): Nelson-Zlupko L, Kauffman E, Dore MM. Source: Social Work. 1995 January; 40(1): 45-54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7863372&dopt=Abstract

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Harm-reduction strategies weapon of choice in BC's battle with drug addiction. Author(s): Kent H. Source: Cmaj : Canadian Medical Association Journal = Journal De L'association Medicale Canadienne. 1996 September 1; 155(5): 571-3. Erratum In: Can Med Assoc J 1996 November 1; 155(9): 1239. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8804264&dopt=Abstract

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Head nurse on a drug addiction ward. Author(s): Bell M. Source: J Psychiatr Nurs. 1966 November-December; 4(6): 546-62. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4288446&dopt=Abstract

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Health education and drug addiction. Author(s): Pintaud CM. Source: Hygie. 1988 March; 7(1): 3-4. English, French. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3371993&dopt=Abstract

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Health insurance for drug addiction: a survey. Author(s): Muller C. Source: The American Journal of Psychiatry. 1972 June; 128(12): 1516-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=5025272&dopt=Abstract

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Here's how we can prevent drug addiction. Author(s): Berger H. Source: Med Times. 1972 March; 100(3): 156 Passim. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=5042581&dopt=Abstract

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How permanent was Vietnam drug addiction? Author(s): Robins LN, Davis DH, Nurco DN. Source: American Journal of Public Health. 1974 December; 64 Suppl(0): 38-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4429174&dopt=Abstract

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Human immunodeficiency virus-associated autonomic neuropathy, drug addiction, and zidovudine treatment. Author(s): Confalonieri F, Villa A. Source: Archives of Internal Medicine. 1993 February 8; 153(3): 400-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8427545&dopt=Abstract

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I have HIV. My #1 disease is drug addiction. Author(s): Fadden J. Source: Women Alive. 2001 Spring; : 12. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11682999&dopt=Abstract

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Imaging opiate receptors in the human brain with positron emission tomography. Potential applications for drug addiction research. Author(s): Sadzot B, Mayberg HS, Frost JJ. Source: Acta Psychiatr Belg. 1990 January-February; 90(1): 9-19. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1670391&dopt=Abstract

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Imaging the roles of the amygdala in drug addiction. Author(s): Kilts CD. Source: Psychopharmacology Bulletin. 2001 Winter; 35(1): 84-94. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12397873&dopt=Abstract

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Immunologic studies on drug addiction. I. Antibodies reactive with methadone and their use for detection of the drug. Author(s): Liu CT, Adler FL. Source: Journal of Immunology (Baltimore, Md. : 1950). 1973 August; 111(2): 472-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4197985&dopt=Abstract

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Immunologic studies on drug addiction: II. Specificity and application of antibodies reactive with methadone. Author(s): De Cato L Jr, Liu C, Adler FL. Source: Clinical Immunology and Immunopathology. 1978 March; 9(3): 293-300. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=414872&dopt=Abstract

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Immunologic studies on drug addiction: III. Antibodies reactive with cocaine metabolites and their use for drug detection. Author(s): Decato L Jr, Liu CT, Adler FL. Source: Journal of Immunological Methods. 1977; 18(3-4): 201-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=412898&dopt=Abstract

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Infected venous pseudoaneurysm. A complication of drug addiction. Author(s): Johnson JE, Lucas CE, Ledgerwood AM, Jacobs LA. Source: Archives of Surgery (Chicago, Ill. : 1960). 1984 September; 119(9): 1097-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6477120&dopt=Abstract

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Influence of stereotactic hypothalamotomy on alcohol and drug addiction. Author(s): Dieckmann G, Schneider H. Source: Appl Neurophysiol. 1978; 41(1-4): 93-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=365104&dopt=Abstract

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Interactions between dopamine and 5-HT3 receptors suggest new treatments for psychosis and drug addiction. Author(s): Tricklebank MD. Source: Trends in Pharmacological Sciences. 1989 April; 10(4): 127-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2665244&dopt=Abstract

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Intra-arterial injections of oral medications. A complication of drug addiction. Author(s): Lindell TD, Porter JM, Langston C. Source: The New England Journal of Medicine. 1972 November 30; 287(22): 1132-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=5082194&dopt=Abstract

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Intravenous drug addiction--staphylococcal septicemia--pulmonary embolism: a triad pathognomonic for tricuspid valve endocarditis? Author(s): Julander I, Arneborn P, Back E, Hoglund C, Svanbom M. Source: Scandinavian Journal of Infectious Diseases. 1983; 15(3): 257-65. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6648371&dopt=Abstract

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Juvenile drug addiction: a typology of heroin addicts and their families. Author(s): Cancrini L, Cingolani S, Compagnoni F, Costantini D, Mazzoni S. Source: Family Process. 1988 September; 27(3): 261-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3224697&dopt=Abstract

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Kuwait drug addiction scene: a changing pattern? Author(s): Bilal AM. Source: Int J Addict. 1989 December; 24(12): 1137-44. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2576755&dopt=Abstract

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Laboratory investigation of drug addiction. Author(s): Marks V. Source: The British Journal of Addiction to Alcohol and Other Drugs. 1966 August; 61(3): 291-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=5231640&dopt=Abstract

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Lack of association between parental alcohol or drug addiction and behavioral inhibition in children. Author(s): Biederman J, Hirshfeld-Becker DR, Rosenbaum JF, Perenick SG, Wood J, Faraone SV. Source: The American Journal of Psychiatry. 2001 October; 158(10): 1731-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11579013&dopt=Abstract

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Learning and homeostasis: drug addiction and the McCollough effect. Author(s): Siegel S, Allan LG. Source: Psychological Bulletin. 1998 September; 124(2): 230-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9747187&dopt=Abstract

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Legal and medical problems of drug addiction facing jurists and experts in forensic medicine. Author(s): Szendrenyi J, Kosa F, Dobranovics I. Source: Acta Med Leg Soc (Liege). 1986; 36(2): 301-4. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2979387&dopt=Abstract

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Letter: Acupuncture for drug addiction. Author(s): Tseung YK. Source: Lancet. 1974 October 5; 2(7884): 839. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4138258&dopt=Abstract

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Letter: Munchausen's syndrome and drug addiction. Author(s): York NG. Source: The Medical Journal of Australia. 1974 April 20; 1(16): 639. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4834338&dopt=Abstract

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Letter: Treatment and drug addiction. Author(s): Morton FL. Source: N Y State J Med. 1974 January; 74(1): 18 Passim. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4521698&dopt=Abstract

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Letter: Treatment of drug addiction. Author(s): Milner G. Source: The Medical Journal of Australia. 1973 November 3; 2(18): 868. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4798713&dopt=Abstract

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Letter: Treatment of drug addiction. Author(s): Arnott DW. Source: The Medical Journal of Australia. 1973 September 15; 2(11): 565-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4795924&dopt=Abstract

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Letter: Treatment of drug addiction. Author(s): Wallace VH. Source: The Medical Journal of Australia. 1973 August 25; 2(8): 408. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4795997&dopt=Abstract

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Limbic-striatal memory systems and drug addiction. Author(s): Robbins TW, Everitt BJ. Source: Neurobiology of Learning and Memory. 2002 November; 78(3): 625-36. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12559840&dopt=Abstract

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Liver pathology in fatal drug addiction. Author(s): Kringsholm B, Christoffersen P. Source: Forensic Science International. 1982 September-October; 20(2): 141-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7118025&dopt=Abstract

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Lung and heart pathology in fatal drug addiction. A consecutive autopsy study. Author(s): Kringsholm B, Christoffersen P. Source: Forensic Science International. 1987 May-June; 34(1-2): 39-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3596405&dopt=Abstract

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Lung disease induced by drug addiction. Author(s): Slade M, Burgess K. Source: Thorax. 1996 May; 51(5): 556. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8711693&dopt=Abstract

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Lung disease induced by drug addiction. Author(s): Benson MK, Bentley AM. Source: Thorax. 1995 November; 50(11): 1125-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8553264&dopt=Abstract

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Lymph-node and thymus pathology in fatal drug addiction. Author(s): Kringsholm B, Christoffersen P. Source: Forensic Science International. 1987 August; 34(4): 245-54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3623368&dopt=Abstract

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Male drug addiction and the Kahn Test of Symbol Arrangement. Author(s): Mann ET. Source: Percept Mot Skills. 1969 December; 29(3): 875-80. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=5365095&dopt=Abstract

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Managing drug addiction in general practice. Author(s): Ryan RP. Source: Journal of the Royal Society of Medicine. 1988 April; 81(4): 243-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3373476&dopt=Abstract

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Managing drug addiction in general practice. Author(s): Cook CC, Lipsedge MS. Source: Journal of the Royal Society of Medicine. 1987 December; 80(12): 782-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3430536&dopt=Abstract

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Managing drug addiction in general practice--the reality behind the guidelines: discussion paper. Author(s): Martin E. Source: Journal of the Royal Society of Medicine. 1987 May; 80(5): 305-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3112379&dopt=Abstract

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Medical and social problems of drug addiction in West Africa. (With special emphasis on psychiatric aspects). Author(s): Lambo TA. Source: West Afr Med J. 1965 December; 14(6): 236-54. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=5864823&dopt=Abstract

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Medical student attitudes toward drug addiction policy. Author(s): Hoffmann NG, Chang AJ, Lewis DC. Source: Journal of Addictive Diseases : the Official Journal of the Asam, American Society of Addiction Medicine. 2000; 19(3): 1-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11076116&dopt=Abstract

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Medically induced drug addiction. Author(s): Portnow JM, Strassman HD. Source: Int J Addict. 1985 April; 20(4): 605-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2863226&dopt=Abstract

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Merton, retreatism and drug addiction: the testing of a theory. Author(s): Fazey C. Source: The Sociological Review. 1973 August; 21(3): 417-36. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4748128&dopt=Abstract

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Methadone and chemotherapy in drug addiction. Genocidal or lifesaving? Author(s): Chappel JN. Source: Jama : the Journal of the American Medical Association. 1974 May 6; 228(6): 7258. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4406260&dopt=Abstract

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MMPI correlates of drug addiction based on drug of choice. Author(s): Trevithick L, Hosch HM. Source: Journal of Consulting and Clinical Psychology. 1978 February; 46(1): 180. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=627654&dopt=Abstract

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Molecular mechanisms of drug addiction. Author(s): Nestler EJ. Source: The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. 1992 July; 12(7): 2439-50. Review. Erratum In: J Neurosci 1992 August; 12(8): Followi. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1319476&dopt=Abstract

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Molecular neurobiology of drug addiction. Author(s): Nestler EJ. Source: Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology. 1994 October; 11(2): 77-87. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7840866&dopt=Abstract

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Morphological findings in fatal drug addiction. An investigation of injection marks, endocrine organs and kidneys. Author(s): Kringsholm B, Christoffersen P. Source: Forensic Science International. 1989 January; 40(1): 15-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2925130&dopt=Abstract

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Multiple-drug addiction in New York City in a selected population group. Author(s): Abeles H, Plew R, Laudeutscher I, Rosenthal HM. Source: Public Health Reports (Washington, D.C. : 1974). 1966 August; 81(8): 685-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4958308&dopt=Abstract

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Muscarinic receptors: a novel therapeutic target for drug addiction. Author(s): Yang G. Source: Trends in Pharmacological Sciences. 2002 December; 23(12): 551. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12457771&dopt=Abstract

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Neonatal drug addiction. Author(s): Fabris C, Prandi G, Perathoner C, Soldi A. Source: Panminerva Medica. 1998 September; 40(3): 239-43. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9785924&dopt=Abstract

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Neonatal drug addiction: an analysis from two moral orientations. Author(s): Becker PH, Burke S. Source: Holistic Nursing Practice. 1988 August; 2(4): 20-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3403634&dopt=Abstract

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Nephropathy in patients with drug addiction. Evolution of pathological and clinical features. Author(s): Eknoyan G, Gyorkey F, Dichoso C, Gyorkey P. Source: Virchows Arch a Pathol Anat Histol. 1975; 365(1): 1-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=804737&dopt=Abstract

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Neural substrates of drug craving and relapse in drug addiction. Author(s): Self DW. Source: Annals of Medicine. 1998 August; 30(4): 379-89. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9783837&dopt=Abstract

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New approaches to the treatment of drug addiction. Author(s): Jones GL. Source: J Med Soc N J. 1967 February; 64(2): 85-8. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=5231706&dopt=Abstract

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New hope for the hopeless. Drug addiction: its treatment, management and the nurse's role. Author(s): Chappel JN. Source: Chart. 1970 October; 67(8): 251-5. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=5202955&dopt=Abstract

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Newer treatment approaches for drug addiction. Author(s): Conrad HT. Source: Med Arts Sci. 1971; 25(1): 15-32. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=5155704&dopt=Abstract

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Nurses talk about their experiences with drug addiction. Author(s): Healy B. Source: Rn. 1992 July; 55(7): 9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1529229&dopt=Abstract

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Obstetric medication versus residential area as perinatal risk factors for subsequent adult drug addiction in offspring. Author(s): Nyberg K, Allebeck P, Eklund G, Jacobson B. Source: Paediatric and Perinatal Epidemiology. 1993 January; 7(1): 23-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8426829&dopt=Abstract

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Occupational hazards in hospitals: accidents, radiation, exposure to noxious chemicals, drug addiction and psychic problems, and assault. Author(s): Gestal JJ. Source: Br J Ind Med. 1987 August; 44(8): 510-20. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3307896&dopt=Abstract

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One nurse's recovery from drug addiction. Author(s): Lacy N. Source: Calif Hosp. 1990 November-December; 4(6): 43-4. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10170638&dopt=Abstract

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One possible approach to the control of drug addiction in Delaware. Author(s): Vandervort WJ. Source: Del Med J. 1966 June; 38(6): 172 Passim. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=5941376&dopt=Abstract

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Opiate receptors and their implications for drug addiction. Author(s): Simon EJ. Source: Nida Res Monogr. 1980 March; 30: 303-8. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6256635&dopt=Abstract

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Orthopaedic aspects of drug addiction. Author(s): Anderson RL Jr. Source: Journal of the National Medical Association. 1974 March; 66(2): 121-4 Passim. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4819888&dopt=Abstract

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Overview of pharmacologic treatment approaches for alcohol and other drug addiction. Intoxication, withdrawal, and relapse prevention. Author(s): Gorelick DA. Source: The Psychiatric Clinics of North America. 1993 March; 16(1): 141-56. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8456040&dopt=Abstract

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Parental rearing and individual vulnerability to drug addiction: a controlled study in a Swedish sample. Author(s): Andersson P, Eisemann M. Source: Nordic Journal of Psychiatry. 2003; 57(2): 147-56. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12745778&dopt=Abstract

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Parent-child cultural disparity and drug addiction. Author(s): Vaillant GE. Source: The Journal of Nervous and Mental Disease. 1966 June; 142(6): 534-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=5920206&dopt=Abstract

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Pathology and toxicology of drug addiction: a combined approach. Author(s): Cameron JM, Robinson AE. Source: Med Sci Law. 1973 October; 13(4): 272-6. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4787064&dopt=Abstract

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Patient-treatment matching in substance abuse. Drug addiction severity. Author(s): Thornton CC, Gottheil E, Weinstein SP, Kerachsky RS. Source: Journal of Substance Abuse Treatment. 1998 November-December; 15(6): 505-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9845864&dopt=Abstract

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Patterns and causes of drug addiction among Puerto Rican females. Author(s): Zahn MA, Ball JC. Source: Addict Dis. 1974; 1(2): 203-13. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4432796&dopt=Abstract

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Patterns of delinquency in drug addiction. Author(s): Gordon AM. Source: The British Journal of Psychiatry; the Journal of Mental Science. 1973 February; 122(567): 205-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4714836&dopt=Abstract

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Pavlovian conditioning of drug reactions: some implications for problems of drug addiction. Author(s): Lynch JJ, Fertziger AP, Teitelbaum HA, Cullen JW, Gantt WH. Source: Cond Reflex. 1973 October-December; 8(4): 211-23. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4747112&dopt=Abstract

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Penile ecthyma gangrenosum. Complication of drug addiction. Author(s): Cunningham DL, Persky L. Source: Urology. 1989 August; 34(2): 109-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2763400&dopt=Abstract

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Perceived client and program moderators of successful therapeutic community treatment for drug addiction. Author(s): Toumbourou J, Hamilton M. Source: Int J Addict. 1993 September; 28(11): 1127-46. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8407032&dopt=Abstract

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Perinatal problems (excluding neonatal withdrawal) in maternal drug addiction: a study of 830 cases. Author(s): Ostrea EM, Chavez CJ. Source: The Journal of Pediatrics. 1979 February; 94(2): 292-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=762627&dopt=Abstract

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Personality factors in drug addiction. Author(s): Butcher JN. Source: Nida Res Monogr. 1988; 89: 87-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3147400&dopt=Abstract

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Pharmacy in medieval Islam and the history of drug addiction. Author(s): Hamarneh S. Source: Medical History. 1972 July; 16(3): 226-37. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4595520&dopt=Abstract

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Physician drug addiction a challenge to medical educators. Author(s): Borsay MA, Leff AM. Source: Ohio State Med J. 1977 November; 73(11): 740-2. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=927771&dopt=Abstract

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Potential human neurotoxicity of MDMA ('Ecstasy'): subjective self-reports, evidence from an Italian drug addiction centre and clinical case studies. Author(s): Schifano F. Source: Neuropsychobiology. 2000; 42(1): 25-33. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10867553&dopt=Abstract

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Pregnancy and drug addiction. Author(s): Fraser A. Source: Midwife Health Visit Community Nurse. 1978 May; 14(5): 132-5. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=247185&dopt=Abstract

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Pregnancy and drug addiction--long-term consequences. Author(s): Fraser AC, Cavanagh S. Source: Journal of the Royal Society of Medicine. 1991 September; 84(9): 530-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1941854&dopt=Abstract

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Preliminary findings of an epidemiological survey of drug addiction in Paris. Author(s): Ingold R, Olivenstein C. Source: Bull Narc. 1983 July-September; 35(3): 73-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6561046&dopt=Abstract

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Problems of implementing and coordinating a programmed project grant on drug addiction. Author(s): Pry NR. Source: J Reprod Med. 1978 June; 20(6): 337-9. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=671415&dopt=Abstract

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Program development and integrated treatment across systems for dual diagnosis: mental illness, drug addiction, and alcoholism (MIDAA). Author(s): Sciacca K, Thompson CM. Source: J Ment Health Adm. 1996 Summer; 23(3): 288-97. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10172686&dopt=Abstract

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Psychiatric aspects of drug addiction in Lebanon. Author(s): Katchadourian HA, Sutherland JV. Source: Int J Addict. 1975; 10(6): 949-62. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1201880&dopt=Abstract

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Psychic dependence? A different formulation of the problem with a view to the reorientation of therapy for chronic drug addiction. Author(s): Cocchi R, Tornati A. Source: Acta Psychiatrica Scandinavica. 1977 November; 56(5): 337-46. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=22989&dopt=Abstract

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Psychodynamic factors in the mother-child relationship in adolescent drug addiction: a comparison of mothers of schizophrenics and mothers of normal adolescent sons. Author(s): Attardo N. Source: Psychotherapy and Psychosomatics. 1965; 13(4): 249-55. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=5837321&dopt=Abstract

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Psychosocial aspects of drug addiction. Author(s): Radin SS. Source: The Journal of School Health. 1966 December; 36(10): 481-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=5180090&dopt=Abstract

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Pulmonary and cardiovascular implications of drug addiction. Author(s): Joseph WL, Fletcher HS, Giordano JM, Adkins PC. Source: The Annals of Thoracic Surgery. 1973 March; 15(3): 263-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4266158&dopt=Abstract

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Pulmonary complications of drug addiction. Author(s): Stern WZ, Subbarao K. Source: Semin Roentgenol. 1983 July; 18(3): 183-97. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6351257&dopt=Abstract

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Pyogenic splenic abscess in intravenous drug addiction. Author(s): Nallathambi MN, Ivatury RR, Lankin DH, Wapnir IL, Stahl WM. Source: The American Surgeon. 1987 June; 53(6): 342-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3579050&dopt=Abstract

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Radiology of musculoskeletal complications of drug addiction. Author(s): Firooznia H, Golimbu C, Rafii M, Lichtman EA. Source: Semin Roentgenol. 1983 July; 18(3): 198-206. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6351258&dopt=Abstract

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Rat brain gangliosides following drug addiction and nutritional deficiency. Author(s): Boegman RJ. Source: Advances in Experimental Medicine and Biology. 1976; 71: 267-73. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=945661&dopt=Abstract

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Recidivism in drug addiction: a behavioral analysis. Author(s): Barbarin OA. Source: Addictive Behaviors. 1979; 4(2): 121-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=38638&dopt=Abstract

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Reflections of a physician recovering from drug addiction. Author(s): Hays JW. Source: J Tenn Med Assoc. 1979 November; 72(11): 851. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=502548&dopt=Abstract

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Regulation of gene expression by dopamine: implications in drug addiction. Author(s): Conneely OM, Power RF, O'Malley BW. Source: Nida Res Monogr. 1992; 126: 84-97. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1491719&dopt=Abstract

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Relapse following withdrawal of drug addiction. Author(s): Islam R. Source: The British Journal of Psychiatry; the Journal of Mental Science. 1993 November; 163: 699. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8298855&dopt=Abstract

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Relation between chronic alcoholism, drug addiction and nutrition with special reference to the thiamine status. Author(s): Somogyi JC, Kopp PM. Source: Bibl Nutr Dieta. 1981; (30): 131-8. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7283962&dopt=Abstract

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Renal complications of drug addiction. Author(s): Olivero J, Bacque F, Carlton CE Jr, Eknoyan G. Source: Urology. 1976 December; 8(6): 526-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11601&dopt=Abstract

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Responding flexibly but not gullibly to drug addiction. Author(s): Strang J, Ghodse H, Johns A. Source: British Medical Journal (Clinical Research Ed.). 1987 November 28; 295(6610): 1364. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3121016&dopt=Abstract

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Richard Lane: a tireless fighter for treatment of drug addiction. Author(s): Novick DM, Hayes MG. Source: Journal of Addictive Diseases : the Official Journal of the Asam, American Society of Addiction Medicine. 1996; 15(4): 119-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8943585&dopt=Abstract

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Role of dopamine, the frontal cortex and memory circuits in drug addiction: insight from imaging studies. Author(s): Volkow ND, Fowler JS, Wang GJ, Goldstein RZ. Source: Neurobiology of Learning and Memory. 2002 November; 78(3): 610-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12559839&dopt=Abstract

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Safe approaches to treating drug addiction. Author(s): Keaney F, Farrell M. Source: The Practitioner. 2000 May; 244(1610): 410, 414-6, 418-20 Passim. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10962832&dopt=Abstract

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Science-based views of drug addiction and its treatment. Author(s): Leshner AI. Source: Jama : the Journal of the American Medical Association. 1999 October 13; 282(14): 1314-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10527162&dopt=Abstract

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Screening for drugs of abuse in urine samples from a drug addiction center. Author(s): Peat MA. Source: Clin Toxicol. 1976; 9(2): 203-19. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=939075&dopt=Abstract

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Secrets and lies: alcohol and drug addiction in dentistry. Author(s): Kittelson L. Source: J Calif Dent Assoc. 1998 October; 26(10): 744-7, 749-50. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9879242&dopt=Abstract

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Setting up a drug addiction unit: a Norwegian experiment. Author(s): Banks GD. Source: The British Journal of Addiction to Alcohol and Other Drugs. 1969 May; 64(1): 81-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=5253633&dopt=Abstract

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Severe mental illness and substance use disorders among former Supplemental Security Income beneficiaries for drug addiction and alcoholism. Author(s): Swartz JA, Lurigio AJ, Goldstein P. Source: Archives of General Psychiatry. 2000 July; 57(7): 701-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10891041&dopt=Abstract

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Sex and drugs and nuclear war: secular, developmental and type A influences upon adolescents' fears of the nuclear threat, AIDS and drug addiction. Author(s): Wilkins R, Lewis C. Source: Journal of Adolescence. 1993 March; 16(1): 23-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8496466&dopt=Abstract

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Signs and symptoms in drug addiction. Author(s): Byrne A. Source: Aust Fam Physician. 1995 March; 24(3): 420. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7717906&dopt=Abstract

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Skin stigmata of adolescent drug addiction. Author(s): Young AW Jr, Digrande EV, Wagers LT. Source: Mod Treat. 1972 February; 9(1): 117-36. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=5029630&dopt=Abstract

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Social and family approach to drug addiction. Author(s): Cordeiro JD, Miguel N, Castanheira JL. Source: Bull Narc. 1978 October-December; 30(4): 43-6. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=258605&dopt=Abstract

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Social policy and drug addiction: a critical study of policy development. Author(s): Smart C. Source: British Journal of Addiction. 1984 March; 79(1): 31-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6584163&dopt=Abstract

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Social service aspects of drug addiction in the newborn. Author(s): Beine EC. Source: Journal of the National Medical Association. 1974 July; 66(4): 313-20 Passimas. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4846793&dopt=Abstract

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Society and medicine: drug addiction. Author(s): Nahum LH. Source: Conn Med. 1971 August; 35(8): 516-8. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=5105686&dopt=Abstract

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Socio-cultural factors affecting drug addiction treatment in Italy (fear of treatment). Author(s): Maremmani I, Zolesi O, Cirillo M, Nardini R, Tagliamonte A, Castrogiovanni P. Source: Drug and Alcohol Dependence. 1990 April; 25(2): 235-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2328659&dopt=Abstract

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Socio-economic versus obstetric risk factors for drug addiction in offspring. Author(s): Nyberg K, Allebeck P, Eklund G, Jacobson B. Source: British Journal of Addiction. 1992 December; 87(12): 1669-76. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1490081&dopt=Abstract

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Some effects of maternal drug addiction on the neonate. Author(s): Lesser-Katz M. Source: Int J Addict. 1982 July; 17(5): 887-96. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7129704&dopt=Abstract

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Sources of anxiety in drug addiction. Author(s): Viney LL, Westbrook MT, Preston C. Source: Journal of Clinical Psychology. 1985 January; 41(1): 124-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3973034&dopt=Abstract

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Spleen and portal lymphnode pathology in fatal drug addiction. Author(s): Kringsholm B, Christoffersen P. Source: Forensic Science International. 1984 August; 25(4): 233-44. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6479771&dopt=Abstract

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Statistical approaches to the classification of alcohol and drug addiction. Author(s): Skinner HA. Source: British Journal of Addiction. 1982 September; 77(3): 259-73. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6958303&dopt=Abstract

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Statistics of drug addiction. Author(s): Goulding R. Source: Med Sci Law. 1968 October; 8(4): 266-70. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=5748400&dopt=Abstract

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Stereotactic cingulumotomy for drug addiction. Author(s): Kanaka TS, Balasubramaniam V. Source: Appl Neurophysiol. 1978; 41(1-4): 86-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=365103&dopt=Abstract

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Stereotaxic cingulumotomy for drug addiction. Author(s): Balasubramaniam V, Kanaka TS, Ramanujam PB. Source: Neurology India. 1973 June; 21(2): 63-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4587421&dopt=Abstract

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Strategies to combat drug addiction. Author(s): Newman R. Source: Lancet. 2001 October 20; 358(9290): 1369. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11684249&dopt=Abstract

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Stress, corticotropin-releasing factor, and drug addiction. Author(s): Koob GF. Source: Annals of the New York Academy of Sciences. 1999; 897: 27-45. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10676433&dopt=Abstract

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Subclavian artery false aneurysm associated with brachial plexus palsy: a complication of parenteral drug addiction. Author(s): O'Leary MR. Source: The American Journal of Emergency Medicine. 1990 March; 8(2): 129-33. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2405865&dopt=Abstract

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Surgical (and medical) sequelae of drug addiction. Author(s): Geelhoed GW. Source: Med Ann Dist Columbia. 1974 June; 43(6): 307-16. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4526339&dopt=Abstract

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Symbolic self-expression in drug addiction. Author(s): Marinow A. Source: Confin Psychiatr. 1980; 23(2): 103-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7418382&dopt=Abstract

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Symposium on alcoholism and drug addiction. Author(s): Trail ID. Source: Nurs Clin North Am. 1976 September; 11(3): 481-2. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1048491&dopt=Abstract

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Synanon in drug addiction. Author(s): Markoff EL. Source: Curr Psychiatr Ther. 1969; 9: 261-72. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=5388676&dopt=Abstract

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Synthesis of qualitative research on drug use in the European Union: report on an EMCDDA project. European Monitoring Centre for Drugs and Drug Addiction. Author(s): Fountain J, Griffiths P. Source: European Addiction Research. 1999 March; 5(1): 4-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10085497&dopt=Abstract

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Tangential symbols: using visual symbolization to teach pharmacological principles of drug addiction to international audiences. Author(s): Giannini AJ. Source: Journal of Clinical Pharmacology. 1993 December; 33(12): 1139-46. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7510314&dopt=Abstract

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Telling the patient the diagnosis of alcoholism or drug addiction: an internist's perspective. Author(s): Lamping C. Source: Md Med J. 1995 June; 44(6): 460-1. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7596240&dopt=Abstract

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The “fatigue factor” in drug addiction: insufficient motivation for treatment. Author(s): Looney M, Metcalf S. Source: Hosp Community Psychiatry. 1974 August; 25(8): 528-30. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4152282&dopt=Abstract

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The application of the principles of toxicology and teratology in evaluating the risks of new drugs for treatment of drug addiction in women of reproductive age. Author(s): Brent RL. Source: Nida Res Monogr. 1995; 149: 130-84. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8775839&dopt=Abstract

•

The Aro Drug Addiction Research and Treatment Centre: a first report. Author(s): Makanjuola JD. Source: British Journal of Addiction. 1986 December; 81(6): 809-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3467780&dopt=Abstract

•

The biological tangle of drug addiction. Author(s): Barnes DM. Source: Science. 1988 July 22; 241(4864): 415-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3393909&dopt=Abstract

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•

The biological, social and clinical bases of drug addiction: commentary and debate. Author(s): Altman J, Everitt BJ, Glautier S, Markou A, Nutt D, Oretti R, Phillips GD, Robbins TW. Source: Psychopharmacology. 1996 June; 125(4): 285-345. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8826538&dopt=Abstract

•

The challenge of illicit drug addiction for general practice. Author(s): Cohen J, Schamroth A. Source: Drug and Alcohol Dependence. 1990 June; 25(3): 315-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2347295&dopt=Abstract

•

The first 100 referrals to a Scottish Drug Addiction Treatment Centre. Author(s): Woodside M. Source: The British Journal of Addiction to Alcohol and Other Drugs. 1973 October; 68(3): 231-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4522605&dopt=Abstract

•

The hospital treatment of alcoholism and drug addiction. Author(s): Warner ML, Mooney AJ 3rd. Source: Primary Care. 1993 March; 20(1): 95-105. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8464951&dopt=Abstract

•

The limitations of control-of-supply models for explaining and preventing alcoholism and drug addiction. Author(s): Peele S. Source: J Stud Alcohol. 1987 January; 48(1): 61-89. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3821120&dopt=Abstract

•

The medical complications of drug addiction and the medical assessment of the intravenous drug user: 25 years later. Author(s): Cherubin CE, Sapira JD. Source: Annals of Internal Medicine. 1993 November 15; 119(10): 1017-28. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8214979&dopt=Abstract

•

The myths of drug addiction. Author(s): Carpenito-Moyet LJ. Source: Nursing Forum. 2003 January-March; 38(1): 3-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12743967&dopt=Abstract

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The nature and the occurrence of birefringent material in different organs in fatal drug addiction. Author(s): Kringsholm B, Christoffersen P. Source: Forensic Science International. 1987 May-June; 34(1-2): 53-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3036675&dopt=Abstract

•

The network of Centres for the Prevention and Treatment of Drug Addiction in the Republic of Slovenia. Author(s): Kastelic A, Rihtar TK. Source: Med Arh. 2001; 55(3): 135-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11769426&dopt=Abstract

•

The neural substrates of drug addiction and dependence. Author(s): Pulvirenti L, Koob GF. Source: Funct Neurol. 1990 April-June; 5(2): 109-19. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2172102&dopt=Abstract

•

The neurobiology of drug addiction. Author(s): Koob GF, Nestler EJ. Source: The Journal of Neuropsychiatry and Clinical Neurosciences. 1997 Summer; 9(3): 482-97. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9276849&dopt=Abstract

•

The neuroscience of drug addiction: Rome built in a day. Author(s): Pulvirenti L, Massotti M. Source: Trends in Pharmacological Sciences. 2002 December; 23(12): 543-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12457766&dopt=Abstract

•

The patient recovering from alcohol or drug addiction: special issues for the anesthesiologist. Author(s): May JA, White HC, Leonard-White A, Warltier DC, Pagel PS. Source: Anesthesia and Analgesia. 2001 June; 92(6): 1601-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11375854&dopt=Abstract

•

The pharmacist's role in a community drug addiction treatment program. Author(s): Burleson K. Source: Hosp Pharm. 1975 August; 10(8): 327-8, 332. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10316679&dopt=Abstract

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The physician and public opinion concerning drug addiction. Author(s): Visscher MB. Source: Minn Med. 1973 March; 56(3): 215-6. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4734616&dopt=Abstract

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The potential of dopamine agonists in drug addiction. Author(s): Kosten TR, George TP, Kosten TA. Source: Expert Opinion on Investigational Drugs. 2002 April; 11(4): 491-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11922858&dopt=Abstract

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The problem of drug addiction among secondary school students in Lublin. Young people's knowledge about the effects of taking drugs. Author(s): Zolnierczuk-Kieliszek D, Chemperek E. Source: Ann Univ Mariae Curie Sklodowska [med]. 2000; 55: 235-44. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11482080&dopt=Abstract

•

The role of corticotropin-releasing factor in drug addiction. Author(s): Sarnyai Z, Shaham Y, Heinrichs SC. Source: Pharmacological Reviews. 2001 June; 53(2): 209-43. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11356984&dopt=Abstract

•

The role of the striatopallidal and extended amygdala systems in drug addiction. Author(s): Koob GF. Source: Annals of the New York Academy of Sciences. 1999 June 29; 877: 445-60. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10415664&dopt=Abstract

•

Theoretical and clinical approaches to the treatment of adolescent drug addiction. Author(s): DeAngelis GG. Source: Am J Occup Ther. 1976 February; 30(2): 87-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1258972&dopt=Abstract

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Three approaches to the treatment of drug addiction. Author(s): Klein JM, Miller SI. Source: Hosp Community Psychiatry. 1986 November; 37(11): 1083-5. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3781496&dopt=Abstract

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Tobacco use as drug addiction: the scientific foundation. Author(s): Henningfield JE, Fant RV. Source: Nicotine & Tobacco Research : Official Journal of the Society for Research on Nicotine and Tobacco. 1999; 1 Suppl 2: S31-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11768184&dopt=Abstract

•

Treatment for drug addiction: it won't work if they don't receive it. Author(s): Onken LS, Blaine JD, Boren JJ. Source: Nida Res Monogr. 1997; 165: 1-3. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9243543&dopt=Abstract

•

Treatment of drug addiction in two different communities. Comparative review. Author(s): Ruiz P, Lowinson JH, Marcus N, Langrod J. Source: N Y State J Med. 1973 September 15; 73(18): 2244-7. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4517128&dopt=Abstract

•

Understanding drug addiction: implications for treatment. Author(s): Leshner AI. Source: Hosp Pract (Off Ed). 1996 October 15; 31(10): 47-54, 57-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8859207&dopt=Abstract

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Volitional problems in carrying through a difficult decision: the case of drug addiction. Author(s): Sjoberg L, Olsson G. Source: Drug and Alcohol Dependence. 1981 April; 7(2): 177-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7249927&dopt=Abstract

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CHAPTER 2. NUTRITION AND DRUG ADDICTION Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and drug addiction.

Finding Nutrition Studies on Drug Addiction The National Institutes of Health’s Office of Dietary Supplements (ODS) offers a searchable bibliographic database called the IBIDS (International Bibliographic Information on Dietary Supplements; National Institutes of Health, Building 31, Room 1B29, 31 Center Drive, MSC 2086, Bethesda, Maryland 20892-2086, Tel: 301-435-2920, Fax: 301-480-1845, E-mail: [email protected]). The IBIDS contains over 460,000 scientific citations and summaries about dietary supplements and nutrition as well as references to published international, scientific literature on dietary supplements such as vitamins, minerals, and botanicals.7 The IBIDS includes references and citations to both human and animal research studies. As a service of the ODS, access to the IBIDS database is available free of charge at the following Web address: http://ods.od.nih.gov/databases/ibids.html. After entering the search area, you have three choices: (1) IBIDS Consumer Database, (2) Full IBIDS Database, or (3) Peer Reviewed Citations Only. Now that you have selected a database, click on the “Advanced” tab. An advanced search allows you to retrieve up to 100 fully explained references in a comprehensive format. Type “drug addiction” (or synonyms) into the search box, and click “Go.” To narrow the search, you can also select the “Title” field.

7

Adapted from http://ods.od.nih.gov. IBIDS is produced by the Office of Dietary Supplements (ODS) at the National Institutes of Health to assist the public, healthcare providers, educators, and researchers in locating credible, scientific information on dietary supplements. IBIDS was developed and will be maintained through an interagency partnership with the Food and Nutrition Information Center of the National Agricultural Library, U.S. Department of Agriculture.

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The following information is typical of that found when using the “Full IBIDS Database” to search for “drug addiction” (or a synonym): •

Circuits, drugs, and drug addiction. Author(s): Department of Neuropharmacology, Scripps Research Institute, La Jolla, California 92037, USA. Source: Koob, G F Adv-Pharmacol. 1998; 42978-82 1054-3589

•

Effects of maternal drug addiction on the fetus. Author(s): Guy's Hospital, London. Source: Gilbody, J S Adverse-Drug-React-Toxicol-Revolume 1991 Summer; 10(2): 77-88 0964-198X

•

Genetic analysis of drug addiction: the role of cAMP response element binding protein. Author(s): University of Pennsylvania School of Medicine, Department of Pharmacology, Philadelphia 19104-6084, USA. Source: Blendy, J A Maldonado, R J-Mol-Med. 1998 February; 76(2): 104-10 0946-2716

•

Safe approaches to treating drug addiction. Author(s): National Addiction Centre, Institute of Psychiatry and The Maudsley Hospital, London. Source: Keaney, F Farrell, M Practitioner. 2000 May; 244(1610): 410, 414-6, 418-20 passim 0032-6518

•

The problem of drug addiction among secondary school students in Lublin. Young people's knowledge about the effects of taking drugs. Author(s): Miedzywydzialowa Katedra i Zaklad Zdrowia Publicznego Akademii Medycznej w Lublinie. Source: Zolnierczuk Kieliszek, D Chemperek, E Ann-Univ-Mariae-Curie-Sklodowska[Med]. 2000; 55: 235-44 0066-2240

•

Tobacco use as drug addiction: the scientific foundation. Author(s): Johns Hopkins University School of Medicine, Baltimore, MD, USA. [email protected] Source: Henningfield, J E Fant, R V Nicotine-Tob-Res. 1999; 1 Suppl 2: S31-5 1462-2203

Federal Resources on Nutrition In addition to the IBIDS, the United States Department of Health and Human Services (HHS) and the United States Department of Agriculture (USDA) provide many sources of information on general nutrition and health. Recommended resources include: •

healthfinder®, HHS’s gateway to health information, including diet and nutrition: http://www.healthfinder.gov/scripts/SearchContext.asp?topic=238&page=0

•

The United States Department of Agriculture’s Web site dedicated to nutrition information: www.nutrition.gov

•

The Food and Drug Administration’s Web site for federal food safety information: www.foodsafety.gov

•

The National Action Plan on Overweight and Obesity sponsored by the United States Surgeon General: http://www.surgeongeneral.gov/topics/obesity/

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•

The Center for Food Safety and Applied Nutrition has an Internet site sponsored by the Food and Drug Administration and the Department of Health and Human Services: http://vm.cfsan.fda.gov/

•

Center for Nutrition Policy and Promotion sponsored by the United States Department of Agriculture: http://www.usda.gov/cnpp/

•

Food and Nutrition Information Center, National Agricultural Library sponsored by the United States Department of Agriculture: http://www.nal.usda.gov/fnic/

•

Food and Nutrition Service sponsored by the United States Department of Agriculture: http://www.fns.usda.gov/fns/

Additional Web Resources A number of additional Web sites offer encyclopedic information covering food and nutrition. The following is a representative sample: •

AOL: http://search.aol.com/cat.adp?id=174&layer=&from=subcats

•

Family Village: http://www.familyvillage.wisc.edu/med_nutrition.html

•

Google: http://directory.google.com/Top/Health/Nutrition/

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Healthnotes: http://www.healthnotes.com/

•

Open Directory Project: http://dmoz.org/Health/Nutrition/

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Yahoo.com: http://dir.yahoo.com/Health/Nutrition/

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WebMDHealth: http://my.webmd.com/nutrition

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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html

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CHAPTER 3. ADDICTION

ALTERNATIVE

MEDICINE

AND

DRUG

Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to drug addiction. At the conclusion of this chapter, we will provide additional sources.

National Center for Complementary and Alternative Medicine The National Center for Complementary and Alternative Medicine (NCCAM) of the National Institutes of Health (http://nccam.nih.gov/) has created a link to the National Library of Medicine’s databases to facilitate research for articles that specifically relate to drug addiction and complementary medicine. To search the database, go to the following Web site: http://www.nlm.nih.gov/nccam/camonpubmed.html. Select “CAM on PubMed.” Enter “drug addiction” (or synonyms) into the search box. Click “Go.” The following references provide information on particular aspects of complementary and alternative medicine that are related to drug addiction: •

Drug addiction and the veterinary profession. Author(s): Roach NJ, Willis J. Source: The Veterinary Record. 2002 June 15; 150(24): 760. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12092631&dopt=Abstract

•

Use of therapeutic touch in treatment of drug addictions. Author(s): Hagemaster J. Source: Holistic Nursing Practice. 2000 April; 14(3): 14-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12119624&dopt=Abstract

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Additional Web Resources A number of additional Web sites offer encyclopedic information covering CAM and related topics. The following is a representative sample: •

Alternative Medicine Foundation, Inc.: http://www.herbmed.org/

•

AOL: http://search.aol.com/cat.adp?id=169&layer=&from=subcats

•

Chinese Medicine: http://www.newcenturynutrition.com/

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drkoop.com: http://www.drkoop.com/InteractiveMedicine/IndexC.html

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Family Village: http://www.familyvillage.wisc.edu/med_altn.htm

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Google: http://directory.google.com/Top/Health/Alternative/

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Healthnotes: http://www.healthnotes.com/

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MedWebPlus: http://medwebplus.com/subject/Alternative_and_Complementary_Medicine

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Open Directory Project: http://dmoz.org/Health/Alternative/

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HealthGate: http://www.tnp.com/

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WebMDHealth: http://my.webmd.com/drugs_and_herbs

•

WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html

•

Yahoo.com: http://dir.yahoo.com/Health/Alternative_Medicine/

The following is a specific Web list relating to drug addiction; please note that any particular subject below may indicate either a therapeutic use, or a contraindication (potential danger), and does not reflect an official recommendation: •

Alternative Therapy Acupuncture Source: Healthnotes, Inc.; www.healthnotes.com Biofeedback Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,675,00.html Quan Chi Chi Gong Source: The Canoe version of A Dictionary of Alternative-Medicine Methods, by Priorities for Health editor Jack Raso, M.S., R.D. Hyperlink: http://www.canoe.ca/AltmedDictionary/q.html

General References A good place to find general background information on CAM is the National Library of Medicine. It has prepared within the MEDLINEplus system an information topic page

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dedicated to complementary and alternative medicine. To access this page, go to the MEDLINEplus site at http://www.nlm.nih.gov/medlineplus/alternativemedicine.html. This Web site provides a general overview of various topics and can lead to a number of general sources.

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CHAPTER 4. DISSERTATIONS ON DRUG ADDICTION Overview In this chapter, we will give you a bibliography on recent dissertations relating to drug addiction. We will also provide you with information on how to use the Internet to stay current on dissertations. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical dissertations that use the generic term “drug addiction” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on drug addiction, we have not necessarily excluded non-medical dissertations in this bibliography.

Dissertations on Drug Addiction ProQuest Digital Dissertations, the largest archive of academic dissertations available, is located at the following Web address: http://wwwlib.umi.com/dissertations. From this archive, we have compiled the following list covering dissertations devoted to drug addiction. You will see that the information provided includes the dissertation’s title, its author, and the institution with which the author is associated. The following covers recent dissertations found when using this search procedure: •

A Self-theory Investigation of Drug Addiction in Relation to Age of Onset by Schiff, Stanley, PhD from New York University, 1959, 180 pages http://wwwlib.umi.com/dissertations/fullcit/6609761

•

A Study of the Effects of Anger-control Group Counseling on Attributional Styles and Levels of Trait Anger in Women Recovering from Alcohol and or Drug Addiction by Gonzalez-Prendes, A. Antonio; PhD from Wayne State University, 2002, 198 pages http://wwwlib.umi.com/dissertations/fullcit/3071782

•

An Intense Study by Interview of Methadone Treated African-American Patients (Methadone Treatment, Drug Addiction) by Hodges, James Elmer, PhD from The Union Institute, 1991, 186 pages http://wwwlib.umi.com/dissertations/fullcit/9217640

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•

Anomie, Perceived Opportunity and Drug Addiction: a Study of Some Correlates of Drug Addicted and Non-addicted Offending Behavior. by Atwell, Wilbur Munroe, PhD from The George Washington University, 1977, 374 pages http://wwwlib.umi.com/dissertations/fullcit/7726455

•

Christian Vs. Eclectic Spiritual Intervention in Alcohol and Drug Addiction Recovery by Jappy, Alistair John; Ma from Trinity Western University (canada), 2002, 166 pages http://wwwlib.umi.com/dissertations/fullcit/MQ77423

•

Drug Addiction and Alcoholism As Qualifying Impairments for Social Security Disability Benefits: the History, Controversies, and Congressional Response by Hunt, Sharon Rose; PhD from Brandeis U., the F. Heller Grad. Sch. for Adv. Stud. in Soc. Wel., 2000, 384 pages http://wwwlib.umi.com/dissertations/fullcit/3001242

•

Drug Addiction, Life Style Personality Factors and Psychopathology by Boynton, Ralph Dewey, PhD from Georgia State University, 1989, 149 pages http://wwwlib.umi.com/dissertations/fullcit/8910176

•

Drug Addiction: from a Study of Women and Criminal Justice by Faith, Karlene, PhD from University of California, Santa Cruz, 1981, 182 pages http://wwwlib.umi.com/dissertations/fullcit/8218359

•

Exploring a Possible Linkage between Drug Addiction and School Dropouts in a Western Massachusetts Urban School System by Ayerve, Miguel A., Edd from University of Massachusetts, 1988, 171 pages http://wwwlib.umi.com/dissertations/fullcit/8906251

•

Family Headship and Drug Addiction among Male Puerto Rican Youths: an Investigation of Quality of Family Life by Puyo, Ana Maria, PhD from Fordham University, 1980, 282 pages http://wwwlib.umi.com/dissertations/fullcit/8012801

•

Identity Transformation in Drug Addiction by Anderson, Tammy L., PhD from The American University, 1991, 377 pages http://wwwlib.umi.com/dissertations/fullcit/9225456

•

Methadone Maintenance and Crime (Drug Addiction) by Spunt, Barry J., PhD from Fordham University, 1990, 293 pages http://wwwlib.umi.com/dissertations/fullcit/9025025

•

The Development of an Educational Component in a Program for the Treatment of Drug Addiction. by Ukott, Gabriel Thomas, PhD from The Ohio State University, 1975, 171 pages http://wwwlib.umi.com/dissertations/fullcit/7526676

•

The Social World of Injection Drug Users and the Adoption of AIDS Preventative Practices (Immune Deficiency, Drug Addiction) by Connors, Margaret Mary, PhD from University of Massachusetts, 1993, 287 pages http://wwwlib.umi.com/dissertations/fullcit/9329586

•

Therapeutic Communities: a Family-centered Approach to Drug Addiction by Brieland, Christine Grant, PhD from University of Illinois at Urbana-champaign, 1983, 173 pages http://wwwlib.umi.com/dissertations/fullcit/8324515

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•

Too Many Pills: Patients, Physicians, and the Myth of Overmedication in America, 1955-1980 (Drug Addiction) by Speaker, Susan Lynn, PhD from University of Pennsylvania, 1992, 220 pages http://wwwlib.umi.com/dissertations/fullcit/9308663

•

Trend-surface Analysis in Human Ecology: Chicago Drug Addiction 1960-1969 by Campbell, Richard Scott, PhD from Washington State University, 1970, 71 pages http://wwwlib.umi.com/dissertations/fullcit/7104388

Keeping Current Ask the medical librarian at your library if it has full and unlimited access to the ProQuest Digital Dissertations database. From the library, you should be able to do more complete searches via http://wwwlib.umi.com/dissertations.

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CHAPTER 5. PATENTS ON DRUG ADDICTION Overview Patents can be physical innovations (e.g. chemicals, pharmaceuticals, medical equipment) or processes (e.g. treatments or diagnostic procedures). The United States Patent and Trademark Office defines a patent as a grant of a property right to the inventor, issued by the Patent and Trademark Office.8 Patents, therefore, are intellectual property. For the United States, the term of a new patent is 20 years from the date when the patent application was filed. If the inventor wishes to receive economic benefits, it is likely that the invention will become commercially available within 20 years of the initial filing. It is important to understand, therefore, that an inventor’s patent does not indicate that a product or service is or will be commercially available. The patent implies only that the inventor has “the right to exclude others from making, using, offering for sale, or selling” the invention in the United States. While this relates to U.S. patents, similar rules govern foreign patents. In this chapter, we show you how to locate information on patents and their inventors. If you find a patent that is particularly interesting to you, contact the inventor or the assignee for further information. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical patents that use the generic term “drug addiction” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on drug addiction, we have not necessarily excluded non-medical patents in this bibliography.

Patents on Drug Addiction By performing a patent search focusing on drug addiction, you can obtain information such as the title of the invention, the names of the inventor(s), the assignee(s) or the company that owns or controls the patent, a short abstract that summarizes the patent, and a few excerpts from the description of the patent. The abstract of a patent tends to be more technical in nature, while the description is often written for the public. Full patent descriptions contain much more information than is presented here (e.g. claims, references, figures, diagrams, etc.). We will tell you how to obtain this information later in the chapter. The following is an 8Adapted

from the United States Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm.

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example of the type of information that you can expect to obtain from a patent search on drug addiction: •

Biodegradable polymer encapsulated pharmaceutical compositions and method for preparing the same Inventor(s): Comiskey; Stephen J. (Doylestown, PA), Hanley; Stephen J. (Lebanon, NJ), Kohn; Rachel S. (Springfield, NJ) Assignee(s): Aventis Pharmaceuticals, Inc. (Bridgewater, NJ) Patent Number: 6,455,526 Date filed: December 7, 1999 Abstract: A new class of biodegradable pharmaceutical compositions useful as sustained release medicamentous compositions, including methods of making and methods of using these compositions, are described and claimed. The method of making these compositions include the steps of: a) dry mixing of a pharmaceutically active molecule with a biodegradable polymer; b) melt extruding the mixture to form a solid solution of the active molecule in the polymer; and c) pulverizing the solid solution to form microparticles such that they can be formed into injectable formulations. Preferred embodiments include pharmaceutical compositions of polylactide-co-glycolide and (+).alpha.-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidine methanol (active ingredient) and a method for its formation. These compositions release the active ingredient at a steady rate over a period of days to weeks. The active ingredient antagonizes the effects of serotonin at the 5HT.sub.2A receptor and are useful in treating various conditions such as, for example, psychoses including schizophrenia, obsessive compulsive disorder, sleep disorder, depression, anorexia, anxiety, drug addiction and bipolar disorders. Excerpt(s): This invention relates to methods for the production of sustained release compositions containing a biodegradable polymer and a pharmaceutically active molecule, which are useful in the treatment of a variety of diseases, including certain psychoses such as, for example, schizophrenia, obsessive compulsive disorder, anxiety, and bipolar disorders. More specifically, the present invention relates to sustained release compositions of a biodegradable polyester and a pharmaceutically active molecule capable of exerting serotonin receptor antagonist activity at the 5HT.sub.2 receptor, method of making the same, and method of treating patients in need of such compositions. It has long been appreciated that the continuous release of certain drugs over an extended period following a single administration could have significant practical advantages in clinical practice. It is also well recognized in the art that delivering a drug to its therapeutic site of action, such as, for example, the central nervous system (CNS) can be a very difficult task because of the numerous chemical and physical barriers which must be overcome in order for such delivery to be successful. A particularly difficult problem is in long term administration of a drug to patients suffering from CNS related diseases. This is particularly true for patients suffering from various CNS related diseases, such as schizophrenia, obsessive compulsive disorders, sleep disorders, depression, anxiety, anorexia and drug addiction. In addition, there is a need to maintain a steady drug level in patients suffering with these diseases so as to provide an improved efficacy in treatment with lower peak drug concentrations. As a result, many methods have been developed to deliver drugs to the CNS effectively. One such method involves preparation of sustained release formulations. The sustained release formulations may however be of various different types. For example, a drug may be chemically modified into a form called a prodrug, that is capable of

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transforming into its active form slowly, either before or after crossing the blood-brain barrier. An example of such a prodrug delivery system consists of the neurotransmitter dopamine attached to a molecular mask derived from the fat-soluble vitamin niacin. The modified dopamine is taken up into the brain where it is then slowly stripped from its prodrug mask to yield free dopamine. Web site: http://www.delphion.com/details?pn=US06455526__ •

Fluorine-containing amino acid derivatives Inventor(s): Kumagai; Toshihito (Tokyo, JP), Nakazato; Atsuro (Tokyo, JP), Sakagami; Kazunari (Tokyo, JP), Tomisawa; Kazuyuki (Tokyo, JP) Assignee(s): Taisho Pharmaceutical Co., Ltd. (Tokyo, JP) Patent Number: 6,316,498 Date filed: July 27, 2000 Abstract: Fluorine-containing amino acid derivatives represented general formula (I), pharmaceutically acceptable salts thereof or hydrates of the same, wherein X.sup.1 represents hydrogen or fluorine; and R.sup.1 and R.sup.2 are the same or different and each represents hydrogen or lower C.sub.1-10 alkyl. These compounds are useful as drugs, in particular, group 2 metabotropic glutamate receptor agonists for treating and preventing psychiatric disorders such as schizophrenia, anxiety and associated diseases, depression, bipolar disturbance and epilepsy, and neurological diseases such as drug addiction, cognition disorder, Alzheimer's disease, Huntington's chorea, Parkinson's disease, motility disturbance associating muscular stiffness, cerebral ischemia, cerebral insufficiency, spinal cord lesion and head disturbance. Excerpt(s): This invention relates to fluorine-containing amino acid derivatives that are useful as drugs; it relates to novel fluorine-containing amino acid derivatives that are useful for the treatment and prevention of psychiatric disorders such as, for example, schizophrenia, anxiety and associated diseases, neurological diseases such as depression, bipolar disorder and epilepsy, as well as drug dependence, cognitive disorders, Alzheimer's disease, Huntington's chorea, Parkinson's disease, movement impairment associated with muscular stiffness, cerebral ischemia, cerebral insufficiency, spinal cord lesions, and head trauma. This specification is based on Japanese Patent Application, No. Hei 10-15444 [1998], the content of which is herein incorporated by reference, as part of this specification. In recent years, with the repeated cloning of glutamate receptor genes, it has become clear that there are surprisingly many subtypes of glutamate receptors. At present, glutamate receptors are broadly classified into two types: the "ionotropic type", in which the receptor has an ion channel structure, and the "metabotropic type", in which the receptor is coupled to G-proteins (Science, 258, 597603, 1992). Ionotropic receptors are classified pharmacologically into three types: Nmethyl-D-asparaginic acid (NMDA),.alpha.-amino-3-hydroxy-5-methyl isoxazole-4propionate AMPA), and kynate (Science, 258, 597-603, 1992). Metabotropic receptors are classified into eight types, type 1 through type 8 (J. Neurosci., 13, 1372-1378, 1993; Neuropharmacol., 34, 1-26, 1995). Web site: http://www.delphion.com/details?pn=US06316498__

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Method for the application of an active substance patch for controlling or alleviating an addiction Inventor(s): Becher; Frank (Koblenz, DE), Wessling; Werner (Rengsdorf, DE) Assignee(s): LTS Lohmann Therapie - Systeme GmbH (DE) Patent Number: 6,143,320 Date filed: October 16, 1998 Abstract: A method for the application of an active substance patch for controlling or alleviating an addiction such as drug addiction, addiction to pills or analgesia is characterized in that two or more active substance patches are applied simultaneously, sequentially or alternately within a given therapy plan under surveillance of the blood level of the active substance in a way that allows the achievement of an active substance blood level which is high enough for a successful suppression of the addiction and remains constantly effective throughout a useful period of administration. Excerpt(s): The invention relates to a method for the application of an active substance patch for controlling or alleviating an addiction such as drug addiction, addiction to pills or analgesia. Furthermore, the invention relates to a utilization of this method. 1.The improper extraction of active substances and, consequently, "dealing" of the pure active substance is extremely difficult and expensive and thus normally impossible and pointless for the addict. 2. The absorption of the medicinal agent can easily be monitored by a surveillance of the blood level. Web site: http://www.delphion.com/details?pn=US06143320__

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Method of dopaminergic and serotonergic neuron formation from neuroprogenitor cells Inventor(s): Hynes; Mary A. (San Mateo, CA), Rosenthal; Arnon (Burlingame, CA), Ye; Weilan (San Mateo, CA) Assignee(s): Genentech, Inc. (So. San Francisco, CA) Patent Number: 6,277,820 Date filed: April 9, 1998 Abstract: The present invention relates to neuronal formation and methods of treating diseases characterized by abnormalities in the activity of dopaminergic (DA) and serotonergic (5HT) neurons. In particular, the invention relates to a method of forming serotonergic neurons in vitro by contacting neuroprogenitor cells to an effective amount of native sequence, variants and functional fragments of FGF-4, FGF-8 and Shh. Additionally, disclosed is a method for forming dopaminergic neurons by contacting neuroprogenitor cells to an effective amount of FGF-8 and Shh. Further described are compositions, cell culture compositions and medical devices which contain sufficient amount of FGF-8, Shh or FGF-8, Shh and FGF-4 to stimulate differentiation into dopaminergic or serotonergic neurons, respectively. Further described are methods of using serotoneurgic neurons to treat disorders relating to food intake, hormone secretion, stress response, pain and immune function, sexual activity, cardiovascular function and temperature regulation, in particular, depression, proclivity to suicide, violent aggressive behavior, obsessive-compulsive behavior and anorexia/bulimia and schizophrenia. Further described are methods of using dopaminergic neurons to treat disorders relating postural reflexes, movement and reward-associated behaviors,

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specifically, Parkinson's disease, schizophrenia and drug addiction. Further described is the coadministration of a neuronal survival factor, for example, NGF, CNTF, BDNF, NT3, NT-4, aFGF, IL-1.beta., TNF.alpha., IGF-1, IGF-2, TGF-.beta., TGF-.beta.1 or skeletal muscle extract. Excerpt(s): The present invention relates to neuronal formation and methods of treating diseases characterized by abnormalities in and the activity of dopaminergic (DA) and serotonergic (5HT) neurons. The vertebrate nervous system is composed of multiple neuronal and non-neuronal cell types which develop in stereotypic positions along the dorso-ventral (D-V) and anterior-posterior (A-P) axes of the early neural tube. The mechanisms controlling this process, which is essential for subsequent formation of functional neural networks, are not fully understood (reviewed in Lumsden and KrumIauf, (1996) Science 274: 1109-1114; Tanabe and Jessell, (1996) Science 274: 11151123. However, it has been proposed that signaling centers which operate along the two main axes of this system establish an epigenetic grid of Cartesian coordinates, and that neural progenitors assess their location on this grid, assuming distinct cell fates accordingly (e.g. Wolpert, (1969) J. Theor. Biol. 25: 1-47; Rubenstein et al., (1994) Science 266: 578-80. Consistent with the epigenetic grid hypothesis, grafting experiments have epeatedly demonstrated that vertebrate neural progenitors are not genetically predetermined, but instead can acquire new stereotypic identities if moved to ectopic locations in the neural plate (Alvarado-Mallartet al., (1990) Develop. Biol. 139: 75-88; Gardner and Barald, (1991) Develop. 113: 1037-1048; Grapin-Botton et al., Develop. 124: 849-859 (1997); Itasaki et al. (1996) Neuron 16: 487-500; Simon et al. (1995) Current Biol. 5: 205-214. In addition, transplantation, as well as explant culture studies have confirmed the existence of signaling centers which can change the fate of juxtaposed neural progenitors. Thus, signaling centers such as the dorsal ectodermal epidermis, roof plate, floor plate and notochord have been shown to instruct cell fates along the DV axis [reviewed in Tanabe and Jessell (1996) Science 274: 1115-1123; Liem et al. (1997) Cell 91: 127-138] whereas signaling centers located in the prechordal plate, paraxial mesoderm, somitic mesoderm, mid-hindbrain boundary (isthmus) and the anterior neural plate [reviewed in Lumsden and Krumlauf (1996) Science 274: 1109-1114; Dale et al. (1997) Cell 90: 257-269; Foley et al. (1997) Develop. 124: 2983-2996; Grapil-Botton et al. (1997 supra; Muhr et al. (1997) Neuron 19: 487-502; Itasaki et al. (1996) Neuron 16: 487500; Shimamura and Rubenstein, (1997) Develop. 124: 2709-2718; Houart et al., (1998) Nature 391: 788-792] can change cell fate along the A-P axis of the neural tube. Finally, in agreement with the notion that the information grids are established by extra-cellular molecules, a number of secreted proteins and chemicals were shown to modify the fate of neural plate cells in a characteristic fashion. Thus, Sonic hedgehog and BMP proteins were shown to influence cell fate along the D-V axis (reviewed in Tanabe and Jessell (1996), supra; Liem et al. (1997) Cell 91: 127-138, whereas FGF2, FGF8, retinoic acid and Wnt1 can change cell fate along the A-P axis [reviewed in Lumsden and Krumlauf (1996), supra; Crossley et al. (1996) Nature 380: 66-68; Shimamura and Rubenstein (1997), supra.]. Web site: http://www.delphion.com/details?pn=US06277820__

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Methods for preparing pharmaceutical compositions and using same to treat drug addiction Inventor(s): Bombardelli; Ezio (Milan, IT), Morazzoni; Paolo (Milan, IT) Assignee(s): Indena S.p.A. (Milan, IT) Patent Number: 5,904,923 Date filed: November 10, 1997 Abstract: The invention discloses to methods for preparing and using a lipophilic extract of the roots of Salvia miltiorrhyza Bunge for treating drug addiction. The Tanshinone IIA and Miltirone components of such lipophilic extracts are preferably used individually or in combination to treat drug addictions, and in particular, to treat alcohol addiction. Excerpt(s): The present invention relates to pharmaceutical compositions for the treatment of alcohol addiction, characterized in that they contain--as the active principle--a purified lipophilic extract of Salvia miltiorrhyza Bunge. The invention also relates to a process for the preparation of the purified lipophilic extract of Salvia miltiorrhyza Bunge, and the extract thus obtained. Furthermore, the invention relates to the use of the pure active principles contained in this extract (Tanshinone IIA and Miltirone) in the treatment of alcohol addiction and to pharmaceutical compositions for said treatment which contain as the active principles Tanshinone IIA and/or Miltirone. The existing approaches for the treatment of alcoholism, in addition to those of a psychological nature (group therapy, etc.), consist in the use of drugs such as disulfiram and calcium carbamide which act on the metabolism of alcohol, inhibiting hepatic aldehyde-dehydrogenase and therefore raising the hematic levels of acetaldehyde, with all the undesiderable phenomena which occur each time ethanol is taken. According to the present state of the art, the sole plant whose derivatives have been used for the treatment of alcoholism is the Pueraria lobata (Radix puerarie), which is widely used in traditional Chinese medicine and forms the subject of Patent Application WO 93/00896. Web site: http://www.delphion.com/details?pn=US05904923__

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Nornicotine enantiomers for use as a treatment for dopamine related conditions and disease states Inventor(s): Bardo; Michael Thomas (Lexington, KY), Crooks; Peter A. (Lexington, KY), Dwoskin; Linda Phyliss (Lexington, KY) Assignee(s): The University of Kentucky Research Foundation (Lexington, KY) Patent Number: 5,776,957 Date filed: November 15, 1996 Abstract: Optically active nornicotine compounds as a treatment for dopamine-related conditions and disease states. Such disease states include the treatment of myasthenia gravis, Parkinson's disease, Alzheimer's disease, schizophrenia, eating disorders, ulcers, drug addiction and as a substitute for psycho-stimulant self-administration. Excerpt(s): This invention is directed to the use of optically active nornicotine compounds as a treatment for dopamine-related conditions and disease states. Such disease states include the treatment of myasthenia gravis, Parkinson's disease, Alzheimer's disease, shizophrenia, eating disorders, drug addiction and use of nornicotine enantiomers as a substitute for psycho-stimulant self-administration. Many

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disease states and conditions are associated with nicotinic receptors and dopamine release. These include myasthenia gravis, Parkinson's disease, Alzheimer's disease, shizophrenia, eating disorders and drug addiction to name a few. The behavioral effects of nicotine are attributed to an action on the CNS, since most of the effects are blocked by mecamylamine (Clarke, 1987) and more recently by dihydro-.beta.-erythroidine (DH.beta.E; Damaj et al., 1995). Mecamylamine is a CNS-active, noncompetitive nicotinic antagonist (Loiacono et al., 1993; Peng et al., 1994), and DH.beta.E is a selective, competitive nicotinic receptor antagonist (Alkondon and Albuquerque, 1991; Mulle et al., 1991). Mecamylamine blocks nicotine interoceptive cues in discrimination studies (Stolerman et al., 1984), and mecamylamine pretreatment has been shown to influence cigarette smoking behavior and the subjective effects of nicotine (Stolerman et al., 1973; Rose et al., 1994). Web site: http://www.delphion.com/details?pn=US05776957__ •

Opioid diarylmethylpiperazines and piperdines Inventor(s): Boswell; Grady Evan (Cary, NC), Bubacz; Dulce Garrido (Cary, NC), Chang; Kwen-Jen (Chapel Hill, NC), Collins; Mark Allan (Raleigh, NC), Davis; Ann Otstot (Raleigh, NC), McNutt, Jr.; Robert Walton (Durham, NC) Assignee(s): Delta Pharmaceuticals, Inc. (Chapel Hill, NC) Patent Number: 5,658,908 Date filed: August 3, 1994 Abstract: Diarylmethylpiperazine compounds having utility as receptor-binding species, e.g., for mediating analgesia, and for combatting drug addiction, alcohol addiction, and drug overdose. The compounds may be administered orally, rectally, topically, nasally, ophthalmically, or parenterally (subcutaneously, intramuscularly, and intravenously), for veterinary and human use, and include delta receptor and mu receptor binding species. Excerpt(s): This application is a 371 of PCT/GB93/00216 filed Feb. 2, 1993. This invention relates generally to diarylmethyl piperazine and diarylmethyl piperidine compounds having utility as receptor-binding species, e.g., as conjugates in agonist/antagonist pairs for verifying/assaying receptor and neurotransmitter function. The compounds of the invention include benzhydryl piperazine compounds useful as mu and/or delta receptor opioid compounds mediating analgesia, as well as compounds having utility in combatting drug addiction, alcohol addiction, drug overdose, mental illness, urinary incontinence, cough, lung edema, diarrhea, depression, and cognitive, respiratory, and gastro-intestinal disorders. In the study of opioid biochemistry, a variety of endogenous opioid compounds and non-endogenous opioid compounds has been identified. In this effort, significant research has been focused on understanding the mechanism of opioid drug action, particularly as it relates to cellular and differentiated tissue opiate receptors. Web site: http://www.delphion.com/details?pn=US05658908__

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Peptide analog Inventor(s): Malin; David H. (Houston, TX), Payza; Kemal (Silver Spring, MD) Assignee(s): University of Houston - Clearlake (Houston, TX) Patent Number: 5,908,832 Date filed: October 7, 1991 Abstract: The present invention relates to an analog of Neuropeptide FF (e.g., daY8Ra) and to a pharmaceutical composition containing same. The invention further relates to methods of using the analog to attenuate the effects of drug addiction, drug tolerance, drug dependence or of abstinence syndrome. Excerpt(s): The present invention relates to a peptide analog and to methods of using same to attenuate the effects of drug addiction, drug tolerance, drug dependence or of abstinence syndrome. The octapeptide NPFF (Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-amide (SEQ ID NO:1)-amide) was originally isolated by Yang et al from bovine brain (Yang et al, Proc. Natl. Acad. Sci., 82:7757-7761 (1985)). It has also been referred to as "morphinemodulating peptide" or "FMRF-NH.sub.2 -like mammalian octapeptide" (Panula et al, Med. Biology, 65:127-35 (1987)) or Neuropeptide FF (Kivipelto et al, Journal of Comparative Neurology). There are reasons to suspect that NPFF may be an "anti-opiate peptide": NPFF is localized in several brain regions rich in endogenous opioids (Ferrarese et al, Regulatory Peptides, 13:245-52 (1986); Panula et al, Med. Biology, 65:127-35 (1987)), is released from the brain by morphine infusion (Tang et al, Proc. Natl. Acad. Sci., 81:5002-5 (1984)), and potently antagonizes analgesic effects of morphine and certain endogenous opioid peptides (Tang et al, Proc. Natl. Acad. Sci., 81:5002-5 (1984); Yang et al, Proc. Natl. Acad. Sci., 82:7757-7761 (1985); Yang et al, Prog. Clin. Biol. Res., 192:313-22 (1985)). IgG from NPFF antiserum augments morphine and stress-induced analgesia (Kavaliers et al, Peptides, 10:741-5 (1989)). There is also evidence that NPFF may participate in opiate tolerance and dependence. IgG prepared from FMRFa antiserum cross-reacts with NPFF and interferes with morphine tolerance (Tang et al, Proc. Natl. Acad. Sci., 81:5002-5 (1984)). NPFF levels in CSF are markedly increased in opiate dependent rats as compared with non-dependent rats (Malin et al, Peptides, 11:969-972 (1990)). NPFF (2.mu.g i.c.v.) precipitates opiate abstinence syndrome in morphine-dependent rats (Malin et al, Peptides, 11:277-280 (1990)), and NPFF (15.mu.g i.c.v.) induces a quasi-morphine-abstinence syndrome (QMAS) in opiate-naive rats (Malin et al, Peptides, 11:277-280 (1990)) (see also Guzman et al, Neuropeptides 14:253261 (1989); Majane et al, Peptides, 8:657-662 (1987); Majane et al, Peptides, 9:1137-1144 (1988)). Third ventricle infusion of IgG from NPFF antiserum reverses opiate dependence, as evidenced by prevention of naloxone-precipitated abstinence syndrome in morphine-dependent rats (Malin et al, Peptides, 11:969-972 (1990)). The mechanism of action of NPFF is not understood as yet, but a recent receptor binding study in spinal cord membranes suggested that the neuropeptide binds to specific NPFF receptors. The.sup.125 I-Y8Fa binding site showed high affinity for NPFF, whereas opioid ligands failed to compete for binding (Allard et al, Brain Research, 500:169-176 (1989)). Web site: http://www.delphion.com/details?pn=US05908832__

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Pharmaceutical composition containing desoxypeganine for the treatment of drug dependence Inventor(s): Asmussen; Bodo (Bendorf, DE), Hille; Thomas (Neuwied, DE), Hoffmann; Hans-Rainer (Neuwied, DE), Opitz; Klaus (Munster, DE) Assignee(s): HF Aezneimittelforschung GmbH (Werne, DE), LTS Lohmann TherapieSysteme AG (Andernach, DE) Patent Number: 6,599,511 Date filed: October 17, 2001 Abstract: Desoxypeganine and its pharmaceutically acceptable acid addition salts can be used in the treatment of drug addiction or drug dependence. Said substances are administered preferably in a continuos and controlled manner. The pharmaceutical administration form enables controlled release, e.g. for oral transdermal or another route of parenteral administration. Excerpt(s): Desoxypeganine and/or its pharmaceutically acceptable acid addition salts can be used for the treatment of drug dependence. These substances are administered in a controlled manner, preferably in a continuous manner. The pharmaceutical administration form makes controlled release possible for, for example, oral, transdermal or alternatively parenteral administration. The invention relates to the use of desoxypeganine and its pharmaceutically suitable acid addition salts for the treatment of drug dependence and/or drug addiction. These compounds are released, for example, continuously or otherwise in a controlled manner from appropriate pharmaceutical formulations, which are administered, for example, orally, transdermally or otherwise parenterally. Such administration forms can also make subcutaneous, sublingual or intramuscular administration possible. Finally, administration as an implant is also possible. The term parenteral, however, also comprises other administration forms apart from the oral form, i.e., for example, also rectal, intravenous, intramuscular, intraoperitoneal and nasal administration. Desoxypeganine or a pharmaceutically acceptable acid addition salt or a mixture of base and salt is used for the substitution therapy of drug addicts such as, for example, opiate addicts, for example heroin addicts or cocaine addicts. Web site: http://www.delphion.com/details?pn=US06599511__

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Subcutaneous implant for delivery of hydromorphone Inventor(s): Grossman; Stuart A. (Towson, MD), Leong; Kam W. (Ellicott City, MD), Lesser; Glenn J. (Baltimore, MD), Lo; Hungnan (Baltimore, MD) Assignee(s): Axxia Technologies (Bethesda, MD) Patent Number: 5,858,388 Date filed: January 30, 1997 Abstract: A non-abusable, non-inflammatory, biocompatible, non-biodegradable, subcutaneous, polymeric implant for the prolonged, controlled release of hydromorphone with near zero-order kinetics is described. Methods of alleviating cancer pain and treating opioid drug addiction with the implant are also described. Excerpt(s): This invention relates to a unique device for the chronic subcutaneous administration of a potent opioid in a form that renders it difficult to divert for illicit use and ensures prolonged steady release of this agent, thereby providing long term pain

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relief or treatment of opioid drug addiction, and preventing the potentially lethal consequences of an uneven release of drug from the device. Approximately 70% of patients with cancer experience pain attributable to their neoplasm or its therapy. As life expectancy has increased in developed and developing countries, cancer and cancerrelated pain have become major social and medical concerns. The worldwide availability of opioid analgesics, the primary therapy for most cancer-related pain, varies greatly. In 1991, 20 developed countries accounted for 86% of the morphine consumed in the world while the remaining 14% of morphine was consumed in the remaining countries having the majority of the world's population. (Joranson, D. E., Journal of Pain and Symptom Management, 8(6):353-360, 1993). The scant use of opiates for the relief of cancer pain for the majority of the world's population is a result of many factors including concerns over drug diversion for illicit use and addiction. Further, many patients with cancer-related pain require long-term continuous dosing of opioid analgesics which often necessitates the ingestion of multiple pills or tablets many times a day. Compliance with this dosing scheme is often poor. Further, enteral drug delivery is poorly tolerated or prohibited in many patients with cancer-related pain in whom continuous drug delivery is a necessity. However, continuous parenteral delivery of opioid analgesics is expensive, cumbersome, and dependent upon the availability of refrigeration, catheters, pumps and trained personnel. Web site: http://www.delphion.com/details?pn=US05858388__ •

Telethermometric psychological evaluation by monitoring of changes in skin perfusion induced by the autonomic nervous system Inventor(s): Anbar; Michael (145 Deer Run Rd., Amherst, NY 14221-1823) Assignee(s): none reported Patent Number: 5,771,261 Date filed: September 13, 1995 Abstract: The present invention comprises methods and apparatus for assessment of the effects mental stress involving the measurement of periodic changes in skin perfusion. Using a remotely mounted infrared camera, dynamic area telethermometry (DAT) measures the autonomic nervous activity by monitoring and quantitatively analyzing the modulation of cutaneous perfusion. When people gets "nervous" their sympathetics "act up" and they blush (vasodilates) or becomes pale (vasoconstricts). A DAT test of the face proves to be a superior "lie detector" test since emotional stress is reflected in an autonomic nervous response that can be measured remotely. DAT is much more sensitive than any visual assessment of skin color or than instrumental measurement of diaphoresis. Not only is it more reliable than currently used polygraph tests, but its noncontact administration is so simple and innocuous that it could be done without the subject's awareness. Furthermore, the same device can be used to meet the needs of a variety of psychiatric and psychological evaluation problems, including depression, drug addiction and dementia, as well as psychological learning disabilities. Excerpt(s): The present invention relates generally to monitoring of the response of the autonomic nervous system to mental stress, involving the measurement of periodic changes in skin perfusion (with blood), which are associated with the regulation of skin temperature by the autonomic system. While this invention is related to other techniques used to measure autonomic hyperactivity such as excessive perspiration or changes heart rate, it is unique in making the measurement remotely, without physical contact with the subject, and in continuously monitoring informative physiological

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parameters on different exposed parts of the human body, especially on the face. The present invention has many significant differences and advantages over older autonomic nervous system tests known in the art. It is well known that the autonomic nervous system is affected by mental stress, resulting in changes in a number of physiological parameters. These include higher heart-rate, higher blood pressure, becoming pale or blushing, as well as exhibiting excessive perspiration (enhanced sudomotor activity); the latter is often detected by decreased galvanic skin resistance. As pointed out by Dr. Lykken in 1991, in Integrative Physiological & Behavioral Science 26: 214-222, by Dr. Steinbrook in 1992 in the New England Journal of Medicine 327:122-123, and by Dr. Furedy in 1993 in the International Journal of Psychophysiology 15:263-267, the classical polygraph tests based primarily on monitoring sudomotor activity are unreliable. Although computerized correlation can significantly increase the reliability of monitoring several interdependent physiological parameters, as was recently pointed out by Dr. Yankee in the Journal of Forensic Science 40:63-68, 1995, the use of polygraphs as "lie detectors" is still very problematic. As recently as 1994, trained interviewers have been used to overcome the shortcomings of polygraph tests, as described in the Journal of Forensic Science 39: 793-807, 1994. However, also this timeconsuming subjective approach has a very limited reliability, as was shown by Dr. Ekman in an extensive study published in American Psychologist 46:913-920, 1991. The use of electroencephalography (EEG) to monitor event-related brain potentials is probably more reliable than the conventional polygraph, but it is impractical as a routine technique from the standpoints of the cost and time involved. The same is true of magnetoencephalography which can measure brain activity without contact, but only in a sophisticated, highly controlled and costly environment. 1. The limitations of the devices used to gather the phychophysiological information. These include the sensitivity and precision of the measuring devices, the level of sophistication of the data analysis, the skill needed to apply these devices, the time it takes to accumulate reliable data, and the cooperation required from the subjects who undergo such a test. Web site: http://www.delphion.com/details?pn=US05771261__ •

Therapeutic uses of polymers and oligomers comprising gamma-hydroxybutyrate Inventor(s): Martin; David P. (Arlington, MA), Williams; Simon F. (Sherborn, MA) Assignee(s): Metabolix, Inc. (Cambridge, MA), Tepha, Inc. (Cambridge, MA) Patent Number: 6,623,730 Date filed: September 14, 2000 Abstract: Oligomers and polymer compositions are provided which comprise GHB and produce GHB after administration in vivo. Devices for the storage and delivery of these polymers and oligomers are also provided. These oligomers and polymer compositions are useful in a variety of applications. The compositions can be used therapeutically, for example, in the treatment of patients with narcolepsy, chronic schizophrenia, catatonic schizophrenia, atypical psychoses, chronic brain syndrome, neurosis, alcoholism, drug addiction and withdrawal, Parkinson's disease and other neuropharmacological illnesses, hypertension, ischemia, circulatory collapse, radiation exposure, cancer, and myocardial infarction. Other uses for the compositions include anesthesia induction, sedation, growth hormone production, heightened sexual desire, anorectic effects, euphoria, smooth muscle relaxation, muscle mass production, and sleep, including rapid eye movement sleep. In a still further embodiment, the oligomers and polymers may be used to produce absence seizures.

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Excerpt(s): The present invention is generally in the field of therapeutic formulations for delivering gamma-hydroxybutyrate. Gamma-hydroxybutyrate ("GHB") is a naturally occurring substance that is widely distributed in the mammalian body, being present, for example, in the brain, kidney, heart, liver, lung and muscle (Nelson, et al., J. Neurochem., 37:1345-48 (1981)). When administered exogenously, GHB readily crosses the blood-brain barrier and penetrates the brain, producing a number of neuropharmacological effects. For over 35 years, GHB has been used as an intravenous agent for the induction of anesthesia and for long-term sedation, without serious sideeffects on circulation or respiration (Entholzner, et al., Anesthetist, 44:345-50 (1995)), and without an accompanying seizure-inducing activity in humans (Tunnicliff, Clinical Toxicology, 35:581-90 (1997)). Patients with chronic schizophrenia characterized by autism, inactivity, and apathy; catatonic schizophrenia; chronic schizophrenia with hallucination and delusion; atypical psychoses; and chronic brain syndrome due to trauma, as well as neurotic patients (Tanaka, et al., Folia Psychiatrica et Neurologica, 20:9-17 (1966)), have all been treated using GHB. It also has recently been suggested that GHB may be a suitable agent for total intravenous anesthesia in patients with coronary artery disease (Kleinschmidt, et al., Euro. J. Anesthesiology, 14:590-99 (1997)), as well as for sedation during spinal anesthesia (Kleinschmidt, et al., Euro. J. Anaesthesiology, 16:23-30 (1999)). In addition to these uses, GHB also is used to treat narcolepsy, a chronic sleep disorder that usually begins in adolescence or early adulthood and lasts hroughout life. Narcolepsy is characterized by sudden sleep attacks lasting usually from a few to thirty minutes, paralysis upon lying down or waking, visual or auditory hallucinations at the onset of sleep, and temporary loss of muscle tone while awake (cataplexy) or asleep. Treatment with GHB substantially reduces these signs and symptoms of narcolepsy in humans (Scharf, Sleep, 21:507-14 (1998)). Web site: http://www.delphion.com/details?pn=US06623730__ •

Transdermal therapeutic system (TTS) containing vitamin E for the treatment of drug dependency Inventor(s): Bracher; Daniel (Holzkirchen, DE) Assignee(s): Hexal AG (Holzkirchen, DE) Patent Number: 5,989,585 Date filed: June 23, 1998 Abstract: The invention relates to a transdermal therapeutic system (TTS) for the administration of active agents for substitution treatment of drug dependency or drug addiction. Excerpt(s): The present invention relates to the transdermal administration of substances which are suited for substitution treatment of drug dependents and drug addicts, in particular to the structure of a transdermal therapeutic system (TTS) and a method for administration of such substances through intact skin. Concerning the suited substances, one could contemplate for example methadone, acetylmethadol, naltrexon, codeine or dihydrocodeine. In principle, the application of other strongly effective pain relievers is possible, for example morphine or buprenorphine. Methadone, mentioned as an example, is used in substitution therapy for opiate addicts, for example heroin addicts. One uses the L-enantiomorph as hydrochloride in the form of an aqueous solution, which is applied orally. The strongly analgesic effect of methadone is also used for drug dependent AIDS patients. Transdermal therapeutic systems for combating drug dependency and drug addiction are known, for example WO-A-9 219 226, WO-A-9 410

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987, EP-B-0 113 562, EP-B-0 117 027 and EP-B-0 280 413. The document WO-A-9 219 226 describes an application system containing lobeline for combating drug dependency. WO-A-9 410 987 relates to a combination of two application systems containing methadone. In EP-B-0 113 562, a container is suggested with which methadone can be applied through the skin. EP-B-0 117 027 describes a salve, a cream or a gel with an amount of methadone. Finally, a pharmaceutical composition is suggested in EP-B-0 280 413 for transdermal application of methadone with the aid of a permeation accelerator. Web site: http://www.delphion.com/details?pn=US05989585__ •

Use of gamma-hydroxybutyric acid amides in the treatment of drug addiction and in particular of alcoholism Inventor(s): Cacciaglia; Roberto (Ospedaletti, IT), Guano; Lorenza (Sanremo, IT), Loche; Antonella (Sanremo, IT), Perlini; Vincenzo (Matelica, IT) Assignee(s): Laboratoric Farmaceutico C.T. S.r.l. (Sanremo, IT) Patent Number: 6,436,998 Date filed: September 2, 1999 Abstract: The present invention relates to the use of.gamma.-hydroxybutyric acid amides in the treatment of drug addiction and alcoholism, more particularly in reducing chronic alcoholics' desire for and habit of consuming alcoholic drinks and in the treatment of the syndrome of abstinence from alcohol. Excerpt(s): The present invention relates to the use of amides of.gamma.-hydroxybutyric acid, herein referred to as GHB, in the treatment of drug addiction, such as heroine, cocaine and, in particular, in the treatment of alcoholism, and more particularly in reducing chronic alcoholics desire for and habit of consuming alcoholic drinks and in the treatment of abstinence syndrome. The salts of 4-hydroxybutyric acid, e.g. the sodium salt, proved to be effective both in the treatment of the syndrome of abstinence from alcohol and in reducing the desire for and addiction to alcohol in alcoholic patients and disclosed in EP-A-344,704 and in the treatment of drug addiction, as reported in WO 93/00083. One of the advantages of said salts is that they do not cause the inconveniences of Disulfiram (Antabuse.RTM.), a drug having several untoward effects, such as for example the symptoms known as the "acetaldehyde syndrome", which may also result in fatality. The sodium salt of GHB is absorbed very quickly by the gastroenteric apparatus with a maximum concentration peak already at about 35-40 min after administration. However, it presents a half-life time of about 20-25 min, its elimination from the body being rather quick [EP-A-635,265]. Web site: http://www.delphion.com/details?pn=US06436998__

Patent Applications on Drug Addiction As of December 2000, U.S. patent applications are open to public viewing.9 Applications are patent requests which have yet to be granted. (The process to achieve a patent can take several years.) The following patent applications have been filed since December 2000 relating to drug addiction: 9

This has been a common practice outside the United States prior to December 2000.

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1,4-piperazine derivatives Inventor(s): Kelly, Michael G.; (Newbury Park, CA), Palmer, Yvette L.; (Yardley, PA) Correspondence: Egon E. Berg; American Home Products Corporation; Patent Law Department - 2B; One Campus Drive; Parsippany; NJ; 07054; US Patent Application Number: 20010014680 Date filed: March 30, 2001 Abstract: Compounds of the formula 1are useful for the treatment of disorder of the central nervous system including anxiety, depression, panic, alcohol and drug addiction, sexual dysfunction, sleep disorders, cognitive disorders, Alzheimer's disease and Parkinson's disease. Excerpt(s): This application claims the benefit of U.S. Provisional Application No. 60/150,702, filed Dec. 17, 1998. U.S. Pat. No. 4,977,159 describes 2-[(4-piperidyl) methyl]1,2,3,4-tetrahydro-9H-pyrido[3,4-B]indole derivatives and their application in treating depressive state, anxiety state or hypertension. This invention relates to novel arylpiperidine derivatives. In accordance with this invention are provided novel arylpiperadine derivatives which are agonists and antagonists of the 5HT1A receptor subtype. By virtue of their high binding affinity to the 5HT1A receptor, compounds of the present invention are useful for the treatment of central nervous system (CNS) disorders such as depression, anxiety, panic, OCD, sleep disorders, sexual dysfunction, alcohol and drug addiction, cognition enhancement, Alzheimer's disease, Parkinson's disease, obesity and migraine. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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3,7-dihydro-purine-2,6-dione derivatives as CRF receptor ligands Inventor(s): Hartz, Richard A.; (Kennett Square, PA) Correspondence: Stephen B. Davis; Bristol-myers Squibb Company; Patent Department; P O Box 4000; Princeton; NJ; 08543-4000; US Patent Application Number: 20030119831 Date filed: November 7, 2002 Abstract: Compounds provided herein are 3,7-dihydro-purine-2,6-dione derivatives of Formula (I): 1Such compounds are particularly useful as CRF receptor ligands, and hence, in the treatment of various neurologically-related disorders such as affective disorder, anxiety and depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heartrelated diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis or hypoglycemia. Excerpt(s): This application claims the priority benefit of U.S. Provisional Appl No. 60/331,829, filed Nov. 20, 2001, the disclosure of which is incorporated herein by reference in its entirety. This invention relates to 3,7-dihydro-purine-2,6-dione derivatives as CRF antagonists, pharmaceutical compositions containing the same, and methods of using the same in the treatment of psychiatric disorders and neurological diseases including affective disorder, anxiety related disorders, depression, headache,

Patents 135

post-traumatic stress disorder, supranuclear palsy, Alzheimer's disease, head and spinal cord traumas, anorexia nervosa or other feeding disorders, as well as treatment of irritable bowel syndrome, gastrointestinal diseases, cardiovascular or heart-related diseases, immune supression, human immunodeficiency virus infections, fertility problems, or a disorder the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF. Corticotropin releasing factor (herein referred to as CRF), a 41 amino acid peptide, is the primary physiological regulator of proopiomelanocortin (POMC)-derived peptide secretion from the anterior pituitary gland [J. Rivier et al., Proc. Nat. Acad. Sci. (USA) 80:4851 (1983); W. Vale et al., Science 213:1394 (1981)]. In addition to its endocrine role at the pituitary gland, immunohistochemical localization of CRF has demonstrated that the hormone has a broad extrahypothalamic distribution in the central nervous system and produces a wide spectrum of autonomic, electrophysiological and behavioral effects consistent with a neurotransmitter or neuromodulator role in brain [W. Vale et al., Rec. Prog. Horm. Res. 39:245 (1983); G. F. Koob, Persp. Behav. Med. 2:39 (1985); E. B. De Souza et al., J. Neurosci. 5:3189 (1985)]. There is also evidence that CRF plays a significant role in integrating the response of the immune system to physiological, psychological, and immunological stressors [J. E. Blalock, Physiological Reviews 69:1 (1989); J. E. Morley, Life Sci. 41:527 (1987)]. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Agent for improving learning or memory Inventor(s): Hirano, Noriyuki; (Kanagawa, JP), Kamei, Junzo; (Kanagawa, JP), Kawamura, Kuniaki; (Kanagawa, JP), Nagase, Hiroshi; (Kanagawa, JP) Correspondence: Birch Stewart Kolasch & Birch; PO Box 747; Falls Church; VA; 220400747; US Patent Application Number: 20030186986 Date filed: May 30, 2002 Abstract: Disclosed is an agent for improving learning and/or memory, which is useful for therapy of dementia accompanying disorder of memory due to a cerebrovascular disease, neurodegenerative disease such as Alzheimer's disease, endocrine disease, nutritional or metabolic disorder, infectious disease, drug addiction or the like. The agent for improving learning and/or memory according to the present invention comprises as an effective ingredient an isoquinoline derivative having a specific structure, such as (4aR, 12aR)-2-methyl-4a-(3-hydroxyphenyl)-1,2,3,4,4a,5- ,12,12aoctahydro-quinoline[2,3-g]isoquinoline or a pharmaceutically acceptable salt thereof. Excerpt(s): The present invention relates to an agent for improving learning and/or memory comprising as an effective ingredient a quinolinoisoquinoline derivative or a pharmaceutically acceptable acid addition salt thereof. Learning means to acquire change in behavior, which continues for a relatively long time, which is caused by experience or practice, or the process for acquiring the change in behavior. Memory means to retain information for a certain time, which information is obtained through experience, and to retrieve the information as required. However, the definitions of these two concepts are not simple, and are not independent for each other but most of them overlap. Therefore, learning ability and mneme are often measured by similar experiments in the field of behavioral pharmacology. Learning includes the steps of encoding, storage, recognition and retrieval. Even if one of these steps is inhibited, disorder of memory occurs (Seiden, L. S. & Dykstra, L. A., Psychopharmacology, a

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biochemical and behavioral approach. Van Nostrand Reinhold Co., New York(1077)). A representative disease accompanying memory disorder and/or learning disability is dementia. The term "dementia" means the continuous state in which the intellectual ability is reduced, which intellectual ability had ever developed to the normal level. Symptoms of dementia include, in addition to memory disorder and/or learning disability, mood disorder, emotional disorder, intellectual disturbance and psychomotor disturbance. Improvement of memory disorder which likely to cause serious problems in social life is an indispensable action of anti-dementia drugs. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Aminoalkyl substituted 5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole and tetrahydro-9H-pyrimidino[4,5-b]indole derivatives: CRF1 specific ligands

5,6,7,8-

Inventor(s): Darrow, James W.; (Wallingford, CT), Horvath, Raymond F.; (North Branford, CT), Maynard, George D.; (Clinton, CT) Correspondence: Steven J. Sarussi; Mcdonnell Boehnen Hulbert & Berghoff; 32nd Floor; 300 S. Wacker Drive; Chicago; IL; 60606; US Patent Application Number: 20030105117 Date filed: August 27, 2002 Abstract: Disclosed are compounds of the formula: 1whereinAr, R.sup.1, W, X and m are substituents as defined herein.These compounds are modulators of CRF receptors and are therefore useful for treating affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia or a disorder the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, in mammals, comprising: administering to the mammal a therapeutically effective amount of a compound of Formula I. Excerpt(s): The present invention relates to aminoalkyl substituted 5,6,7,8-tetrahydro9H-pyridino[2,3-b]indole and 5,6,7,8-tetrahydro-9H-pyrimidino[4,5-b]indole derivatives, pharmaceutical compositions containing such compounds and their use in treating psychiatric disorders, neurological diseases, immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress. Corticotropin releasing factor (herein referred to as CRF), a 41 amino acid peptide, is the primary physiological regulator of proopiomelanocortin (POMC) derived peptide secretion from the anterior pituitary gland [J. Rivier et al., Proc. Nat. Acad. Sci. (USA) 80:4851 (1983); W. Vale et al., Science 213:1394 (1981)]. In addition to its endocrine role at the pituitary gland, immunohistochemical localization of CRF has demonstrated that the hormone has a broad extrahypothalamic distribution in the central nervous system and produces a wide spectrum of autonomic, electrophysiological and behavioral effects consistent with a neurotransmitter or neuromodulator role in brain [W. Vale et al., Rec. Prog. Horm. Res. 39:245 (1983); G. F. Koob, Persp. Behav. Med. 2:39 (1985); E. B. De Souza et al., J. Neurosci. 5:3189 (1985)]. There is also evidence that CRF plays a significant role in integrating the response of the immune system to physiological, psychological, and immunological stressors [J. E.

Patents 137

Blalock, Physiological Reviews 69:1 (1989); J. E. Morley, Life Sci. 41:527 (1987)]. Clinical data provide evidence that CRF has a role in psychiatric disorders and neurological diseases including depression, anxiety-related disorders and feeding disorders. A role for CRF has also been postulated in the etiology and pathophysiology of Alzheimer's disease, Parkinson's disease, Huntington's disease, progressive supranuclear palsy and amyotrophic lateral sclerosis as they relate to the dysfunction of CRF neurons in the central nervous system [for review see E. B. De Souza, Hosp. Practice 23:59 (1988)]. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Antipsychotic aminomethyl derivatives of 7,8-dihydro-3H-6,9-dioxa-2,3-diaz- acyclopenta[a]naphthalene Inventor(s): Stack, Gary P.; (Ambler, PA), Tran, Megan; (Hoboken, NJ) Correspondence: Rebecca R. Barrett; Five Giralda Farms; Patent Law Department; Madison; NJ; 07940; US Patent Application Number: 20020183331 Date filed: April 23, 2002 Abstract: Compounds of the formula: 1useful for treatment of disorders of the dopaminergic system, such as schizophrenia, schizoaffective disorder, bipolar disorder, Parkinson's disease, L-DOPA induced pychoses and dyskinesias, Tourette's syndrome and hyperprolactinemia and in the treatment of drug addiction such as the addiction to ethanol, nicotine or cocaine and related illnesses. Excerpt(s): This invention relates to antipsychotic aminomethyl derivatives of 7,8dihydro-3H-6,9-dioxa-2,3-diaza-cyclopenta[a]naphthalene, to processes for preparing them, methods of using them and to pharmaceutical compositions containing them. The clinical treatment of schizophrenia has long been defined by the dopamine hypothesis of schizophrenia, which holds that schizophrenia is a result of hyperactivity of dopaminergic neurotransmission, particularly in limbic brain structures such as nucleus accumbens (the mesolimbic dopamine system). Indeed, the positive symptoms of schizophrenia (hallucinations, delusions, thought disorder) are successfully treated with neuroleptics, which block dopamine receptors. However, such treatment is accompanied by the production of movement disorders or dyskinesias (extrapyramidal side effects), due to the blockade of nigrostriatal dopamine receptors. In addition, neuroleptics do not treat the negative symptoms of schizophrenia (social withdrawal, anhedonia, poverty of speech) which are related to a relative hypoactivity of neurotransmission in the mesocortical dopamine system and which respond to treatment by dopamine agonists. Efforts to induce antipsychotic activity with dopamine autoreceptor agonists have been successful (Corsini et al., Adv. Biochem. Psychopharmacol. 16, 645-648, 1977; Tamminga et al., Psychiatry 398-402, 1986). Dopamine autoreceptor agonists produce a functional antagonism of dopaminergic neurotransmission by the reduction of neuronal firing and the inhibition of dopamine synthesis and release. Since dopamine autoreceptor agonists are partial agonists at postsynaptic dopamine receptors, they provide a residual level of stimulation sufficient to prevent the production of dyskinesias. Indeed, partial agonists are capable of functioning as either agonists or antagonists depending on the level of dopaminergic stimulation in a given tissue or brain region, and would therefore be expected to have efficacy versus both positive and negative symptoms of schizophrenia. Thus, novel dopamine partial agonists are of great interest for the treatment of schizophrenia and related disorders.

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Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Aryloxy piperidinyl derivatives for the treatment of depression Inventor(s): Mewshaw, Richard E.; (King of Prussia, PA), Zhou, Dahui; (East Brunswick, NJ), Zhou, Ping; (Plainsboro, NJ) Correspondence: Joseph M. Mazzarese; American Home Products Corporation; Patent Law Department; Five Giralda Farms; Madison; NJ; 07940; US Patent Application Number: 20020091141 Date filed: November 15, 2001 Abstract: This invention provides compounds useful in treating serotonin-related central nervous system disorders, including anxiety, generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, sleep disorders, sexual dysfunction, alcohol and drug addiction, Alzheimer's disease, Parkinson's disease, obesity and migraine, the compounds having the general formula: 1wherein: R.sub.1 and R.sub.2 may each be H or an alkyl or alkoxy group; or R.sub.1 and R.sub.2 may be concatenated to form a bicyclic ring system with the phenyl ring to which they are bound; X is selected from hydrogen, halogen, cyano, C.sub.1--C.sub.6 alkoxy; Z is (CH.sub.2)n or carbonyl; n is 0, 1 or 2; the dashed line indicates an optional double bond; or a pharmaceutically acceptable salt thereof. Excerpt(s): This application claims priority from copending provisional application(s) serial No. 60/252,140 filed on Nov. 16, 2000, the entire disclosure of which is hereby incorporated by reference. This invention relates to new aryloxy indole derivatives as pharmaceuticals which are useful for the treatment in mammals of diseases affected by disorders of the serotonin-affected neurological systems, such as depression, anxiety, panic disorder, obsessive-compulsive disorder, sleep disorders, sexual dysfunction, alcohol and drug, addiction, Alzheimer's disease, Parkinson's disease, obesity and migraine, as well as methods of enhancing cognition. Pharmaceuticals which enhance serotonergic neurotransmission are of useful benefit for the treatment of many psychiatric disorders, including depression and anxiety. The first generation of nonselective serotonin-affecting drugs operated through a variety of physiological functions which endowed them with several side effect liabilities. The more currently prescribed drugs, the selective serotonin (5-HT) reuptake inhibitors (SSRIs), act predominately by inhibiting 5-HT, which is released at the synapses, from being actively removed from the synaptic cleft via a presynaptic serotonin transport carrier. Since SSRIs require several weeks before they exert their full therapeutic effect, this 5-HT blockade mechanism per se cannot account for their therapeutic activity. It is speculated that this two week induction which occurs before a full antidepressant effect is observed, is due to the involvement of the 5-HT.sub.1A autoreceptors which suppress the firing activity of 5-HT neuron, causing a dampening of the therapeutic effect. Studies suggest that after several weeks of SSRI administration, a desensitization of the 5-HT autoreceptors occurs allowing a full antidepressant effect in most patients. Recent studies by Artigas et al. (Trends Neurosci., 1996, 19, 378-383) suggest a combination of 5-HT.sub.1A activity and inhibition of 5-HT uptake within a single molecular entity can achieve a more robust and fast-acting antidepressant effect. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Aryloxy-and arylthiosubstituted pyrimidines and triazines and derivatives thereof Inventor(s): Chorvat, Robert John; (West Chester, PA), Rajagopalan, Parthasarathi; (Wilmington, DE) Correspondence: Bristol-myers Squibb Squibb Pharma Company; Patent Department; P.O. Box 4000; Princeton; NJ; 08543-4000; US Patent Application Number: 20020040026 Date filed: October 2, 2001 Abstract: The present invention provides novel compounds, and pharmaceutical compositions thereof, and methods of using same in the treatment of affective disorders, anxiety, depression, post-traumatic stress disorders, eating disorders, supranuclear palsey, irritable bowl syndrome, immune supression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa, drug and alcohol withdrawal symptoms, drug addiction, inflammatory disorders, or fertility problems. The novel compounds provided by this invention are those of formula: 1wherein R.sup.1, R.sup.3, R.sup.5, Q, Z, Y, V, X and X' are as defined herein. Excerpt(s): The present invention relates to novel compounds, pharmaceutical compositions containing said compounds and to methods of using same in the treatment of affective disorders, anxiety, depression, post-traumatic stress disorders, eating disorders, supranuclear palsey, irritable bowl syndrome, immune supression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa, drug and alcohol withdrawal symptoms, drug addiction, inflammatory disorders, or fertility problems. Corticotropin releasing factor (herein referred to as CRF), a 41 amino acid peptide, is the primary physiological regulator of proopiomelanocortin(POMC)-derived peptide secretion from the anterior pituitary gland [J. Rivier et al., Proc. Nat. Acad. Sci. (USA) 80:4851 (1983); W. Vale et al., Science 213:1394 (1981)]. In addition to its endocrine role at the pituitary gland, immunohistochemical localization of CRF has demonstrated that the hormone has a broad extrahypothalamic distribution in the central nervous system and produces a wide spectrum of autonomic, electrophysiological and behavioral effects consistent with a neurotransmitter or neuromodulator role in brain [W. Vale et al., Rec. Prog. Horm. Res. 39:245 (1983); G. F. Koob, Persp. Behav. Med. 2:39 (1985); E. B. De Souza et al., J. Neurosci. 5:3189 (1985)]. There is also evidence demonstrating that CRF may also play a significant role in integrating the response of the immune system to physiological, psychological, and immunological stressors [J. E. Blalock, Physiological Reviews 69:1 (1989); J. E. Morley, Life Sci. 41:527 (1987)]. Clinical data has demonstrated that CRF may have implications in psychiatric disorders and neurological diseases including depression, anxiety-related disorders and feeding disorders. A role for CRF has also been postulated in the etiology and pathophysiology of Alzheimer's disease, Parkinson's disease, Huntington's disease, progressive supranuclear palsy and amyotrophic lateral sclerosis as they relate to the dysfunction of CRF neurons in the central nervous system [for review see E. B. De Souza, Hosp. Practice 23:59 (1988)]. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Cocaine receptor binding ligands Inventor(s): Abraham, Philip; (Cary, NC), Boja, John W.; (Cuyahega Falls, OH), Carroll, Frank I.; (Durham, NC), Kuhar, Michael J.; (Atlanta, GA), Lewin, Anita H.; (Chapel Hill, NC) Correspondence: Oblon Spivak Mcclelland Maier & Neustadt PC; Fourth Floor; 1755 Jefferson Davis Highway; Arlington; VA; 22202; US Patent Application Number: 20030023090 Date filed: September 20, 2001 Abstract: The invention relates to novel compounds which show high affinity for cocaine receptors in the brain, particularly dopamine and serotonin transporter sites. The compounds may be used as imaging or pharmaceutical agents, in the diagnosis and treatment of drug addiction, depression, anorexia and neurodegenerative diseases. Excerpt(s): This application is a continuation-in-part application of U.S. patent application Ser. No. 08/706,263, filed Sep., 4, 1996, which is a continuation in part of U.S. patent application Ser. No. 08/506,541, filed Jul. 24, 1995, which is a continuation-in-part of (1) U.S. patent application Ser. no. 07/972,472, filed Mar. 23, 1993, which issued May 9, 1995 as U.S. Pat. No. 5,413,779; (2) U.S. patent application Ser. No. 08/164,576, filed Dec. 10, 1993, which is in turn a continuation-in-part of U.S. patent application Ser. No. 07/792,648, filed Nov. 15, 1991, now U.S. Pat. No. 5,380,848, which is in turn a continuation-in-part of U.S. patent application Ser. No. 07/564,755, filed Aug. 9, 1990, now U.S. Pat. No. 5,128,118 and U.S. PCT Application PCT/US91/05553, filed Aug. 9, 1991, filed in the U.S. PCT Receiving Office and designating the United States; and (3) U.S. patent application Ser. No. 08/436,970, filed May 8, 1995, all of which are incorporated herein by reference in their entirety. This invention is directed to a class of binding ligands for cocaine receptors and other receptors in the brain. Specifically, a novel family of compounds shows high binding specificity and activity, and, in a radiolabeled form, can be used to bind to these receptors, for biochemical assays and imaging techniques. Such imaging is useful for determining effective doses of new drug candidates in human populations. In addition, the high specificity, slow onset and long duration of the action of these compounds at the receptors makes them particularly well suited for therapeutic uses, for example as substitute medication for psychostimulant abuse. Some of these compounds may be useful in treating Parkinson's Disease or depression, by virtue of their inhibitory properties at monoamine transporters. Sites of specific interest included cocaine receptors associated with dopamine (DA) transporter sites. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Dihydroimidazo[2,1-b]thiazole antidepressant agents

and

dihydro-5h-thiazolo[3,2-A]pyrimidines

as

Inventor(s): Doyle, Kevin James; (Nottingham, GB), Kerrigan, Frank; (Nottingham, GB), Watts, John Paul; (Nottingham, GB) Correspondence: Bromberg & Sunstein Llp; 125 Summer Street; Boston; MA; 02110-1618; US Patent Application Number: 20030166628 Date filed: January 16, 2003

Patents 141

Abstract: The present invention relates to certain novel substituted dihydroimidazo[2,1b]thiazole and dihydro-5H-thiazolo[3,2-a]pyrimidine compounds of Formula (I) including pharmaceutically acceptable salts thereof in which have affinity for 5HT.sub.1A receptors and which inhibits neuronal reuptake of 5-hydroxytryptamine and/or noradrenaline, to processes for their preparation, to pharmaceutical compositions containing them and to their use in the treatment of depression, anxiety, psychoses (for example schizophrenia), tardive dyskinesia, obesity, drug addiction, drug abuse, cognitive disorders, Alzheimer's disease, obsessive-compulsive behaviour, panic attacks, social phobias, eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperlipidaemia, stress, as an aid to smoking cessation and in the treatment and/or prophylaxis of seizures, neurological disorders such as epilepsy and/or in which there is neurological damage such as stroke, brain trauma, cerebral ischaemia, head injuries and haemorrhage. Excerpt(s): The present invention relates to certain novel substituted dihydroimidazo[2,1-b]thiazole and dihydro-5H-thiazolo[3,2-a]pyrimidine compounds which have affinity for 5-HT.sub.1A receptors and which inhibit neuronal reuptake of 5hydroxytryptamine and/or noradrenaline, to processes for their preparation, to pharmaceutical compositions containing them and to their use in the treatment of depression, anxiety, psychoses (for example schizophrenia), tardive dyskinesia, obesity, drug addiction, drug abuse, cognitive disorders, Alzheimer's disease, obsessivecompulsive behaviour, panic attacks, social phobias, eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperlipidaemia, stress, as an aid to smoking cessation and in the treatment and/or prophylaxis of seizures, neurological disorders such as epilepsy and/or conditions in which there is neurological damage such as stroke, brain trauma, cerebral ischaemia, head injuries and haemorrhage. are useful in the treatment of depression, anxiety, Parkinson's disease, obesity, cognitive disorders, seizures, neurological disorders such as epilepsy, and as neuroprotective agents to protect against conditions such as stroke. The compounds of the present invention are not disclosed or suggested in this document. Sharpe C. J and Shadbolt R. S. (Journal of Medicinal Chemistry, 1971, Vol 14 No.10, p977-982) disclose certain dihydroimidazo[2,1-b]thiazole compounds having antidepressant activity. However, the document also states that these compounds were generally less active and more toxic than the imidazolines also disclosed in the document. The compounds of the present invention are not disclosed or suggested in this document. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Dopamine D4 ligands for the treatment of novelty-seeking disorders Inventor(s): Fliri, Antor F.; (Stonington, CT), Sanner, Mark A.; (Old Saybrook, CT), Seymour, Patricia A.; (Westerly, RI), Zorn, Stevin H.; (North Stonington, CT) Correspondence: Paul H. Ginsburg; Pfizer Inc; 20th Floor; 235 East 42nd Street; New York; NY; 10017-5755; US Patent Application Number: 20020049209 Date filed: July 26, 2001 Abstract: The present invention provides a method of treating or preventing a noveltyseeking disorder such as pathological gambling, attention deficit disorder with hyperactivity disorder, substance addiction, drug addiction, alcohol addiction and sex

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addiction. using a compound which is a dopamine D4 receptor ligand, or a pharmaceutically acceptable salt thereof. Excerpt(s): The present invention relates to a method of treating or preventing a noveltyseeking disorder selected from pathological gambling, attention deficit disorder with hyperactivity disorder, substance addiction, such as drug addiction and alcohol addiction, and sex addiction, using a dopamine D4 ligand. It also relates to a method of treating or preventing such disorders in mammals by administering a pyrido[1,2a]pyrazine derivative, benzimidazole derivative, bicyclic compound, spirocyclic benzo furan derivative, indole derivative or a related compound that is a dopamine D4 receptor ligand. It has been determined that dopamine D4 receptors are related to various behavioral and personality disorders including novelty seeking disorders (See, e.g., Tarazi et al., Mol. Psychiatry, 4, 529-538(1999). The trait of novelty seeking was found to be related to dopaminergic activity in alcoholic men (Wiesbeck et al., Psychoneuroendocrinology, 20, 7(1999)). A large Finnish study provides support for an association between the D4 receptor gene (DRD4) and the behavioral trait of novelty seeking (Ekelund et al., Am. J. Psychiatry, 156, 1453-5 (1999)). Recent evidence has accumulated which supports a clinical linkage between attention deficit disorder with hyperactivity disorder, which has been associated with the novelty seeking trait, and dopamine receptor expression (see, e.g., Tarazi et al., supra; Anderson et al., Neuroscience & Biobehavioral Rev., 24, 137-41 (2000)) and dopamine transporter gene expression (see, e.g., Dougherty et al., The Lancet, 354, 2132-2133 (1999)). Further evidence has been found for an association between the D4 gene and a susceptibility to pathological gambling (Comings, CNS Spectr., 3, 20-37 (1998)) and a susceptibility to opioid addiction and substance abuse (Kotler et al., Mol. Psychiatry, 2, 251-254 (1997)). The following references refer, collectively, to pyrido[1,2a]pyrazine derivatives, benzimidazole derivatives, bicyclic compounds, spirocyclic benzofuran derivatives, indole derivatives or related compounds that exhibit activity as dopamine D4 receptor ligands: U.S. Pat. No. 5,852,031, issued on Dec. 22, 1998; U.S. Pat. No. 5,883,094, issued on Mar. 16, 1999; U.S. Pat. No. 5,889,010, issued on Mar. 30, 1999; PCT International Application PCT/IB97/00978, published as WO98/08835 on Mar. 5, 1998; U.S. patent application Ser. No. 5,877,317 issued on Mar. 2, 1999; U.S. patent application Ser. No. 5,021,420, issued on Jun. 4, 1991; U.S. patent application Ser. No. 5,633,376, issued on May 27, 1997; U.S. patent application, Ser. No. 5,432,177, issued on Nov. 9, 1994; U.S. patent application Ser. No. 5,622,950, issued on Apr. 22, 1997, PCT International Application No. PCT/EP93/01438, published as WO94/00458 on Jan. 6, 1994; PCT International Application No. PCT/IB98/01198, published as WO99/09025 on Feb. 25, 1999; U.S. patent application Ser. No. 5,998,414, issued on Dec. 7, 1999; U.S. patent application Ser. No. 5,968,478, issued on Oct. 19, 1999; U.s. patent application Ser. No. 6,040,448, issued on Mar. 21, 2000; U.S. patent application Ser. No. 6,051,605, issued on Apr. 18, 2000; U.S. patent application Ser. No. 5,945,421, issued on Aug. 31, 1999; and U.S. patent application Ser. No. 5,798,350, issued on Aug. 25, 1998. All of the foregoing PCT International Applications designate the United States. The foregoing patents and patent applications are incorporated by reference in their entirety. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Enantiomerically pure opioid diarylmethylpiperzine and methods of using same Inventor(s): Chang, Kwen-Jen; (Chapel Hill, NC) Correspondence: Intellectual Property / Technology Law; PO Box 14329; Research Triangle Park; NC; 27709; US Patent Application Number: 20030114462 Date filed: September 25, 2002 Abstract: (-)3-((S)-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)(3-thienyl)methyl)ph- enol and pharmaceutically acceptable esters or salts thereof, in essentially enantiomerically pure form have utility as receptor-binding species, e.g., as therapeutic agents for mediating analgesia; as co-administered agents with various other bioactive compositions, including anesthetics, barbiturates, analgesics, etc., for reducing, treating, reversing or preventing drug-mediated respiratory depression that may be directly or indirectly caused by use of such various bioactive compositions; as a conjugate in agonist/antagonist pairs for verifying/assaying receptor and neurotransmitter function; and as a therapeutic agent having utility in combating drug addiction, cardiac disorders, alcohol addiction, drug overdose, cough, lung edema, diarrhea, respiratory, and gastro-intestinal disorders. Excerpt(s): The present invention relates to a novel, essentially enantiomerically pure diarylmethylpiperazine compound having utility as a receptor-binding species, e.g., as a mu and/or delta receptor opioid compound mediating analgesia; as a therapeutic agent for co-administration with various other bioactive compositions, including anesthetics, barbiturates, analgesics, etc. for reducing, treating, reversing or preventing drugmediated respiratory depression that may be directly or indirectly caused by use of such various bioactive compositions; as a conjugate in agonist/antagonist pairing for verifying/assaying receptor and neurotransmitter function; and as a therapeutic agent having utility in combating drug addiction, alcohol addiction, cardiac disorders, drug overdose, mental illness, cough, lung edema, diarrhea, respiratory, and gastro-intestinal disorders. In the study of opioid biochemistry, a variety of endogenous opioid compounds and non-endogenous opioid compounds has been identified. In this effort, significant research has been focused on understanding the mechanism of opioid drug action, particularly as it relates to cellular and differentiated tissue opiate receptors. Opioid drugs typically are classified by their binding selectivity in respect of the cellular and differentiated tissue receptors to which a specific drug species binds as a ligand. These receptors include mu (.mu.), delta (.delta.), sigma (.pi.) and kappa (.kappa.) receptors. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Hapten-carrier conjugates for use in drug-abuse therapy and methods for preparation of same Inventor(s): Exley, Mark A.; (Chestnut Hill, MA), Fox, Barbara S.; (Wayland, MA), Gefter, Malcolm L.; (Lincoln, MA), Greenstein, Julia L.; (West Newton, MA), Powers, Stephen P.; (Waltham, MA), Schad, Victoria C.; (Cambridge, MA), Swain, Philip A.; (Boston, MA) Correspondence: William D. Noonan, M.D.; Klarquist Sparkman Campbell; Leigh & Whinston, Llp; 121 SW Salmon ST., Suite 1600; Portland; OR; 97204-2988; US Patent Application Number: 20020032316 Date filed: June 14, 2001 Abstract: Hapten-carrier conjugates capable of eliciting anti-hapten antibodies in vivo by administering, in a therapeutic composition, are disclosed. Methods of preparing said conjugates and therapeutic compositions are also disclosed. Where the hapten is a drug of abuse, a therapeutic composition containing the hapten-carrier conjugate is particularly useful in the treatment of drug addiction, more particularly, cocaine addiction. Passive immunization using antibodies raised against conjugates of the instant invention is also disclosed. The therapeutic composition is suitable for cotherapy with other conventional drugs. Excerpt(s): This application is a continuation-in-part of U.S. patent application Ser. No. 08/563,673 filed Nov. 28, 1995, which is a continuation-in-part of U.S. patent application Ser. No. 08/414,971 filed Mar. 30, 1995. The present invention relates to treatment of drug abuse. More specifically, the present invention relates to methods of treating drug abuse using drug/hapten-carrier conjugates which elicit antibody responses and/or using the antibodies to the drug/hapten-carrier conjugates. The prevalence of drug use and abuse worldwide, especially in the United States, has reached epidemic levels. There are a plethora of drugs, both legal and illegal, the abuse of which have become serious public policy issues affecting all strata of society with its obvious medical and social consequences. Some users live in an extremely high risk population associated with poverty and illegal activity. Other users who might classify themselves as recreational users are at risk due to (a) properties of the drug(s) which make them addictive, (b) a predisposition of the user to become a heavy user or (c) a combination of factors including personal circumstances, hardship, environment and accessibility. Adequate treatment of drug abuse, including polydrug abuse, requires innovative and creative programs of intervention. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Imidazolyl derivatives as corticotropin releasing factor inhibitors Inventor(s): Dasgupta, Bireshwar; (Middletown, CT), Dubowchik, Gene M.; (Middlefield, CT), Han, Xiaojun; (Cheshire, CT), Michne, Jodi A.; (Middletown, CT), Vrudhula, Vivekananda M.; (Killingworth, CT), Zuev, Dmitry; (Wallingford, CT) Correspondence: Stephen B. Davis; Bristol-myers Squibb Company; Patent Department; P O Box 4000; Princeton; NJ; 08543-4000; US Patent Application Number: 20020183375 Date filed: January 11, 2002

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Abstract: The present invention relates to novel heterocyclic antagonists of Formula (I) and pharmaceutical compositions comprising said antagonists of the corticotropin releasing factor receptor ("CRF receptor") 1useful for the treatment of depression, anxiety, affective disorders, feeding disorders, post-traumatic stress disorder, headache, drug addiction, inflammatory disorders, drug or alcohol withdrawal symptoms and other conditions the treatment of which can be effected by the antagonism of the CRF-1 receptor. Excerpt(s): This non-provisional application claims priority from provisional application U.S. Ser. No. 60/264,570 filed Jan. 26, 2001. The present invention relates to antagonists and pharmaceutical compositions comprising said antagonists of the corticotropin releasing factor receptor ("CRF receptor") useful for the treatment of depression, anxiety, affective disorders, feeding disorders, post-traumatic stress disorder, headache, drug addiction, inflammatory disorders, drug or alcohol withdrawal symptoms and other conditions the treatment of which can be effected by the antagonism of the CRF-1 receptor. It has been shown that the neuropeptide, corticotropin releasing factor ("CRF"), acting through its binding to the CRF-1 receptor, is a primary mediator of stress- and anxiety-related physiological responses in humans and other mammals by stimulating ACTH secretion from the anterior pituitary gland. See A. J. Dunn, et al., Brain Res. Rev., 15: 71-100 (1990). Antagonists of the CRF-1 receptor, both peptides (J. Gulyas, et al., Proc. Natl. Acad. Sci. U.S.A., 92: 10575-10579 (1995) and small molecules (J. R. McCarthy, et al., Curr. Pharm. Design, 5: 289-315 (1999), have demonstrated the ability to ameliorate the effects of stressful stimuli in several animal models. In addition, marked elevations of CRF in cerebrospinal fluid have been detected in a large portion of individuals diagnosed with major depression and anxiety disorders, and the levels correlate with severity of the disease. See F. Holsboer, J. Psychiatric Res., 33: 181-214 (1999). Following antidepressant treatment, the increased CRF levels observed in depressed patients were reduced. See C. M. Banki, et al., Eur. Neuropsychopharmacol., 2: 107-113 (1992); see also Effects of the high-affinity corticotropin-releasing hormone receptor 1 antagonist R121919 in major depression: the first 20 patients treated. Zobel A W, Nickel T, Kunzel H E, Ackl N, Sonntag A. Ising M, Holsboer F J Psychiatr Res 2000, 34, 171-181. CRF has also been shown to be a key mediator of several immune system functions through its effect on glucocorticoid plasma levels. See E. L. Webster, et al., Ann. N.Y. Acad. Sci., 840: 21-32 (1998). Recent reviews of the activity of CRF-1 antagonists include P. J. Gilligan, et al., J. Med. Chem., 43: 1641-1660 (2000) and J. R. McCarthy, et al., Ann. Rep. Med. Chem., 34: 11-20 (1999). There appears a need to discover novel small molecule CRF antagonists in order to treat a wide variety of human disorders including depression, anxiety, bipolar disorder, and other stress-related illnesses. See WO 98/35967, WO 99/01454, WO 99/10350, wo 99/67247, 00/01675, WO 00/01697, WO 00/39127, WO 00/59907, WO 00/59908, EP 778277, EP 812831. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

MC4-R as target for the identification of compounds used to treat drug addiction Inventor(s): Duman, Ronald; (Guilford, CT) Correspondence: Anita L. Meiklejohn, PH.D.; Fish & Richardson P.C.; 225 Franklin Street; Boston; MA; 02110-2804; US Patent Application Number: 20030017966 Date filed: August 23, 2002

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Abstract: The present invention relates to drug screening assays and therapeutic methods for the treatment of addictive behavior disorders, such as cocaine and morphine addiction utilizing the melanocortin 4-receptor (MC4-R) as the target for intervention. The invention also relates to compounds that antagonize the activity or expression of the MC4-R, and the use of such compounds in the treatment of addictive behavior disorders. Excerpt(s): The present invention is in the field of drug discovery to treat addictive behavior, particularly drug addiction. The present invention specifically provides drug screening assays and therapeutic methods for the treatment of addictive behavior, particularly drug addiction, involving the melanocortin 4-receptor (MC4-R). The invention also provides novel methods of using antagonists of the activity or expression of MC4-R to treat addictive disorders. It is well known that the chronic administration of opioids, cocaine and other drugs of abuse results in tolerance and, eventually, dependence. The use of cocaine, opiates, and alcohol are extremely widespread in many countries, despite the well known adverse effects of their use. Drug abuse endures as one of the major public health problems in the United States, and throughout the world. One of the core features of addictive disorders, in laboratory animals as well as in humans, is that drugs of abuse are acutely reinforcing and produce intense drug craving following chronic exposure. Behavioral and pharmacological studies have implicated the mesolimbic dopamine system (containing the ventral tegmental area [VTA] and its projections, e.g., the nucleus accumbens [NAc]) in the acute reinforcement and craving seen with opiates, cocaine, alcohol, and other drugs of abuse. An important goal of research in this area is to identify changes in this neural pathway that are caused by rugs of abuse and account for the intense craving seen with chronic drug use. Another critical goal is the identification of factors that can inhibit or reverse these changes to the neural pathway. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Monomeric and dimeric heterocycles, and therapeutic uses thereof Inventor(s): Araldi, Gian Luca; (San Diego, CA), Kozikowski, Alan P.; (Princeton, NJ), Tamiz, Amir P.; (Washington, DC) Correspondence: Patent Group; Foley Hoag Llp; World Trade Center West; 155 Seaport BLVD.; Boston; MA; 02210-2600; US Patent Application Number: 20030144289 Date filed: July 30, 2002 Abstract: The invention provides compounds of formula (I):X--L--X.sup.1 (I)wherein X, L, and X.sup.1 have any of the meanings defined in the specification; as well a pharmaceutical composition comprising a compound of formula I; intermediates and methods useful for preparing a compound of formula I; and therapeutic methods for treating drug addiction, Parkinson's disease, depression, or a disease wherein the administration of cocaine is indicated, comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof to a mammal in need of such treatment. Excerpt(s): This application claims the benefit of priority to U.S. Provisional Patent Application No. 60/103,460, filed Oct. 7, 1998, the specification of which is hereby incorporated by reference; and U.S. Provisional Patent Application No. 60/103,423, filed Oct. 7, 1998, the specification of which is hereby incorporated by reference. Cocaine

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abuse is one of the greatest concerns of the American public today, and has therefore become a focus of medical, social and political leaders. Cocaine is one of the most addictive substances known, and addicts may lose their ability to function at work or in interpersonal situations. Drug dependence and the great profits that are made throughout the distribution network of cocaine have fueled a rise in drug-associated crime in the United States and in Colombia. Although the incidence of casual cocaine use has decreased substantially in the last few years, the number of weekly users is rising. The rise has accompanied a change in the chemical form often used to free base, or "crack," and the route of administration used from nasal to inhalation by smoking or intravenous injection. Psychological and behavioral approaches are important in a treatment program because peer pressure and environmental cues are closely associated with a relapse to addiction. However, behavioral observations have identified a window of about ten weeks after cessation of cocaine use where the susceptibility to relapse is greatest. Clearly, there is a need to increase the success rate of outpatient detoxification programs through the development of pharmacological agents that will assist during this critical period. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Novel indole and benzothiazole derivatives Inventor(s): Gluchowski, Charles; (Wayne, NJ), Jeon, Yoon T.; (Ridgewood, NJ) Correspondence: John P. White; Cooper & Dunham Llp; 1185 Avenue OF The Americas; New York; NY; 10036; US Patent Application Number: 20020049239 Date filed: September 28, 2001 Abstract: This invention is directed to novel indole and benzothiazole compounds which are selective for cloned human alpha 2 receptors. This invention is also related to uses of these compounds for any indication where use of an alpha 2 agonist may be appropriate. Specifically, this includes use as analgesic, sedative and anaesthetic agents. In addition, this invention includes using such compounds for lowering intraocular pressure, presbyopia, treating migraine, hypertension, alcohol withdrawal, drug addiction, rheumatoid arthritis, ischemic pain, spasticity, diarrhea, nasal decongestion, urinary incontinence as well as for use as cognition enhancers and ocular vasoconstriction agents. The invention further provides a pharmaceutical composition comprising a therapeutically effective amount of the above-defined compounds and a pharmaceutically acceptable carrier. Excerpt(s): Throughout this application, various references are referred to within parentheses. Disclosures of these publications in their entireties are hereby incorporated by reference into this application to describe more fully the state of the art to which this invention pertains. Alpha adrenergic receptors are plasma membrane receptors which are located in the peripheral and central nervous systems throughout the body. They are members of a diverse family of structurally related receptors which contain seven putative helical domains and transduce signals by coupling to guanine nucleotide binding proteins (G-proteins). These receptors are important for controlling many physiological functions and, thus, have been important targets for drug development during the past 40 years. Examples of alpha adrenergic drugs include clonidine, phenoxybenzamine and prazosin (for treatment of hypertension), naphazoline (for nasal decongestion), medetomidine (for veterinary analgesia), UK-14,304 and paminocionidine (for glaucoma). However, most of these drugs produce undesirable side

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effects, possibly due to their interactions with other receptor subtypes. For example, clonidine is a well known centrally acting antihypertensive agent. However, it also produces untoward side effects such as analgesia, sedation, bradycardia and dry mouth which may be due to its lack of selectivity at.alpha.sub.2 receptors.alpha.-Adrenergic receptors were originally proposed to have only two (alpha and beta) subtypes (Berthelsen, S.; Pettinger W. Life Sci., 21, 595 (1977)). However, modern molecular biological and pharmacological techniques have led to the identification of at least 6 subtypes (.alpha.sub.1a,.alpha.sub.1b,.alpha.sub.1c,.alpha.sub.2a,.alpha.sub.2b and.alpha.sub.2c) of the adrenergic receptors (Bylund, D. B., Trends Pharmacol. Sci., 9, 356 (1988)). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

REMEDIES FOR DRUG ADDICTION Inventor(s): ENDOH, TAKASHI; (CHIGASAKI-SHI, JP), INADA, HIDEAKI; (KAMAKURA-SHI, JP), KAWAMURA, KUNIAKI; (KAMAKURA-SHI, JP), NAGASE, HIROSHI; (KAMAKURA-SHI, JP), OSHIMA, KOJI; (YOKOHAMA-SHI, JP), SUZUKI, TSUTOMU; (YOKOHAMA-SHI, JP) Correspondence: Birch Stewart Kolasch & Birch; PO Box 747; Falls Church; VA; 220400747; US Patent Application Number: 20010044449 Date filed: July 12, 1999 Abstract: A remedy for drug dependence in which the active ingredient is an opioid.kappa. receptor agonist in which the typical compound is represented by the following formula. 1An opioid.kappa. receptor agonist in accordance with the present invention is different from a conventional symptomatic treatment manner for the drug dependence. The opioid.kappa. receptor agonist in accordance with the present invention is a promising remedy for drug dependence with little adverse effects which affects expression mechanism of a reward effect so as to inhibit development both psychic dependence and physical dependence. Excerpt(s): The present invention relates to a remedy for drug dependence. In addition, the present invention relates to a dopamine-release inhibitor, in which dopamine is heavily associated with drug dependence. When a person repeatedly take a natural substance such as opium, cocaine, or marijuana, or takes a specific drug such as heroin, barbiturates, or stimulants, it is impossible to suddenly withhold the drug. Then, their major goal in life tends to focus on obtaining these substances and drugs. In addition, brutal crimes may be provoked. Moreover, serious incidents, which affect the state of the nation, may also be provoked. There is substantially the same underlying cause in these problems of drug abuse as in habituation to consuming common substances, for example, alcohol or tobacco. World Health Organization (WHO) defines both drug dependence and drug abuse. That is, drug dependence is defined as follows: "A state, psychic and sometimes also physical, resulting from the interaction between a living organism and a drug, characterized by behavioural and other responses that always include a compulsion to take the drug on a continuous or periodic basis in order to experience its psychic effects, and sometimes to avoid the discomfort of its absence." Drug dependence is further classified as a state of psychic dependence on a drug, that is, psychic dependence, or a state in which a body is adapted to existing the drug, that is, physical dependence.

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Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Substance with sedative effect Inventor(s): Krylov, Boris Vladimirovich; (Pavlovo, RU), Shchegolev, Boris Fedorovich; (St-Petersburg, RU) Correspondence: Boris Leschinsky; P.O. Box 72; Waldwick; NJ; 07463; US Patent Application Number: 20030181516 Date filed: March 14, 2003 Abstract: A substance with sedative effect comprises a therapeutically effective amount of a gamma-pyrone such as comenic acid, meconic acid, chelidonic acid, and alike in a pharmaceutically acceptable carrier. When administered at a daily dosage of between 5 and 200 mg of active ingredient per kilogram of a body weight of a patient, the substance can be used to treat various neurotic disorders such as insomnia, anxiety, neurosis, depression as well as withdrawal symptoms for drug addiction patients, especially for patients addicted to opioid-based drugs. The substance can be delivered in a number of ways of systemic administration of a pharmaceutical agent including oral, parenteral, transdermal, and transmucosal administration. For drug addicted patients, the preferred method of administration involves a subcutaneous implant providing a continuous release of an active ingredient at an effective daily rate over the entire treatment period ranging from 5 to 30 days, and preferably from 13 to 20 days. Excerpt(s): This application claims foreign priority benefits of a Russian Patent Application No. 2002107079/14 filed Mar. 19, 2002 with the same title. The present invention relates generally to pharmaceutical compounds and methods for their use to cause sedative and analgesic effects in animals and humans. More specifically, the invention relates to the use of gamma-pyrones in pharmaceutically acceptable forms for the treatment of various neurotic disorders. For the purposes of this description, the term "neurotic disorder" includes among others such conditions as anxiety, pain, insomnia, depression, neurosis as well as pain and other symptoms associated with treatment of chemical and drug abuse patients. All of these conditions involve the neurons of the central nervous system. Sedative compounds known in the art are a chemically varied group of compositions of natural and synthetic origin that predominantly have a tranquilizing effect on the central nervous system. Different sedatives produce different physiological effects. Understanding of these effects is helpful in selectively treating various disorders. This mechanism of action is not always entirely clear but it is believed that sedative drugs in general are intended to cause selective suppression of subcortical (limbus) and cortical brain structures, which regulate emotions. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Therapeutic agents Inventor(s): Birch, Alan Martin; (Nottingham, GB), Bradley, Paul Anthony; (Nottingham, GB) Correspondence: Herbert B. Keil; Keil & Weinkauf; 1101 Connecticut Avenue, N.W.; Washington; DC; 20036; US Patent Application Number: 20010008903 Date filed: December 27, 2000 Abstract: Compounds of formula I 1and pharmaceutically acceptable salts thereof in which A is methylene or --O--; B is methylene or --O--; G.sub.1-G.sub.2-G.sub.3 form a heteroaromatic or heteroaliphatic chain; g is 0, 1 or 2; U is an alkylene chain optionally substituted by one or more alkyl; Q represents a divalent group containing nitrogen atoms; and T is an optionally substituted aryl or heteroaryl group, have utility in the treatment of central nervous system disorders, for example depression, anxiety, psychoses (for example schizophrenia), tardive dyskinesia, Parkinson's disease, obesity, hypertension, Tourette's syndrome, sexual dysfunction, drug addiction, drug abuse, cognitive disorders, Alzheimer's disease, senile dementia, obsessive-compulsive behaviour, panic attacks, social phobias, eating disorders and anorexia, cardiovascular and cerebrovascular disorders, non-insulin dependent diabetes mellitus, hyperglycaemia, constipation, arrhythmia, disorders of the neuroendocrine system, stress, and spasticity. Excerpt(s): The present invention relates to novel dioxinoindole and thienobenzodioxin compounds which have affinity for 5-HT.sub.1A and/or D.sub.2-like (D.sub.2, D.sub.3 and/or D.sub.4 sub-types) receptors, to processes for their preparation, to pharmaceutical compositions containing them and to their use in the treatment, of central nervous system disorders, for example depression, anxiety, psychoses (for example schizophrenia), tardive dyskinesia, Parkinson's disease, obesity, hypertension, Tourette's syndrome, sexual dysfunction, drug addiction, drug abuse, cognitive disorders, Alzheimer's disease, senile dementia, obsessive-compulsive behaviour, panic attacks, social phobias, eating disorders and anorexia, cardiovascular and cerebrovascular disorders, non-insulin dependent diabetes mellitus, hyperglycaemia, constipation, arrhythmia, disorders of the neuroendocrine system, stress, and spasticity. and T is an optionally substituted aromatic group optionally containing one or more N atoms. These compounds are described as being useful in the treatment of central nervous system disorders. T represents phenyl, 1- or 2-naphthyl, 1-naphth[2,1d][1,2,3]oxadia- zolyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2- or 3-thienyl, 2- or 3furyl, 2-, 3- or benzo[b]furanyl, 2,3-dihydro-7-benzo[b]furanyl, 2-, 3- or 7benzo[b]thiophenyl, 3-, 4-5-pyrazolyl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-2yl, 5-tetrazolyl, 2-, 3- or 4-quinolinyl, 2- or 4-quinazolinyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-oxazolyl, 3 isothiazolyl or 2-, 4- or 5-thiazolyl each of which may be optionally substituted by one or more substituents selected from a) halo, b) an alkyl group containing 1 to 4 carbon atoms optionally substituted by one or more halo, c) an alkoxy group containing 1 to 3 carbon atoms optionally substituted by one or more halo, d) an alkylthio group containing 1 to 3 carbon atoms optionally substituted by one or more halo, e) hydroxy, f) an acyloxy group containing 1 to 3 carbon atoms, g) hydroxymethyl, h) cyano, i) an alkanoyl group containing 1 to 6 carbon atoms, j) an alkoxycarbonyl group containing 2 to 6 carbon atoms, k) a carbamoyl group or carbamoylmethyl group each optionally N-substituted by one or two alkyl groups each containing 1 to 3 carbon atoms, I) a sulphamoyl or sulphamoylmethyl group each optionally N-substituted by one or two alkyl groups each containing 1 to 3 carbon atoms, m) an amino group

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optionally substituted by one or two alkyl groups each containing 1 to 5 carbon atoms, n) 1-pyrrolidinyl or 1 -piperidinyl, o) nitro or p) acetamido. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

TRANSGENIC ANIMAL WHOSE EXPRESSION OF THE OPIATE RECEPTORS IS MODIFIED Inventor(s): DIERICH, ANDREE; (STRASBOURG, FR), KIEFFER, BRIGITTE; (ERSTEIN, FR), LEMEUR, MARIANNE; (STRASBOURG, FR), MATTHES, HANS W.D.; (STRASBOURG, FR), SIMONIN, FREDERIC HERVE; (BISCHHEIM, FR) Correspondence: Young & Thompson; 745 South 23rd Street 2nd Floor; Arlington; VA; 22202 Patent Application Number: 20010047519 Date filed: March 11, 1999 Abstract: The invention concerns the use of a non-human transgenic mammal whose expression of a gene coding for an opiate receptor is modified, particularly in the nerve tissues with respect to a normal expression, in particular in the nerve tissues, for producing a medicine for the treatment of pathological conditions involving opiate receptors, in particular severe acute or chronic pains, drug addiction or the prevention or the treatment of transplant rejections. Excerpt(s): The invention relates to a non-human transgenic animal in which the expression of at least one of the genes which code for opiate receptors is modified. Opiates--the prototype of which is morphine--are the most potent analgesics available to medicine today. However, their use is limited by a range of secondary effects, including effects on autonomous functions (constipation, respiratory depression, hypotension, diuresis) and psychotropic effects. the kappa receptor, like the other two receptors, is said to play a role in the analgesic action of opiates. On the other hand, and in contrast to mu and delta, it is said to have a dysphorizing psychotropic action, an action which has been regarded as an advantage for the development of potent analgesics lacking a toxicomanogenic potential. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Use of y-hydroxybutyric acid amides in the treatment of drug addiction and in particular of alcoholism Inventor(s): Cacciaglia, Roberto; (Ospedaletti, IT), Guano, Lorenza; (Sanremo, IT), Loche, Antonella; (Sanremo, IT), Perlini, Vincenzo; (Matelica, IT) Correspondence: James V. Costigan, ESQ.; Headman & Costigan, P.C.; Suite 2003; 1185 Avenue OF The Americas; New York; NY; 10036-2646; US Patent Application Number: 20020165224 Date filed: December 11, 2001 Abstract: Gamma-hydroxybutryic acid amides are used in the treatment of drug addiction and especially in the treatment of alcoholism. Excerpt(s): The present invention relates to the use of amides of.gamma.-hydroxybutyric acid, herein referred to as GHB, in the treatment of drug addiction, such as heroine,

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cocaine and, in particular, in the treatment of alcoholism, and more particularly in reducing chronic alcoholics desire for and habit of consuming alcoholic drinks and in the treatment of abstinence syndrome. The salts of 4-hydroxybutyric acid, e.g. the sodium salt, proved to be effective both in the treatment of the syndrome of abstinence from alcohol and in reducing the desire for and addiction to alcohol in alcoholic patients and disclosed in EP-A- 344,704 and in the treatment of drug addiction, as reported in WO 93/00083. One of the advantages of said salts is that they do not cause the inconveniences of Disulfiram (Antabuse.RTM.), a drug having several untoward effects, such as for example the symptoms known as the "acetaldehyde syndrome", which may also result in fatality. The sodium salt of GHB is absorbed very quickly by the gastroenteric apparatus with a maximum concentration peak already at about 35-40 min after administration. However, it presents a half-life time of about 20-25 min, its elimination from the body being rather quick [EP-A-635,265]. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

Keeping Current In order to stay informed about patents and patent applications dealing with drug addiction, you can access the U.S. Patent Office archive via the Internet at the following Web address: http://www.uspto.gov/patft/index.html. You will see two broad options: (1) Issued Patent, and (2) Published Applications. To see a list of issued patents, perform the following steps: Under “Issued Patents,” click “Quick Search.” Then, type “drug addiction” (or synonyms) into the “Term 1” box. After clicking on the search button, scroll down to see the various patents which have been granted to date on drug addiction. You can also use this procedure to view pending patent applications concerning drug addiction. Simply go back to http://www.uspto.gov/patft/index.html. Select “Quick Search” under “Published Applications.” Then proceed with the steps listed above.

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CHAPTER 6. BOOKS ON DRUG ADDICTION Overview This chapter provides bibliographic book references relating to drug addiction. In addition to online booksellers such as www.amazon.com and www.bn.com, excellent sources for book titles on drug addiction include the Combined Health Information Database and the National Library of Medicine. Your local medical library also may have these titles available for loan.

Book Summaries: Federal Agencies The Combined Health Information Database collects various book abstracts from a variety of healthcare institutions and federal agencies. To access these summaries, go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. You will need to use the “Detailed Search” option. To find book summaries, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer. For the format option, select “Monograph/Book.” Now type “drug addiction” (or synonyms) into the “For these words:” box. You should check back periodically with this database which is updated every three months. The following is a typical result when searching for books on drug addiction: •

Responding to AIDS Source: State of the World 1989; A Worldwide Institute Report on Progress Toward a Sustainable Society. Contact: W. W. Norton and Company, Incorporated, 500 5th Ave, New York, NY, 10110, (212) 354-5500. Summary: This book chapter presents an historical overview of the Acquired immunodeficiency syndrome (AIDS) pandemic and the transmission of Human immunodeficiency virus (HIV). It describes different patterns of HIV transmission in different parts of the world. It discusses the impact of AIDS on developing nations, with particular reference to their health care systems, child health, and other epidemics such as tuberculosis. It discusses the efforts in Western nations at prevention including modification of high-risk behaviors, such as safer sex practices, stopping drug

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addiction, needle exchange programs, treatment, outreach, mandatory HIV-antibody testing, prevention campaigns, and reaching minorities. In developing nations, it notes the need for international cooperation of professional skills, resources, and experience which can be met through the World Health Organization (WHO). •

Directory of HIV Organizations in Hawaii Contact: Hawaii Department of Health, AIDS/STD Project, AIDS Prevention Project, PO Box 3378, Honolulu, HI, 96816, (808) 735-5303. Summary: This directory lists organizations that provide services related to Human immunodeficiency virus (HIV) in Hawaii. The directory is broken into organizations on Oahu, and organizations based on other islands. Each entry includes name of the organization, address, telephone number, contact person, and a describe of services. Services include condom information, drug addiction treatment, homosexual services, community care, nursing, needle exchange, and churches.

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A Vision Beyond Survival: A Resource Guide for Incarcerated Women Contact: National Womens Law Center, 11 Dupont Cir NW Ste 800, Washington, DC, 20036, (202) 588-5180. Summary: This manual provides legal and practical information for incarcerated women in Washington, DC, and women in the community who have a history involving the criminal justice system. It also includes the names and phone numbers of individuals and organizations who may be of assistance to them. The manual is a compilation of information provided in the Women's Education and Empowerment Series, a 12-week legal education seminar series conducted in a DC correctional center. The guide is divided into five major sections: 1) Negotiating the Prison System; 2) Community Transitions; 3) Maintaining Family Ties; 4) Staying Healthy; and 5) Community Resources. Several chapters in each section are devoted to key issues, such as sexual harassment, the parole process, child custody, housing, public benefits, and job training. A chapter in the health section discusses AIDS and other sexually transmitted diseases, including prevention, symptoms, testing, services for infected inmates, medical care, and education. Two other chapters address pregnancy and getting help for drug addiction and alcoholism.

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Circle of Hope: Our Stories of AIDS, Addiction and Recovery Contact: Hazelden Foundation, Educational Materials, PO Box 176, Center City, MN, 55012-0176, (651) 213-4000, http://www.hazelden.org. Summary: This monograph examines the interrelationship between Acquired immunodeficiency syndrome (AIDS) and addiction. It discusses drug addiction, alcoholism, sexually compulsive behavior and childhood abuse, living with Human immunodeficiency virus (HIV) infection, recovery, and healing. It describes implementation of the Twelve-Step Program of Alcoholics Anonymous as a holistic alternative to decreasing susceptibility to disease and increasing recovery from addiction. This monograph recounts personal experiences of persons in correctional facilities, Vietnam veterans, drug users, homosexuals, alcoholics, and persons with sexually compulsive behavior. Stories of native and new age spirituality, treatment, abusive childhoods, lost childhoods, and parents with AIDS are also included.

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Sharing Needles and the Spread of HIV in Italy's Addict Population Source: Needle Sharing Among Intravenous Drug Abusers: National and International Perspectives. Contact: US Government Printing Office, PO Box 371954, Pittsburgh, PA, 15250-7954, (202) 512-1800, http://www.access.gpo.gov. Summary: This paper was presented at the National Institute on Drug Abuse Technical Review Meeting on Needle Sharing Among Intravenous Drug Abusers; National and International Perspectives held in Bethesda, MD on May 18-19, 1987. It focuses on the drug abusing population in Italy, its evolution, and the incidence of Acquired immunodeficiency syndrome (AIDS) cases among drug addicts. Studies evaluating the correlations between Human immunodeficiency virus (HIV) infection and drug addiction patterns are reviewed. One study used 268 opiate addicts who had been screened for Human immunodeficiency virus (HIV). Subjects were administered a questionnaire to determine the possible correlation between HIV infection and the duration of addiction, needle sharing practices in the past, sexual behavior, and health education. Findings indicate that of subjects who acknowledged needle sharing, 37 percent were seropositive, 40 percent admitted changing sexual partners, and 88.3 percent declared they had never used condoms.

Book Summaries: Online Booksellers Commercial Internet-based booksellers, such as Amazon.com and Barnes&Noble.com, offer summaries which have been supplied by each title’s publisher. Some summaries also include customer reviews. Your local bookseller may have access to in-house and commercial databases that index all published books (e.g. Books in Print). IMPORTANT NOTE: Online booksellers typically produce search results for medical and non-medical books. When searching for “drug addiction” at online booksellers’ Web sites, you may discover non-medical books that use the generic term “drug addiction” (or a synonym) in their titles. The following is indicative of the results you might find when searching for “drug addiction” (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): •

Alcoholism, Drug Addiction, and the Road to Recovery: Life on the Edge by Barry Stimmel; ISBN: 0789005530; http://www.amazon.com/exec/obidos/ASIN/0789005530/icongroupinterna

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Crimes Without Victims: Deviant Behavior and Public Policy: Abortion, Homosexuality, Drug Addiction by Edwin M. Schur; ISBN: 0131929305; http://www.amazon.com/exec/obidos/ASIN/0131929305/icongroupinterna

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Drug Addiction and Drug Policy: The Struggle to Control Dependence by Philip B. Heymann (Editor), William N. Brownsberger (Editor) (2001); ISBN: 0674003276; http://www.amazon.com/exec/obidos/ASIN/0674003276/icongroupinterna

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Drug Addiction and Related Clinical Problems by Alessandro Tagliamonte (Editor), I. Maremmani (Editor); ISBN: 3211826742; http://www.amazon.com/exec/obidos/ASIN/3211826742/icongroupinterna

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Drug addiction research and the health of women; ISBN: 0160495695; http://www.amazon.com/exec/obidos/ASIN/0160495695/icongroupinterna

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Food for Recovery : The Complete Nutritional Companion for Overcoming Alcoholism, Drug Addiction, and Eating Disorders by Joseph D., M.D. Beasley, Susan Knightly; ISBN: 0517881810; http://www.amazon.com/exec/obidos/ASIN/0517881810/icongroupinterna

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God Exists: One Man's Discovery of God-Leading to Recovery from Alcoholism and Drug Addiction by F. W. Roman (2000); ISBN: 075960276X; http://www.amazon.com/exec/obidos/ASIN/075960276X/icongroupinterna

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Love First: A New Approach to Intervention for Alcoholism and Drug Addiction (A Hazelden Guidebook) by Jeff Jay, Debra Erickson Jay; ISBN: 1568385218; http://www.amazon.com/exec/obidos/ASIN/1568385218/icongroupinterna

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Loving the Addict, Hating the Addiction: For Christian Families Coping With Drug Addiction by Kecia C. Sims (2003); ISBN: 059528888X; http://www.amazon.com/exec/obidos/ASIN/059528888X/icongroupinterna

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Molecular Biology of Drug Addiction by Rafael Maldonado (Editor), Ivan A. Ross; ISBN: 1588290603; http://www.amazon.com/exec/obidos/ASIN/1588290603/icongroupinterna

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Neurochemical Markers of Degenerative Nervous Diseases and Drug Addiction (Progress in Hplc-Hpce , Vol 7) by G.A. Qureshi (Editor) (1998); ISBN: 9067642770; http://www.amazon.com/exec/obidos/ASIN/9067642770/icongroupinterna

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Prescription Drug Addiction: The Hidden Epidemic by Rod Colvin (2001); ISBN: 1886039526; http://www.amazon.com/exec/obidos/ASIN/1886039526/icongroupinterna

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Recovery from Drug Addiction (Drug Abuse Prevention Library) by Seamus Cavan; ISBN: 0823932842; http://www.amazon.com/exec/obidos/ASIN/0823932842/icongroupinterna

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The Craving Brain : A bold new approach to breaking free from *drug addiction *overeating *alcoholism *gambling by Ronald A. Ruden (Author) (2000); ISBN: 0060928999; http://www.amazon.com/exec/obidos/ASIN/0060928999/icongroupinterna

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The Tao of Sobriety: Helping You to Recover from Alcohol and Drug Addiction by David Gregson, et al (2002); ISBN: 0312242506; http://www.amazon.com/exec/obidos/ASIN/0312242506/icongroupinterna

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Wasted: The Story of My Son's Drug Addiction. by William, Chapin; ISBN: 0070105359; http://www.amazon.com/exec/obidos/ASIN/0070105359/icongroupinterna

The National Library of Medicine Book Index The National Library of Medicine at the National Institutes of Health has a massive database of books published on healthcare and biomedicine. Go to the following Internet site, http://locatorplus.gov/, and then select “Search LOCATORplus.” Once you are in the search area, simply type “drug addiction” (or synonyms) into the search box, and select “books

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only.” From there, results can be sorted by publication date, author, or relevance. The following was recently catalogued by the National Library of Medicine:10 •

[Bibliographies on various phases of drug addiction. Author: Addiction Research Center (Lexington, Ky.); Year: 1962; Lexington, Ky.] U. S. Public Health Service [1962?]-

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A decade of alcoholism research; a review of the research activities of the Alcoholism and Drug Addiction Research Foundation of Ontario, 1951-1961. By Robert E. Popham & Wolfgang Schmidt. Author: Popham, Robert E.; Year: 1962; [Toronto] Univ. of Toronto Press; Alcoholism and

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A doctor discusses narcotics and drug addiction, by Louis Relin in consultation with Robert L. Sharoff. Author: Relin, Louis.; Year: 1968; Chicago, Budlong, c1968

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An interim report; a study of the administration of narcotic control relating to the causes, prevention and control of drug addiction constituted pursuant to Senate joint resolution no. 16, Laws of 1963. Author: New Jersey. Legislature. Narcotic Drug Study Commission.; Year: 1964; [Trenton] 1964

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Aspects of drug addiction; a report on a survey carried out under the auspices of the Royal London Prisoners' Aid Society. Author: Silberman, Martin.; Year: 1967; London, Royal London Prisoners' Aid Society [1967]

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Chasing the dragon; a report on drug addiction in Hong Kong. Author: Hess, Albert G.; Year: 1965; Amsterdam, North-Holland Pub. Co., 1965

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Crimes without victims; deviant behavior and public policy: abortion, homosexuality, drug addiction. Author: Schur, Edwin M.; Year: 1965; Englewood Cliffs, N. J., PrenticeHall [c1965]

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Drug addiction in Britain. Author: O'Callaghan, Sean.; Year: 1970; London, Hale [1970]; ISBN: 70911463X

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Drug addiction in youth. Author: Harms, Ernest,; Year: 1964; Oxford, New York, Pergamon Press [1964]

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Drug addiction. Author: Office of Health Economics (London, England); Year: 1967; London [1967]

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Drug addiction. A Process statement. Author: Lord Shayne.; Year: 1968; [London, The Process, London Chapter, 1968]

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Drug addiction; with special reference to India [by] R. N. Chopra and I. C. Chopra. Author: Chopra, R. N. (Ram Nath),; Year: 1965; New Delhi, Council of Scientific; Industrial Research [c1965]

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Endocrinologic approach to the etiology and treatment of functional hypoglycemia; or, Physicians guideline to diagnosis and treatment of hypoglycemia or the hypoadrenocortical state. Covers non-surgical treatment of all hypoglycemia states including those of alcoholism and drug addiction. Author: Hypoglycemia Foundation.; Year: 1966; [Scarsdale, N. Y., c1966]

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Euro-Ibero American Seminar: Cooperation on Drugs and Drug Addiction Policies: conference proceedings Author: Robertson, Kathy.; Year: 1999; Luxembourg: Office for

10

In addition to LOCATORPlus, in collaboration with authors and publishers, the National Center for Biotechnology Information (NCBI) is currently adapting biomedical books for the Web. The books may be accessed in two ways: (1) by searching directly using any search term or phrase (in the same way as the bibliographic database PubMed), or (2) by following the links to PubMed abstracts. Each PubMed abstract has a "Books" button that displays a facsimile of the abstract in which some phrases are hypertext links. These phrases are also found in the books available at NCBI. Click on hyperlinked results in the list of books in which the phrase is found. Currently, the majority of the links are between the books and PubMed. In the future, more links will be created between the books and other types of information, such as gene and protein sequences and macromolecular structures. See http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Books.

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Official Publications of the European Communities; Lanham, Md.: Bernan Associates [distributor], 1999; ISBN: 9291680591 •

Facts about narcotic drug addiction. Author: National Institute of Mental Health (U.S.). Public Information Section.; Year: 1965; [Bethesda, Md., 1965]

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Flicker-fusion in chronic barbiturate usage; a quantitative study in the pathophysiology of drug addiction. [Tr. from the Swedish]. Author: Ideström, Carl Magnus.; Year: 1954; Stockholm, 1954

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Main topics: psychiatric epidemiology and drug addiction among young people; abstracts. Edited by Thomas Videbech.; Year: 1970; Copenhagen, Munksgaard, 1970; ISBN: 8716002229

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Narcotic drug addiction. Author: National Institute of Mental Health (U.S.); Year: 1963; Washington [1963]

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Now you're living. Basic information for scientific education for prevention of alcoholism and drug addiction. Author: Narcotics Education, inc.; Year: 1964; Washington [c1964]

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Problems in addiction; alcohol and drug addiction. Author: Bier, William C. (William Christian),; Year: 1962; New York, Fordham Univ. Press [c1962]

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Psychotropic drug addiction or withdrawal symptoms in man, January 1964-August 1968. 207 citations. Author: National Library of Medicine (U.S.); Year: 1969; [Bethesda, Md.] 1969

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Rehabilitation in drug addiction; a report on a five-year community experiment of the New York Demonstration Center: prepared by Demonstration Center staff, Leon Brill [et al.]. Author: National Institute of Mental Health (U.S.). New York Demonstration Center.; Year: 1963; Bethesda, Md. [1963]

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Selected audiovisual listing. Subject: drug addiction. Author: National Medical Audiovisual Center. Cataloging and Special Reference Section.; Year: 1968; Atlanta [1968?]

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Summary of proceedings; Title XIX projects, alcoholism and drug addiction, program analysis and evaluation, funding comprehensive mental health programs. Hotel Viking, Newport, Rhode Island, June 16-18, 1969. Author: Interstate Clearing House on Mental Health (U.S.); Year: 1969; Chicago, Interstate Clearing House on Mental Health, Council of State Governments [1969]

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The chemical crutch; a handbook on drug addiction. Author: McNicol, John.; Year: 1967; [London, National Assn. on

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With Christ in the world of drug addiction. Author: Copestake, David R.; Year: 1967; [London] Epworth Press [1967]

Chapters on Drug Addiction In order to find chapters that specifically relate to drug addiction, an excellent source of abstracts is the Combined Health Information Database. You will need to limit your search to book chapters and drug addiction using the “Detailed Search” option. Go to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find book chapters, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Book Chapter.” Type “drug addiction” (or synonyms) into the “For these words:” box. The following is a typical result when searching for book chapters on drug addiction:

Books

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Hepatitis C: Diagnosis and Treatment Source: in McDonald, J.W.D.; Burroughs, A.K.; Feagan, B.G., eds. Evidence Based Gastroenterology and Hepatology. London, UK: BMJ Publishing Group. 1999. p. 294304. Contact: Available from BMJ Publishing Group. BMA Books, BMA House, Tavistock Square, London WCIH 9JR. Fax 44 (0)20 7383 6402. E-mail: [email protected]. Website: www.bmjbooks.com. PRICE: Contact publisher for price. Summary: Hepatitis C is often characterized by a progression to chronic disease. This chapter on the diagnosis and treatment of hepatitis C is from a book that emphasizes the approaches of evidence based medicine in gastroenterology (the study of the gastrointestinal tract and gastrointestinal diseases) and hepatology (the study of the liver and liver diseases). The author of this chapter notes that since chronic hepatitis C is generally silent, its diagnosis often happens in conjunction with investigation for another disease. Systematic screening should be recommended in subjects who have a history of blood transfusion or intravenous drug addiction. The ELISA is the appropriate test for screening. In ELISA positive subjects, the presence of chronic infection is established by the detection of serum HCV RNA by polymerase chain reaction (PCR). A liver biopsy is recommended in patients who are HCV RNA positive with increased ALT levels in order to assess the severity of the liver disease and determine whether there is an indication for therapy. Combination therapy with interferon and ribavirin is now standard therapy, and results in a sustained response in approximately 40 percent of patients. Genotyping of the virus and the measure of baseline viral load are useful to assess the probability of sustained response and to determine the appropriate duration of combination therapy. 5 tables. 66 references.

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CHAPTER 7. MULTIMEDIA ON DRUG ADDICTION Overview In this chapter, we show you how to keep current on multimedia sources of information on drug addiction. We start with sources that have been summarized by federal agencies, and then show you how to find bibliographic information catalogued by the National Library of Medicine.

Video Recordings An excellent source of multimedia information on drug addiction is the Combined Health Information Database. You will need to limit your search to “Videorecording” and “drug addiction” using the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find video productions, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Videorecording (videotape, videocassette, etc.).” Type “drug addiction” (or synonyms) into the “For these words:” box. The following is a typical result when searching for video recordings on drug addiction: •

CYBIL: Personal Perspectives on AIDS and Related Disorders Summary: In this videorecording, an interview between a social worker and a client provides a personal perspective on Acquired immunodeficiency syndrome (AIDS), caused by Human immunodeficiency virus (HIV). The Person with AIDS (PWA) in this interview describes the psychological factors associated with her diagnosis and manifestation of symptoms, her rejection by her family, and the attitudinal barriers that separate her from her co-workers and some hospital staff members. The PWA also discusses her drug addiction and experiences in various treatment programs. The videorecording emphasizes the need for effective patient support services and patient education programs.

•

Clean, Sober & Positive Contact: Lamont Productions, Incorporated, 834 Allison Street NW, Washington, DC, 20011, (202) 291-6353.

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Summary: This documentary begins with a discussion of the incidence and prevalence of both HIV/AIDS and alcohol and other drug addiction in the United States. The narrator explains that behaviors associated with the use of alcohol and other drugs (AOD) increase the risk of HIV transmission. For those who are already HIV positive, the use and abuse of alcohol and other drugs can accelerate disease progression by compromising physical health status. The video combines one-on-one interviews and actual segments from mutual help and support group meetings for people who are former addicts and are HIV positive. These individuals explain how they have adjusted to their diagnoses, and how their decision to remain abstinent has improved their quality of life and enhanced their physical and mental health. The support group members are unanimous in their opinion that participation in an organized recovery program is a vital and positive part of their lives. •

AIDS and Chemical Dependency Contact: Hazelden Foundation, Educational Materials, PO Box 176, Center City, MN, 55012-0176, (651) 213-4000, http://www.hazelden.org. Summary: This is a videorecording of a lecture given by a physician to an audience of health professionals, explaining the relationship between chemical dependency and Acquired immunodeficiency syndrome (AIDS). Both drug addiction and alcoholism increase the risk of Human immunodeficiency virus (HIV) transmission, either by needle sharing or by decreased awareness of safer sexual practices. In addition, they weaken the immune system, increasing opportunistic infections in HIV-positive persons. The use of antibody testing to identify HIV-positive persons and get them into treatment programs which strengthen their immune systems is also discussed.

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Street Smarts Contact: Milestone Productions, 1565 16th Ave, San Francisco, CA, 94122, (415) 641-8436. Summary: This video uses clay animation to provide basic information about the dangers of substance abuse and HIV/AIDS. The first module of the video emphasizes the fact that although people using drugs on the street may look like they're having fun, they are actually at great risk for transmitting HIV. The video strongly discourages the use of alcohol, crack, and ice. The first module also explains that HIV is transmitted by sharing needles, by having sex with someone infected by HIV, and by the birth of a child to an HIV-positive mother. The second module warns the viewer that people who use drugs can become violent, may get involved in prostitution, could suffer from brain damage, and might not protect themselves from HIV/AIDS. It also stresses the importance of getting help with drug addiction and staying in school. The third module emphasizes that youth should recognize the potential for trouble. Youth are strongly encouraged to make their own decisions about drugs and sex and to protect themselves from HIV/AIDS and other STDs. The video also discusses sexual abstinence and the use of condoms. A review section is also provided.

•

Pediatric AIDS: A Time of Crisis Contact: Association for the Care of Childrens Health, National Center for Family Centered Care, 19 Mantua Rd, Mt Royal, NJ, 08061, (609) 224-1742, http://www.acch.org. Summary: This videorecording describes the comprehensive support program which Albert Einstein Hospital in Bronx, NY, provides children with AIDS and their parents or foster parents. In the opening scenes, Heidi Perez, a young Black mother, is shown with

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her baby girl and husband at a city playground. She tells of her panic when she learned that she, her husband, and their daughter were infected with HIV, and of the tremendous support and reassurance that the Albert Einstein program gave her. A group of parents and foster parents is shown meeting with Dr. Ayre Rubenstein and a social worker, Anita Septimus. Foster parents discuss facing the death of children they have come to love. The narrator states that a successful program is comprehensive, flexible, and provides a single, identifiable individual to whom the parents can turn when confronted with the rapidly changing conditions of children with AIDS. In the final scenes, the Hispanic father, Pedro Perez, tells of his grief that his former drug addiction has brought a fatal virus to his wife and daughter, and of his hope to see one more summer. •

AIDS Education for Pre - Release Inmates: What You Need to Know About AIDS Contact: Texas Department of Criminal Justice, Health Services Division, HIV Program, Health Services Complex, 3009 Hwy 30 W, Huntsville, TX, 77340-0769, (936) 437-3539, http://www.tdcj.state.tx.us. Summary: This videorecording presents facts about AIDS in a question-and-answer format. Topics include: HIV transmission, including common misconceptions about casual contact transmission; risk factors, such as anal intercourse and sharing IV drug needles; and reducing risk by using condoms, not engaging in male-to-male sex, not having sex in exchange for drugs or money, avoiding the use of alcohol, which may reduce inhibitions, and using clean needles. The viewer is advised to get help in overcoming a drug addiction by contacting his or her parole officer. The viewer is also referred to the local Health Department for HIV-antibody testing, and to the Health Department and Planned Parenthood for more information. A presentation guide is included, containing the text of the videorecording.

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Tracy's Choices Contact: M V P Productions, P O Box 4126, Rockford, IL, 61110, (815) 877-1514. Summary: This videotape chronicles the life and death of Tracy Eichman, the first person in Illinois to be arrested, tried, convicted, and incarcerated for the knowing attempt to transmit HIV. Through interviews and news excerpts, the video sketches Tracy's involvement with alcohol and illegal drugs. Drug addiction led Tracy to prostitution at the age of 17. Following her arrest and conviction Tracy became a "born again Christian." The video emphasizes the role that spirituality and Christianity played in Tracy's recovery from drug addiction and influencing her decision to become a spokesperson for a lifestyle free of illegal drug use, alcohol abuse, and premarital sex. The video contains interviews with Tracy's arresting officer, a doctor, and a dentist. Each speaker underscores the importance of sexual and drug abuse abstinence, good decision making skills, personal responsibility, and adhering to Christian ethics, morals, and doctrine.

Audio Recordings The Combined Health Information Database contains abstracts on audio productions. To search CHID, go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find audio productions, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option

164 Drug Addiction

“Sound Recordings.” Type “drug addiction” (or synonyms) into the “For these words:” box. The following is a typical result when searching for sound recordings on drug addiction: •

Multiple Losses - Multiple Challenges Contact: Health Impact, PO Box 9443, Seattle, WA, 98109-9443, (206) 284-3865, http://www.healthimpact.org/. Summary: This sound recording discusses the variety of losses suffered by persons who test positive for Human immunodeficiency virus (HIV) antibodies as they progress through the continuum of the disease to a diagnosis of Acquired immunodeficiency syndrome (AIDS). The disease progresses differently in each individual and patient management must be planned accordingly. Jobs, homes, independence, support of family and friends because of their own fear of becoming infected, physical strength, and faith are the most common losses which Persons with AIDS (PWA's) suffer. Assistance from a variety of sources is available and how to choose which agency or resource is most appropriate in each case is discussed. Psychological help in dealing with the stigma associated with some risk factors, such as drug addiction and homosexuality, is explained. References and a post-test questionnaire are listed in the booklet that accompanies this sound recording.

Bibliography: Multimedia on Drug Addiction The National Library of Medicine is a rich source of information on healthcare-related multimedia productions including slides, computer software, and databases. To access the multimedia database, go to the following Web site: http://locatorplus.gov/. Select “Search LOCATORplus.” Once in the search area, simply type in drug addiction (or synonyms). Then, in the option box provided below the search box, select “Audiovisuals and Computer Files.” From there, you can choose to sort results by publication date, author, or relevance. The following multimedia has been indexed on drug addiction: •

Alcoholism and drug addiction [sound recording]: the disease concept Source: the Fortune Companies; Year: 1979; Format: Sound recording; Atlanta, Ga.: The Companies, c1979

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Prescription drug addiction [videorecording] Source: GWC; Year: 2003; Format: Videorecording; Cahokia, IL: GWC, c2003

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The lecture series on alcoholism and other drug addiction [videorecording] Source: by James R. Milam; produced by Video IV, in association with the Addiction Freedom Institute; Year: 1987; Format: Videorecording; Kirkland, WA:

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CHAPTER 8. ADDICTION

PERIODICALS

AND

NEWS

ON

DRUG

Overview In this chapter, we suggest a number of news sources and present various periodicals that cover drug addiction.

News Services and Press Releases One of the simplest ways of tracking press releases on drug addiction is to search the news wires. In the following sample of sources, we will briefly describe how to access each service. These services only post recent news intended for public viewing. PR Newswire To access the PR Newswire archive, simply go to http://www.prnewswire.com/. Select your country. Type “drug addiction” (or synonyms) into the search box. You will automatically receive information on relevant news releases posted within the last 30 days. The search results are shown by order of relevance. Reuters Health The Reuters’ Medical News and Health eLine databases can be very useful in exploring news archives relating to drug addiction. While some of the listed articles are free to view, others are available for purchase for a nominal fee. To access this archive, go to http://www.reutershealth.com/en/index.html and search by “drug addiction” (or synonyms). The following was recently listed in this archive for drug addiction: •

Drums may help beat drug addiction: researcher Source: Reuters Health eLine Date: April 18, 2003

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•

Brain changes similar in gambling, drug addiction Source: Reuters Health eLine Date: March 20, 2003

•

Catalyst licenses potential treatment for drug addiction Source: Reuters Industry Breifing Date: October 14, 2002

•

Germany's supervised drug addiction centres produce encouraging results Source: Reuters Medical News Date: September 24, 2002

•

Gene mutation linked to drug addiction Source: Reuters Health eLine Date: June 10, 2002

•

Drug addiction: a growing problem for Russia Source: Reuters Medical News Date: May 21, 2001

•

Early life stress may contribute to drug addiction Source: Reuters Health eLine Date: October 27, 2000

•

Plant compound could treat drug addiction Source: Reuters Health eLine Date: November 24, 1999

•

Use of ibogaine to treat drug addiction examined Source: Reuters Medical News Date: November 09, 1999

•

Women with drug addictions benefit from gender-specific drug treatment Source: Reuters Medical News Date: July 05, 1999 The NIH

Within MEDLINEplus, the NIH has made an agreement with the New York Times Syndicate, the AP News Service, and Reuters to deliver news that can be browsed by the public. Search news releases at http://www.nlm.nih.gov/medlineplus/alphanews_a.html. MEDLINEplus allows you to browse across an alphabetical index. Or you can search by date at the following Web page: http://www.nlm.nih.gov/medlineplus/newsbydate.html. Often, news items are indexed by MEDLINEplus within its search engine. Business Wire Business Wire is similar to PR Newswire. To access this archive, simply go to http://www.businesswire.com/. You can scan the news by industry category or company name.

Periodicals and News

167

Market Wire Market Wire is more focused on technology than the other wires. To browse the latest press releases by topic, such as alternative medicine, biotechnology, fitness, healthcare, legal, nutrition, and pharmaceuticals, access Market Wire’s Medical/Health channel at http://www.marketwire.com/mw/release_index?channel=MedicalHealth. Or simply go to Market Wire’s home page at http://www.marketwire.com/mw/home, type “drug addiction” (or synonyms) into the search box, and click on “Search News.” As this service is technology oriented, you may wish to use it when searching for press releases covering diagnostic procedures or tests. Search Engines Medical news is also available in the news sections of commercial Internet search engines. See the health news page at Yahoo (http://dir.yahoo.com/Health/News_and_Media/), or you can use this Web site’s general news search page at http://news.yahoo.com/. Type in “drug addiction” (or synonyms). If you know the name of a company that is relevant to drug addiction, you can go to any stock trading Web site (such as http://www.etrade.com/) and search for the company name there. News items across various news sources are reported on indicated hyperlinks. Google offers a similar service at http://news.google.com/. BBC Covering news from a more European perspective, the British Broadcasting Corporation (BBC) allows the public free access to their news archive located at http://www.bbc.co.uk/. Search by “drug addiction” (or synonyms).

Newsletter Articles Use the Combined Health Information Database, and limit your search criteria to “newsletter articles.” Again, you will need to use the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. Go to the bottom of the search page where “You may refine your search by.” Select the dates and language that you prefer. For the format option, select “Newsletter Article.” Type “drug addiction” (or synonyms) into the “For these words:” box. You should check back periodically with this database as it is updated every three months. The following is a typical result when searching for newsletter articles on drug addiction: •

Reducing the Harmful Effects of Weight Control Source: The Weight Control Digest. p.569,572-574, Nov/Dec 1996. Contact: Weight Control Digest, 1555 W. Mockingbird Lane, Suite 203, Dallas, TX 75235. (800) 736-7323. Summary: This article discusses the concept of "harm reduction" was originally developed as an approach to the treatment of drug addiction. Rather than demand abstinence, the counselor accepts the client where he is and works to reduce the harm by reducing the amount or frequency of drug use, according to the authors. Harm reduction is now used as an approach in obesity treatment as well. Rather than the all or

168 Drug Addiction

nothing attitude of target weights, what the client weighs is viewed as a continuum, from more weight to less weight. The aim is to move the client down the scale to reduce the harm of high weight. Thus this modality, the authors say, focuses on the idea that self-esteem will lead to weight loss, rather than the other way around.

Academic Periodicals covering Drug Addiction Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to drug addiction. In addition to these sources, you can search for articles covering drug addiction that have been published by any of the periodicals listed in previous chapters. To find the latest studies published, go to http://www.ncbi.nlm.nih.gov/pubmed, type the name of the periodical into the search box, and click “Go.” If you want complete details about the historical contents of a journal, you can also visit the following Web site: http://www.ncbi.nlm.nih.gov/entrez/jrbrowser.cgi. Here, type in the name of the journal or its abbreviation, and you will receive an index of published articles. At http://locatorplus.gov/, you can retrieve more indexing information on medical periodicals (e.g. the name of the publisher). Select the button “Search LOCATORplus.” Then type in the name of the journal and select the advanced search option “Journal Title Search.”

169

APPENDICES

171

APPENDIX A. PHYSICIAN RESOURCES Overview In this chapter, we focus on databases and Internet-based guidelines and information resources created or written for a professional audience.

NIH Guidelines Commonly referred to as “clinical” or “professional” guidelines, the National Institutes of Health publish physician guidelines for the most common diseases. Publications are available at the following by relevant Institute11: •

Office of the Director (OD); guidelines consolidated across agencies available at http://www.nih.gov/health/consumer/conkey.htm

•

National Institute of General Medical Sciences (NIGMS); fact sheets available at http://www.nigms.nih.gov/news/facts/

•

National Library of Medicine (NLM); extensive encyclopedia (A.D.A.M., Inc.) with guidelines: http://www.nlm.nih.gov/medlineplus/healthtopics.html

•

National Cancer Institute (NCI); guidelines available at http://www.cancer.gov/cancerinfo/list.aspx?viewid=5f35036e-5497-4d86-8c2c714a9f7c8d25

•

National Eye Institute (NEI); guidelines available at http://www.nei.nih.gov/order/index.htm

•

National Heart, Lung, and Blood Institute (NHLBI); guidelines available at http://www.nhlbi.nih.gov/guidelines/index.htm

•

National Human Genome Research Institute (NHGRI); research available at http://www.genome.gov/page.cfm?pageID=10000375

•

National Institute on Aging (NIA); guidelines available at http://www.nia.nih.gov/health/

11

These publications are typically written by one or more of the various NIH Institutes.

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•

National Institute on Alcohol Abuse and Alcoholism (NIAAA); guidelines available at http://www.niaaa.nih.gov/publications/publications.htm

•

National Institute of Allergy and Infectious Diseases (NIAID); guidelines available at http://www.niaid.nih.gov/publications/

•

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); fact sheets and guidelines available at http://www.niams.nih.gov/hi/index.htm

•

National Institute of Child Health and Human Development (NICHD); guidelines available at http://www.nichd.nih.gov/publications/pubskey.cfm

•

National Institute on Deafness and Other Communication Disorders (NIDCD); fact sheets and guidelines at http://www.nidcd.nih.gov/health/

•

National Institute of Dental and Craniofacial Research (NIDCR); guidelines available at http://www.nidr.nih.gov/health/

•

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); guidelines available at http://www.niddk.nih.gov/health/health.htm

•

National Institute on Drug Abuse (NIDA); guidelines available at http://www.nida.nih.gov/DrugAbuse.html

•

National Institute of Environmental Health Sciences (NIEHS); environmental health information available at http://www.niehs.nih.gov/external/facts.htm

•

National Institute of Mental Health (NIMH); guidelines available at http://www.nimh.nih.gov/practitioners/index.cfm

•

National Institute of Neurological Disorders and Stroke (NINDS); neurological disorder information pages available at http://www.ninds.nih.gov/health_and_medical/disorder_index.htm

•

National Institute of Nursing Research (NINR); publications on selected illnesses at http://www.nih.gov/ninr/news-info/publications.html

•

National Institute of Biomedical Imaging and Bioengineering; general information at http://grants.nih.gov/grants/becon/becon_info.htm

•

Center for Information Technology (CIT); referrals to other agencies based on keyword searches available at http://kb.nih.gov/www_query_main.asp

•

National Center for Complementary and Alternative Medicine (NCCAM); health information available at http://nccam.nih.gov/health/

•

National Center for Research Resources (NCRR); various information directories available at http://www.ncrr.nih.gov/publications.asp

•

Office of Rare Diseases; various fact sheets available at http://rarediseases.info.nih.gov/html/resources/rep_pubs.html

•

Centers for Disease Control and Prevention; various fact sheets on infectious diseases available at http://www.cdc.gov/publications.htm

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NIH Databases In addition to the various Institutes of Health that publish professional guidelines, the NIH has designed a number of databases for professionals.12 Physician-oriented resources provide a wide variety of information related to the biomedical and health sciences, both past and present. The format of these resources varies. Searchable databases, bibliographic citations, full-text articles (when available), archival collections, and images are all available. The following are referenced by the National Library of Medicine:13 •

Bioethics: Access to published literature on the ethical, legal, and public policy issues surrounding healthcare and biomedical research. This information is provided in conjunction with the Kennedy Institute of Ethics located at Georgetown University, Washington, D.C.: http://www.nlm.nih.gov/databases/databases_bioethics.html

•

HIV/AIDS Resources: Describes various links and databases dedicated to HIV/AIDS research: http://www.nlm.nih.gov/pubs/factsheets/aidsinfs.html

•

NLM Online Exhibitions: Describes “Exhibitions in the History of Medicine”: http://www.nlm.nih.gov/exhibition/exhibition.html. Additional resources for historical scholarship in medicine: http://www.nlm.nih.gov/hmd/hmd.html

•

Biotechnology Information: Access to public databases. The National Center for Biotechnology Information conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information for the better understanding of molecular processes affecting human health and disease: http://www.ncbi.nlm.nih.gov/

•

Population Information: The National Library of Medicine provides access to worldwide coverage of population, family planning, and related health issues, including family planning technology and programs, fertility, and population law and policy: http://www.nlm.nih.gov/databases/databases_population.html

•

Cancer Information: Access to cancer-oriented databases: http://www.nlm.nih.gov/databases/databases_cancer.html

•

Profiles in Science: Offering the archival collections of prominent twentieth-century biomedical scientists to the public through modern digital technology: http://www.profiles.nlm.nih.gov/

•

Chemical Information: Provides links to various chemical databases and references: http://sis.nlm.nih.gov/Chem/ChemMain.html

•

Clinical Alerts: Reports the release of findings from the NIH-funded clinical trials where such release could significantly affect morbidity and mortality: http://www.nlm.nih.gov/databases/alerts/clinical_alerts.html

•

Space Life Sciences: Provides links and information to space-based research (including NASA): http://www.nlm.nih.gov/databases/databases_space.html

•

MEDLINE: Bibliographic database covering the fields of medicine, nursing, dentistry, veterinary medicine, the healthcare system, and the pre-clinical sciences: http://www.nlm.nih.gov/databases/databases_medline.html

12

Remember, for the general public, the National Library of Medicine recommends the databases referenced in MEDLINEplus (http://medlineplus.gov/ or http://www.nlm.nih.gov/medlineplus/databases.html). 13 See http://www.nlm.nih.gov/databases/databases.html.

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•

Toxicology and Environmental Health Information (TOXNET): Databases covering toxicology and environmental health: http://sis.nlm.nih.gov/Tox/ToxMain.html

•

Visible Human Interface: Anatomically detailed, three-dimensional representations of normal male and female human bodies: http://www.nlm.nih.gov/research/visible/visible_human.html The Combined Health Information Database

A comprehensive source of information on clinical guidelines written for professionals is the Combined Health Information Database. You will need to limit your search to one of the following: Brochure/Pamphlet, Fact Sheet, or Information Package, and “drug addiction” using the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find associations, use the drop boxes at the bottom of the search page where “You may refine your search by.” For the publication date, select “All Years.” Select your preferred language and the format option “Fact Sheet.” Type “drug addiction” (or synonyms) into the “For these words:” box. The following is a sample result: •

Drug Dependence Treatment: Competing Priorities of HIV Positive and HIV Negative Drug Users Source: Aspects of HIV Management in Injecting Drug Users. Contact: Wellcome Foundation, Group Marketing, Langley Court, Beckenham. Summary: This paper, presented at an international seminar on managing Human immunodeficiency virus (HIV) among Injecting drug users (IDU's), studies the competing treatment priorities of those who are HIV-positive and those who are HIVnegative. It says that those who deal with drug addiction have a duty to care for the overall health and well-being of IDU's. It studies patterns of drug use, the process of changing behavior, attracting IDU's to treatment, prescribing methadone, and checking on the general state of their health.

•

1991 Florida Youth Risk Behavior Survey Report Contact: Florida Department of Education, Center For Prevention and Student Assistance, Florida Education Center, AIDS Information Services, 325 W Gaines St, Tallahassee, FL, 32399, (904) 488-7835. Summary: This report presents the results of a survey to determine the prevalence of health-risk behaviors among Florida youth in grades nine through twelve. Behaviors surveyed included violence and suicide; physical exercise, diet, weight; substance use; sexual activity; and accidents and injuries. Statistical results are presented for males and females in each category. The report summary states that the risk-taking behaviors of Florida youth are making them vulnerable to homicide, automobile accidents, unwanted pregnancies, drug addiction, Acquired immunodeficiency syndrome (AIDS) and Human immunodeficiency virus (HIV) infection, along with other Sexually transmitted diseases (STD's). Suggestions are made for reducing these risk behaviors, including a recommendation for comprehensive health education.

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The NLM Gateway14 The NLM (National Library of Medicine) Gateway is a Web-based system that lets users search simultaneously in multiple retrieval systems at the U.S. National Library of Medicine (NLM). It allows users of NLM services to initiate searches from one Web interface, providing one-stop searching for many of NLM’s information resources or databases.15 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “drug addiction” (or synonyms) into the search box and click “Search.” The results will be presented in a tabular form, indicating the number of references in each database category. Results Summary Category Journal Articles Books / Periodicals / Audio Visual Consumer Health Meeting Abstracts Other Collections Total

Items Found 136412 6493 872 3124 484 147385

HSTAT16 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.17 These documents include clinical practice guidelines, quickreference guides for clinicians, consumer health brochures, evidence reports and technology assessments from the Agency for Healthcare Research and Quality (AHRQ), as well as AHRQ’s Put Prevention Into Practice.18 Simply search by “drug addiction” (or synonyms) at the following Web site: http://text.nlm.nih.gov.

Coffee Break: Tutorials for Biologists19 Coffee Break is a general healthcare site that takes a scientific view of the news and covers recent breakthroughs in biology that may one day assist physicians in developing treatments. Here you will find a collection of short reports on recent biological discoveries. Each report incorporates interactive tutorials that demonstrate how bioinformatics tools are 14

Adapted from NLM: http://gateway.nlm.nih.gov/gw/Cmd?Overview.x.

15

The NLM Gateway is currently being developed by the Lister Hill National Center for Biomedical Communications (LHNCBC) at the National Library of Medicine (NLM) of the National Institutes of Health (NIH). 16 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 17 18

The HSTAT URL is http://hstat.nlm.nih.gov/.

Other important documents in HSTAT include: the National Institutes of Health (NIH) Consensus Conference Reports and Technology Assessment Reports; the HIV/AIDS Treatment Information Service (ATIS) resource documents; the Substance Abuse and Mental Health Services Administration's Center for Substance Abuse Treatment (SAMHSA/CSAT) Treatment Improvement Protocols (TIP) and Center for Substance Abuse Prevention (SAMHSA/CSAP) Prevention Enhancement Protocols System (PEPS); the Public Health Service (PHS) Preventive Services Task Force's Guide to Clinical Preventive Services; the independent, nonfederal Task Force on Community Services’ Guide to Community Preventive Services; and the Health Technology Advisory Committee (HTAC) of the Minnesota Health Care Commission (MHCC) health technology evaluations. 19 Adapted from http://www.ncbi.nlm.nih.gov/Coffeebreak/Archive/FAQ.html.

176 Drug Addiction

used as a part of the research process. Currently, all Coffee Breaks are written by NCBI staff.20 Each report is about 400 words and is usually based on a discovery reported in one or more articles from recently published, peer-reviewed literature.21 This site has new articles every few weeks, so it can be considered an online magazine of sorts. It is intended for general background information. You can access the Coffee Break Web site at the following hyperlink: http://www.ncbi.nlm.nih.gov/Coffeebreak/.

Other Commercial Databases In addition to resources maintained by official agencies, other databases exist that are commercial ventures addressing medical professionals. Here are some examples that may interest you: •

CliniWeb International: Index and table of contents to selected clinical information on the Internet; see http://www.ohsu.edu/cliniweb/.

•

Medical World Search: Searches full text from thousands of selected medical sites on the Internet; see http://www.mwsearch.com/.

20

The figure that accompanies each article is frequently supplied by an expert external to NCBI, in which case the source of the figure is cited. The result is an interactive tutorial that tells a biological story. 21 After a brief introduction that sets the work described into a broader context, the report focuses on how a molecular understanding can provide explanations of observed biology and lead to therapies for diseases. Each vignette is accompanied by a figure and hypertext links that lead to a series of pages that interactively show how NCBI tools and resources are used in the research process.

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APPENDIX B. PATIENT RESOURCES Overview Official agencies, as well as federally funded institutions supported by national grants, frequently publish a variety of guidelines written with the patient in mind. These are typically called “Fact Sheets” or “Guidelines.” They can take the form of a brochure, information kit, pamphlet, or flyer. Often they are only a few pages in length. Since new guidelines on drug addiction can appear at any moment and be published by a number of sources, the best approach to finding guidelines is to systematically scan the Internet-based services that post them.

Patient Guideline Sources The remainder of this chapter directs you to sources which either publish or can help you find additional guidelines on topics related to drug addiction. Due to space limitations, these sources are listed in a concise manner. Do not hesitate to consult the following sources by either using the Internet hyperlink provided, or, in cases where the contact information is provided, contacting the publisher or author directly. The National Institutes of Health The NIH gateway to patients is located at http://health.nih.gov/. From this site, you can search across various sources and institutes, a number of which are summarized below. Topic Pages: MEDLINEplus The National Library of Medicine has created a vast and patient-oriented healthcare information portal called MEDLINEplus. Within this Internet-based system are “health topic pages” which list links to available materials relevant to drug addiction. To access this system, log on to http://www.nlm.nih.gov/medlineplus/healthtopics.html. From there you can either search using the alphabetical index or browse by broad topic areas. Recently, MEDLINEplus listed the following when searched for “drug addiction”:

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•

Other guides Amphetamine Abuse http://www.nlm.nih.gov/medlineplus/amphetamineabuse.html Marijuana Abuse http://www.nlm.nih.gov/medlineplus/marijuanaabuse.html

You may also choose to use the search utility provided by MEDLINEplus at the following Web address: http://www.nlm.nih.gov/medlineplus/. Simply type a keyword into the search box and click “Search.” This utility is similar to the NIH search utility, with the exception that it only includes materials that are linked within the MEDLINEplus system (mostly patient-oriented information). It also has the disadvantage of generating unstructured results. We recommend, therefore, that you use this method only if you have a very targeted search. The Combined Health Information Database (CHID) CHID Online is a reference tool that maintains a database directory of thousands of journal articles and patient education guidelines on drug addiction. CHID offers summaries that describe the guidelines available, including contact information and pricing. CHID’s general Web site is http://chid.nih.gov/. To search this database, go to http://chid.nih.gov/detail/detail.html. In particular, you can use the advanced search options to look up pamphlets, reports, brochures, and information kits. The following was recently posted in this archive: •

Reaching the Other World: Portraits and Stories of Americans Fighting Drug Addiction and AIDS Contact: Project Change, 100 Westchester Rd, Boston, MA, 02130, (617) 432-1068. Summary: This brochure tells the stories of eight persons who have Acquired immunodeficiency syndrome (AIDS) and are also drug addicts. The pictures of the individuals are shown along with a quotation concerning AIDS and their drug addiction. This is part of a larger group of photos and quotations intended for display in public galleries. Healthfinder™

Healthfinder™ is sponsored by the U.S. Department of Health and Human Services and offers links to hundreds of other sites that contain healthcare information. This Web site is located at http://www.healthfinder.gov. Again, keyword searches can be used to find guidelines. The following was recently found in this database: •

NIDA's Asian Americans and Pacific Islanders Calendar--2003 Summary: This is a science-based resource calendar on the health effects of drugs of abuse and on drug addiction, its prevention, and its treatment. Source: National Institute on Drug Abuse, National Institutes of Health http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=7171

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The NIH Search Utility The NIH search utility allows you to search for documents on over 100 selected Web sites that comprise the NIH-WEB-SPACE. Each of these servers is “crawled” and indexed on an ongoing basis. Your search will produce a list of various documents, all of which will relate in some way to drug addiction. The drawbacks of this approach are that the information is not organized by theme and that the references are often a mix of information for professionals and patients. Nevertheless, a large number of the listed Web sites provide useful background information. We can only recommend this route, therefore, for relatively rare or specific disorders, or when using highly targeted searches. To use the NIH search utility, visit the following Web page: http://search.nih.gov/index.html. Additional Web Sources A number of Web sites are available to the public that often link to government sites. These can also point you in the direction of essential information. The following is a representative sample: •

AOL: http://search.aol.com/cat.adp?id=168&layer=&from=subcats

•

Family Village: http://www.familyvillage.wisc.edu/specific.htm

•

Google: http://directory.google.com/Top/Health/Conditions_and_Diseases/

•

Med Help International: http://www.medhelp.org/HealthTopics/A.html

•

Open Directory Project: http://dmoz.org/Health/Conditions_and_Diseases/

•

Yahoo.com: http://dir.yahoo.com/Health/Diseases_and_Conditions/

•

WebMDHealth: http://my.webmd.com/health_topics

Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to drug addiction. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with drug addiction. The National Health Information Center (NHIC) The National Health Information Center (NHIC) offers a free referral service to help people find organizations that provide information about drug addiction. For more information, see the NHIC’s Web site at http://www.health.gov/NHIC/ or contact an information specialist by calling 1-800-336-4797. Directory of Health Organizations The Directory of Health Organizations, provided by the National Library of Medicine Specialized Information Services, is a comprehensive source of information on associations. The Directory of Health Organizations database can be accessed via the Internet at

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http://www.sis.nlm.nih.gov/Dir/DirMain.html. It is composed of two parts: DIRLINE and Health Hotlines. The DIRLINE database comprises some 10,000 records of organizations, research centers, and government institutes and associations that primarily focus on health and biomedicine. To access DIRLINE directly, go to the following Web site: http://dirline.nlm.nih.gov/. Simply type in “drug addiction” (or a synonym), and you will receive information on all relevant organizations listed in the database. Health Hotlines directs you to toll-free numbers to over 300 organizations. You can access this database directly at http://www.sis.nlm.nih.gov/hotlines/. On this page, you are given the option to search by keyword or by browsing the subject list. When you have received your search results, click on the name of the organization for its description and contact information. The Combined Health Information Database Another comprehensive source of information on healthcare associations is the Combined Health Information Database. Using the “Detailed Search” option, you will need to limit your search to “Organizations” and “drug addiction”. Type the following hyperlink into your Web browser: http://chid.nih.gov/detail/detail.html. To find associations, use the drop boxes at the bottom of the search page where “You may refine your search by.” For publication date, select “All Years.” Then, select your preferred language and the format option “Organization Resource Sheet.” Type “drug addiction” (or synonyms) into the “For these words:” box. You should check back periodically with this database since it is updated every three months. The National Organization for Rare Disorders, Inc. The National Organization for Rare Disorders, Inc. has prepared a Web site that provides, at no charge, lists of associations organized by health topic. You can access this database at the following Web site: http://www.rarediseases.org/search/orgsearch.html. Type “drug addiction” (or a synonym) into the search box, and click “Submit Query.”

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APPENDIX C. FINDING MEDICAL LIBRARIES Overview In this Appendix, we show you how to quickly find a medical library in your area.

Preparation Your local public library and medical libraries have interlibrary loan programs with the National Library of Medicine (NLM), one of the largest medical collections in the world. According to the NLM, most of the literature in the general and historical collections of the National Library of Medicine is available on interlibrary loan to any library. If you would like to access NLM medical literature, then visit a library in your area that can request the publications for you.22

Finding a Local Medical Library The quickest method to locate medical libraries is to use the Internet-based directory published by the National Network of Libraries of Medicine (NN/LM). This network includes 4626 members and affiliates that provide many services to librarians, health professionals, and the public. To find a library in your area, simply visit http://nnlm.gov/members/adv.html or call 1-800-338-7657.

Medical Libraries in the U.S. and Canada In addition to the NN/LM, the National Library of Medicine (NLM) lists a number of libraries with reference facilities that are open to the public. The following is the NLM’s list and includes hyperlinks to each library’s Web site. These Web pages can provide information on hours of operation and other restrictions. The list below is a small sample of

22

Adapted from the NLM: http://www.nlm.nih.gov/psd/cas/interlibrary.html.

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libraries recommended by the National Library of Medicine (sorted alphabetically by name of the U.S. state or Canadian province where the library is located)23: •

Alabama: Health InfoNet of Jefferson County (Jefferson County Library Cooperative, Lister Hill Library of the Health Sciences), http://www.uab.edu/infonet/

•

Alabama: Richard M. Scrushy Library (American Sports Medicine Institute)

•

Arizona: Samaritan Regional Medical Center: The Learning Center (Samaritan Health System, Phoenix, Arizona), http://www.samaritan.edu/library/bannerlibs.htm

•

California: Kris Kelly Health Information Center (St. Joseph Health System, Humboldt), http://www.humboldt1.com/~kkhic/index.html

•

California: Community Health Library of Los Gatos, http://www.healthlib.org/orgresources.html

•

California: Consumer Health Program and Services (CHIPS) (County of Los Angeles Public Library, Los Angeles County Harbor-UCLA Medical Center Library) - Carson, CA, http://www.colapublib.org/services/chips.html

•

California: Gateway Health Library (Sutter Gould Medical Foundation)

•

California: Health Library (Stanford University Medical Center), http://wwwmed.stanford.edu/healthlibrary/

•

California: Patient Education Resource Center - Health Information and Resources (University of California, San Francisco), http://sfghdean.ucsf.edu/barnett/PERC/default.asp

•

California: Redwood Health Library (Petaluma Health Care District), http://www.phcd.org/rdwdlib.html

•

California: Los Gatos PlaneTree Health Library, http://planetreesanjose.org/

•

California: Sutter Resource Library (Sutter Hospitals Foundation, Sacramento), http://suttermedicalcenter.org/library/

•

California: Health Sciences Libraries (University of California, Davis), http://www.lib.ucdavis.edu/healthsci/

•

California: ValleyCare Health Library & Ryan Comer Cancer Resource Center (ValleyCare Health System, Pleasanton), http://gaelnet.stmarysca.edu/other.libs/gbal/east/vchl.html

•

California: Washington Community Health Resource Library (Fremont), http://www.healthlibrary.org/

•

Colorado: William V. Gervasini Memorial Library (Exempla Healthcare), http://www.saintjosephdenver.org/yourhealth/libraries/

•

Connecticut: Hartford Hospital Health Science Libraries (Hartford Hospital), http://www.harthosp.org/library/

•

Connecticut: Healthnet: Connecticut Consumer Health Information Center (University of Connecticut Health Center, Lyman Maynard Stowe Library), http://library.uchc.edu/departm/hnet/

23

Abstracted from http://www.nlm.nih.gov/medlineplus/libraries.html.

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•

Connecticut: Waterbury Hospital Health Center Library (Waterbury Hospital, Waterbury), http://www.waterburyhospital.com/library/consumer.shtml

•

Delaware: Consumer Health Library (Christiana Care Health System, Eugene du Pont Preventive Medicine & Rehabilitation Institute, Wilmington), http://www.christianacare.org/health_guide/health_guide_pmri_health_info.cfm

•

Delaware: Lewis B. Flinn Library (Delaware Academy of Medicine, Wilmington), http://www.delamed.org/chls.html

•

Georgia: Family Resource Library (Medical College of Georgia, Augusta), http://cmc.mcg.edu/kids_families/fam_resources/fam_res_lib/frl.htm

•

Georgia: Health Resource Center (Medical Center of Central Georgia, Macon), http://www.mccg.org/hrc/hrchome.asp

•

Hawaii: Hawaii Medical Library: Consumer Health Information Service (Hawaii Medical Library, Honolulu), http://hml.org/CHIS/

•

Idaho: DeArmond Consumer Health Library (Kootenai Medical Center, Coeur d’Alene), http://www.nicon.org/DeArmond/index.htm

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Illinois: Health Learning Center of Northwestern Memorial Hospital (Chicago), http://www.nmh.org/health_info/hlc.html

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Illinois: Medical Library (OSF Saint Francis Medical Center, Peoria), http://www.osfsaintfrancis.org/general/library/

•

Kentucky: Medical Library - Services for Patients, Families, Students & the Public (Central Baptist Hospital, Lexington), http://www.centralbap.com/education/community/library.cfm

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Kentucky: University of Kentucky - Health Information Library (Chandler Medical Center, Lexington), http://www.mc.uky.edu/PatientEd/

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Louisiana: Alton Ochsner Medical Foundation Library (Alton Ochsner Medical Foundation, New Orleans), http://www.ochsner.org/library/

•

Louisiana: Louisiana State University Health Sciences Center Medical LibraryShreveport, http://lib-sh.lsuhsc.edu/

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Maine: Franklin Memorial Hospital Medical Library (Franklin Memorial Hospital, Farmington), http://www.fchn.org/fmh/lib.htm

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Maine: Gerrish-True Health Sciences Library (Central Maine Medical Center, Lewiston), http://www.cmmc.org/library/library.html

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Maine: Hadley Parrot Health Science Library (Eastern Maine Healthcare, Bangor), http://www.emh.org/hll/hpl/guide.htm

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Maine: Maine Medical Center Library (Maine Medical Center, Portland), http://www.mmc.org/library/

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Maine: Parkview Hospital (Brunswick), http://www.parkviewhospital.org/

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Maine: Southern Maine Medical Center Health Sciences Library (Southern Maine Medical Center, Biddeford), http://www.smmc.org/services/service.php3?choice=10

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Maine: Stephens Memorial Hospital’s Health Information Library (Western Maine Health, Norway), http://www.wmhcc.org/Library/

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Manitoba, Canada: Consumer & Patient Health Information Service (University of Manitoba Libraries), http://www.umanitoba.ca/libraries/units/health/reference/chis.html

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Manitoba, Canada: J.W. Crane Memorial Library (Deer Lodge Centre, Winnipeg), http://www.deerlodge.mb.ca/crane_library/about.asp

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Maryland: Health Information Center at the Wheaton Regional Library (Montgomery County, Dept. of Public Libraries, Wheaton Regional Library), http://www.mont.lib.md.us/healthinfo/hic.asp

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Massachusetts: Baystate Medical Center Library (Baystate Health System), http://www.baystatehealth.com/1024/

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Massachusetts: Boston University Medical Center Alumni Medical Library (Boston University Medical Center), http://med-libwww.bu.edu/library/lib.html

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Massachusetts: Lowell General Hospital Health Sciences Library (Lowell General Hospital, Lowell), http://www.lowellgeneral.org/library/HomePageLinks/WWW.htm

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Massachusetts: Paul E. Woodard Health Sciences Library (New England Baptist Hospital, Boston), http://www.nebh.org/health_lib.asp

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Massachusetts: St. Luke’s Hospital Health Sciences Library (St. Luke’s Hospital, Southcoast Health System, New Bedford), http://www.southcoast.org/library/

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Massachusetts: Treadwell Library Consumer Health Reference Center (Massachusetts General Hospital), http://www.mgh.harvard.edu/library/chrcindex.html

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Massachusetts: UMass HealthNet (University of Massachusetts Medical School, Worchester), http://healthnet.umassmed.edu/

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Michigan: Botsford General Hospital Library - Consumer Health (Botsford General Hospital, Library & Internet Services), http://www.botsfordlibrary.org/consumer.htm

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Michigan: Helen DeRoy Medical Library (Providence Hospital and Medical Centers), http://www.providence-hospital.org/library/

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Michigan: Marquette General Hospital - Consumer Health Library (Marquette General Hospital, Health Information Center), http://www.mgh.org/center.html

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Michigan: Patient Education Resouce Center - University of Michigan Cancer Center (University of Michigan Comprehensive Cancer Center, Ann Arbor), http://www.cancer.med.umich.edu/learn/leares.htm

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Michigan: Sladen Library & Center for Health Information Resources - Consumer Health Information (Detroit), http://www.henryford.com/body.cfm?id=39330

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Montana: Center for Health Information (St. Patrick Hospital and Health Sciences Center, Missoula)

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National: Consumer Health Library Directory (Medical Library Association, Consumer and Patient Health Information Section), http://caphis.mlanet.org/directory/index.html

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National: National Network of Libraries of Medicine (National Library of Medicine) provides library services for health professionals in the United States who do not have access to a medical library, http://nnlm.gov/

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National: NN/LM List of Libraries Serving the Public (National Network of Libraries of Medicine), http://nnlm.gov/members/

Finding Medical Libraries

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Nevada: Health Science Library, West Charleston Library (Las Vegas-Clark County Library District, Las Vegas), http://www.lvccld.org/special_collections/medical/index.htm

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New Hampshire: Dartmouth Biomedical Libraries (Dartmouth College Library, Hanover), http://www.dartmouth.edu/~biomed/resources.htmld/conshealth.htmld/

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New Jersey: Consumer Health Library (Rahway Hospital, Rahway), http://www.rahwayhospital.com/library.htm

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New Jersey: Dr. Walter Phillips Health Sciences Library (Englewood Hospital and Medical Center, Englewood), http://www.englewoodhospital.com/links/index.htm

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New Jersey: Meland Foundation (Englewood Hospital and Medical Center, Englewood), http://www.geocities.com/ResearchTriangle/9360/

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New York: Choices in Health Information (New York Public Library) - NLM Consumer Pilot Project participant, http://www.nypl.org/branch/health/links.html

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New York: Health Information Center (Upstate Medical University, State University of New York, Syracuse), http://www.upstate.edu/library/hic/

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New York: Health Sciences Library (Long Island Jewish Medical Center, New Hyde Park), http://www.lij.edu/library/library.html

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New York: ViaHealth Medical Library (Rochester General Hospital), http://www.nyam.org/library/

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Ohio: Consumer Health Library (Akron General Medical Center, Medical & Consumer Health Library), http://www.akrongeneral.org/hwlibrary.htm

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Oklahoma: The Health Information Center at Saint Francis Hospital (Saint Francis Health System, Tulsa), http://www.sfh-tulsa.com/services/healthinfo.asp

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Oregon: Planetree Health Resource Center (Mid-Columbia Medical Center, The Dalles), http://www.mcmc.net/phrc/

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Pennsylvania: Community Health Information Library (Milton S. Hershey Medical Center, Hershey), http://www.hmc.psu.edu/commhealth/

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Pennsylvania: Community Health Resource Library (Geisinger Medical Center, Danville), http://www.geisinger.edu/education/commlib.shtml

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Pennsylvania: HealthInfo Library (Moses Taylor Hospital, Scranton), http://www.mth.org/healthwellness.html

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Pennsylvania: Hopwood Library (University of Pittsburgh, Health Sciences Library System, Pittsburgh), http://www.hsls.pitt.edu/guides/chi/hopwood/index_html

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Pennsylvania: Koop Community Health Information Center (College of Physicians of Philadelphia), http://www.collphyphil.org/kooppg1.shtml

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Pennsylvania: Learning Resources Center - Medical Library (Susquehanna Health System, Williamsport), http://www.shscares.org/services/lrc/index.asp

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Pennsylvania: Medical Library (UPMC Health System, Pittsburgh), http://www.upmc.edu/passavant/library.htm

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Quebec, Canada: Medical Library (Montreal General Hospital), http://www.mghlib.mcgill.ca/

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South Dakota: Rapid City Regional Hospital Medical Library (Rapid City Regional Hospital), http://www.rcrh.org/Services/Library/Default.asp

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Texas: Houston HealthWays (Houston Academy of Medicine-Texas Medical Center Library), http://hhw.library.tmc.edu/

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Washington: Community Health Library (Kittitas Valley Community Hospital), http://www.kvch.com/

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Washington: Southwest Washington Medical Center Library (Southwest Washington Medical Center, Vancouver), http://www.swmedicalcenter.com/body.cfm?id=72

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ONLINE GLOSSARIES The Internet provides access to a number of free-to-use medical dictionaries. The National Library of Medicine has compiled the following list of online dictionaries: •

ADAM Medical Encyclopedia (A.D.A.M., Inc.), comprehensive medical reference: http://www.nlm.nih.gov/medlineplus/encyclopedia.html

•

MedicineNet.com Medical Dictionary (MedicineNet, Inc.): http://www.medterms.com/Script/Main/hp.asp

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Merriam-Webster Medical Dictionary (Inteli-Health, Inc.): http://www.intelihealth.com/IH/

•

Multilingual Glossary of Technical and Popular Medical Terms in Eight European Languages (European Commission) - Danish, Dutch, English, French, German, Italian, Portuguese, and Spanish: http://allserv.rug.ac.be/~rvdstich/eugloss/welcome.html

•

On-line Medical Dictionary (CancerWEB): http://cancerweb.ncl.ac.uk/omd/

•

Rare Diseases Terms (Office of Rare Diseases): http://ord.aspensys.com/asp/diseases/diseases.asp

•

Technology Glossary (National Library of Medicine) - Health Care Technology: http://www.nlm.nih.gov/nichsr/ta101/ta10108.htm

Beyond these, MEDLINEplus contains a very patient-friendly encyclopedia covering every aspect of medicine (licensed from A.D.A.M., Inc.). The ADAM Medical Encyclopedia can be accessed at http://www.nlm.nih.gov/medlineplus/encyclopedia.html. ADAM is also available on commercial Web sites such as drkoop.com (http://www.drkoop.com/) and Web MD (http://my.webmd.com/adam/asset/adam_disease_articles/a_to_z/a).

Online Dictionary Directories The following are additional online directories compiled by the National Library of Medicine, including a number of specialized medical dictionaries: •

Medical Dictionaries: Medical & Biological (World Health Organization): http://www.who.int/hlt/virtuallibrary/English/diction.htm#Medical

•

MEL-Michigan Electronic Library List of Online Health and Medical Dictionaries (Michigan Electronic Library): http://mel.lib.mi.us/health/health-dictionaries.html

•

Patient Education: Glossaries (DMOZ Open Directory Project): http://dmoz.org/Health/Education/Patient_Education/Glossaries/

•

Web of Online Dictionaries (Bucknell University): http://www.yourdictionary.com/diction5.html#medicine

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DRUG ADDICTION DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. Abdominal: Having to do with the abdomen, which is the part of the body between the chest and the hips that contains the pancreas, stomach, intestines, liver, gallbladder, and other organs. [NIH] Abdominal Pain: Sensation of discomfort, distress, or agony in the abdominal region. [NIH] Abscess: Accumulation of purulent material in tissues, organs, or circumscribed spaces, usually associated with signs of infection. [NIH] Accidents, Radiation: Accidental dispersal of radioactive materials from a radiation source. Accidents at nuclear reactors can involve large groups of the population from dispersion of radioactivity into the environment and through fallout or a few individuals with high injurious doses. [NIH] Accommodation: Adjustment, especially that of the eye for various distances. [EU] Acetaldehyde: A colorless, flammable liquid used in the manufacture of acetic acid, perfumes, and flavors. It is also an intermediate in the metabolism of alcohol. It has a general narcotic action and also causes irritation of mucous membranes. Large doses may cause death from respiratory paralysis. [NIH] Acetylcholine: A neurotransmitter. Acetylcholine in vertebrates is the major transmitter at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. It is generally not used as an administered drug because it is broken down very rapidly by cholinesterases, but it is useful in some ophthalmological applications. [NIH] Adaptability: Ability to develop some form of tolerance to conditions extremely different from those under which a living organism evolved. [NIH] Adaptation: 1. The adjustment of an organism to its environment, or the process by which it enhances such fitness. 2. The normal ability of the eye to adjust itself to variations in the intensity of light; the adjustment to such variations. 3. The decline in the frequency of firing of a neuron, particularly of a receptor, under conditions of constant stimulation. 4. In dentistry, (a) the proper fitting of a denture, (b) the degree of proximity and interlocking of restorative material to a tooth preparation, (c) the exact adjustment of bands to teeth. 5. In microbiology, the adjustment of bacterial physiology to a new environment. [EU] Adjustment: The dynamic process wherein the thoughts, feelings, behavior, and biophysiological mechanisms of the individual continually change to adjust to the environment. [NIH] Adolescence: The period of life beginning with the appearance of secondary sex characteristics and terminating with the cessation of somatic growth. The years usually referred to as adolescence lie between 13 and 18 years of age. [NIH] Adrenal Cortex: The outer layer of the adrenal gland. It secretes mineralocorticoids, androgens, and glucocorticoids. [NIH] Adrenal Medulla: The inner part of the adrenal gland; it synthesizes, stores and releases catecholamines. [NIH] Adrenergic: Activated by, characteristic of, or secreting epinephrine or substances with

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similar activity; the term is applied to those nerve fibres that liberate norepinephrine at a synapse when a nerve impulse passes, i.e., the sympathetic fibres. [EU] Adverse Effect: An unwanted side effect of treatment. [NIH] Afferent: Concerned with the transmission of neural impulse toward the central part of the nervous system. [NIH] Affinity: 1. Inherent likeness or relationship. 2. A special attraction for a specific element, organ, or structure. 3. Chemical affinity; the force that binds atoms in molecules; the tendency of substances to combine by chemical reaction. 4. The strength of noncovalent chemical binding between two substances as measured by the dissociation constant of the complex. 5. In immunology, a thermodynamic expression of the strength of interaction between a single antigen-binding site and a single antigenic determinant (and thus of the stereochemical compatibility between them), most accurately applied to interactions among simple, uniform antigenic determinants such as haptens. Expressed as the association constant (K litres mole -1), which, owing to the heterogeneity of affinities in a population of antibody molecules of a given specificity, actually represents an average value (mean intrinsic association constant). 6. The reciprocal of the dissociation constant. [EU] Agonist: In anatomy, a prime mover. In pharmacology, a drug that has affinity for and stimulates physiologic activity at cell receptors normally stimulated by naturally occurring substances. [EU] Akathisia: 1. A condition of motor restlessness in which there is a feeling of muscular quivering, an urge to move about constantly, and an inability to sit still, a common extrapyramidal side effect of neuroleptic drugs. 2. An inability to sit down because of intense anxiety at the thought of doing so. [EU] Albumin: 1. Any protein that is soluble in water and moderately concentrated salt solutions and is coagulable by heat. 2. Serum albumin; the major plasma protein (approximately 60 per cent of the total), which is responsible for much of the plasma colloidal osmotic pressure and serves as a transport protein carrying large organic anions, such as fatty acids, bilirubin, and many drugs, and also carrying certain hormones, such as cortisol and thyroxine, when their specific binding globulins are saturated. Albumin is synthesized in the liver. Low serum levels occur in protein malnutrition, active inflammation and serious hepatic and renal disease. [EU] Aldehyde Dehydrogenase: An enzyme that oxidizes an aldehyde in the presence of NAD+ and water to an acid and NADH. EC 1.2.1.3. Before 1978, it was classified as EC 1.1.1.70. [NIH]

Algorithms: A procedure consisting of a sequence of algebraic formulas and/or logical steps to calculate or determine a given task. [NIH] Alimentary: Pertaining to food or nutritive material, or to the organs of digestion. [EU] Alkaline: Having the reactions of an alkali. [EU] Alkaloid: A member of a large group of chemicals that are made by plants and have nitrogen in them. Some alkaloids have been shown to work against cancer. [NIH] Allergen: An antigenic substance capable of producing immediate-type hypersensitivity (allergy). [EU] Alpha Particles: Positively charged particles composed of two protons and two neutrons, i.e., helium nuclei, emitted during disintegration of very heavy isotopes; a beam of alpha particles or an alpha ray has very strong ionizing power, but weak penetrability. [NIH] Alpha-1: A protein with the property of inactivating proteolytic enzymes such as leucocyte collagenase and elastase. [NIH]

Dictionary 191

Alternative medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used instead of standard treatments. Alternative medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Alveoli: Tiny air sacs at the end of the bronchioles in the lungs. [NIH] Amantadine: An antiviral that is used in the prophylactic or symptomatic treatment of Influenza A. It is also used as an antiparkinsonian agent, to treat extrapyramidal reactions, and for postherpetic neuralgia. The mechanisms of its effects in movement disorders are not well understood but probably reflect an increase in synthesis and release of dopamine, with perhaps some inhibition of dopamine uptake. [NIH] Amenorrhea: Absence of menstruation. [NIH] Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining protein conformation. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Amphetamine: A powerful central nervous system stimulant and sympathomimetic. Amphetamine has multiple mechanisms of action including blocking uptake of adrenergics and dopamine, stimulation of release of monamines, and inhibiting monoamine oxidase. Amphetamine is also a drug of abuse and a psychotomimetic. The l- and the d,l-forms are included here. The l-form has less central nervous system activity but stronger cardiovascular effects. The d-form is dextroamphetamine. [NIH] Ampulla: A sac-like enlargement of a canal or duct. [NIH] Amygdala: Almond-shaped group of basal nuclei anterior to the inferior horn of the lateral ventricle of the brain, within the temporal lobe. The amygdala is part of the limbic system. [NIH]

Anaesthesia: Loss of feeling or sensation. Although the term is used for loss of tactile sensibility, or of any of the other senses, it is applied especially to loss of the sensation of pain, as it is induced to permit performance of surgery or other painful procedures. [EU] Anaesthetic: 1. Pertaining to, characterized by, or producing anaesthesia. 2. A drug or agent that is used to abolish the sensation of pain. [EU] Anal: Having to do with the anus, which is the posterior opening of the large bowel. [NIH] Analgesic: An agent that alleviates pain without causing loss of consciousness. [EU] Analog: In chemistry, a substance that is similar, but not identical, to another. [NIH] Analogous: Resembling or similar in some respects, as in function or appearance, but not in origin or development;. [EU] Anaphylatoxins: The family of peptides C3a, C4a, C5a, and C5a des-arginine produced in the serum during complement activation. They produce smooth muscle contraction, mast cell histamine release, affect platelet aggregation, and act as mediators of the local inflammatory process. The order of anaphylatoxin activity from strongest to weakest is C5a, C3a, C4a, and C5a des-arginine. The latter is the so-called "classical" anaphylatoxin but shows no spasmogenic activity though it contains some chemotactic ability. [NIH]

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Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Androgens: A class of sex hormones associated with the development and maintenance of the secondary male sex characteristics, sperm induction, and sexual differentiation. In addition to increasing virility and libido, they also increase nitrogen and water retention and stimulate skeletal growth. [NIH] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] Anesthesia: A state characterized by loss of feeling or sensation. This depression of nerve function is usually the result of pharmacologic action and is induced to allow performance of surgery or other painful procedures. [NIH] Anesthetics: Agents that are capable of inducing a total or partial loss of sensation, especially tactile sensation and pain. They may act to induce general anesthesia, in which an unconscious state is achieved, or may act locally to induce numbness or lack of sensation at a targeted site. [NIH] Aneurysm: A sac formed by the dilatation of the wall of an artery, a vein, or the heart. [NIH] Angina: Chest pain that originates in the heart. [NIH] Angina Pectoris: The symptom of paroxysmal pain consequent to myocardial ischemia usually of distinctive character, location and radiation, and provoked by a transient stressful situation during which the oxygen requirements of the myocardium exceed the capacity of the coronary circulation to supply it. [NIH] Animal model: An animal with a disease either the same as or like a disease in humans. Animal models are used to study the development and progression of diseases and to test new treatments before they are given to humans. Animals with transplanted human cancers or other tissues are called xenograft models. [NIH] Anions: Negatively charged atoms, radicals or groups of atoms which travel to the anode or positive pole during electrolysis. [NIH] Ankle: That part of the lower limb directly above the foot. [NIH] Annealing: The spontaneous alignment of two single DNA strands to form a double helix. [NIH]

Anorexia: Lack or loss of appetite for food. Appetite is psychologic, dependent on memory and associations. Anorexia can be brought about by unattractive food, surroundings, or company. [NIH] Anorexia Nervosa: The chief symptoms are inability to eat, weight loss, and amenorrhea. [NIH]

Antagonism: Interference with, or inhibition of, the growth of a living organism by another living organism, due either to creation of unfavorable conditions (e. g. exhaustion of food supplies) or to production of a specific antibiotic substance (e. g. penicillin). [NIH] Antiallergic: Counteracting allergy or allergic conditions. [EU] Antibacterial: A substance that destroys bacteria or suppresses their growth or reproduction. [EU] Antibiotic: A drug used to treat infections caused by bacteria and other microorganisms. [NIH]

Antibodies: Immunoglobulin molecules having a specific amino acid sequence by virtue of which they interact only with the antigen that induced their synthesis in cells of the lymphoid series (especially plasma cells), or with an antigen closely related to it. [NIH] Antibody: A type of protein made by certain white blood cells in response to a foreign

Dictionary 193

substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen. [NIH] Anticoagulant: A drug that helps prevent blood clots from forming. Also called a blood thinner. [NIH] Antidepressant: A drug used to treat depression. [NIH] Antiemetic: An agent that prevents or alleviates nausea and vomiting. Also antinauseant. [EU]

Antigen: Any substance which is capable, under appropriate conditions, of inducing a specific immune response and of reacting with the products of that response, that is, with specific antibody or specifically sensitized T-lymphocytes, or both. Antigens may be soluble substances, such as toxins and foreign proteins, or particulate, such as bacteria and tissue cells; however, only the portion of the protein or polysaccharide molecule known as the antigenic determinant (q.v.) combines with antibody or a specific receptor on a lymphocyte. Abbreviated Ag. [EU] Antigen-Antibody Complex: The complex formed by the binding of antigen and antibody molecules. The deposition of large antigen-antibody complexes leading to tissue damage causes immune complex diseases. [NIH] Antihypertensive: An agent that reduces high blood pressure. [EU] Anti-inflammatory: Having to do with reducing inflammation. [NIH] Anti-Inflammatory Agents: Substances that reduce or suppress inflammation. [NIH] Antimetabolite: A chemical that is very similar to one required in a normal biochemical reaction in cells. Antimetabolites can stop or slow down the reaction. [NIH] Antimicrobial: Killing microorganisms, or suppressing their multiplication or growth. [EU] Antineoplastic: Inhibiting or preventing the development of neoplasms, checking the maturation and proliferation of malignant cells. [EU] Antipsychotic: Effective in the treatment of psychosis. Antipsychotic drugs (called also neuroleptic drugs and major tranquilizers) are a chemically diverse (including phenothiazines, thioxanthenes, butyrophenones, dibenzoxazepines, dibenzodiazepines, and diphenylbutylpiperidines) but pharmacologically similar class of drugs used to treat schizophrenic, paranoid, schizoaffective, and other psychotic disorders; acute delirium and dementia, and manic episodes (during induction of lithium therapy); to control the movement disorders associated with Huntington's chorea, Gilles de la Tourette's syndrome, and ballismus; and to treat intractable hiccups and severe nausea and vomiting. Antipsychotic agents bind to dopamine, histamine, muscarinic cholinergic, a-adrenergic, and serotonin receptors. Blockade of dopaminergic transmission in various areas is thought to be responsible for their major effects : antipsychotic action by blockade in the mesolimbic and mesocortical areas; extrapyramidal side effects (dystonia, akathisia, parkinsonism, and tardive dyskinesia) by blockade in the basal ganglia; and antiemetic effects by blockade in the chemoreceptor trigger zone of the medulla. Sedation and autonomic side effects (orthostatic hypotension, blurred vision, dry mouth, nasal congestion and constipation) are caused by blockade of histamine, cholinergic, and adrenergic receptors. [EU] Antiserum: The blood serum obtained from an animal after it has been immunized with a particular antigen. It will contain antibodies which are specific for that antigen as well as antibodies specific for any other antigen with which the animal has previously been immunized. [NIH]

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Antispasmodic: An agent that relieves spasm. [EU] Antitussive: An agent that relieves or prevents cough. [EU] Antiviral: Destroying viruses or suppressing their replication. [EU] Anus: The opening of the rectum to the outside of the body. [NIH] Anxiety: Persistent feeling of dread, apprehension, and impending disaster. [NIH] Anxiety Disorders: Disorders in which anxiety (persistent feelings of apprehension, tension, or uneasiness) is the predominant disturbance. [NIH] Aorta: The main trunk of the systemic arteries. [NIH] Apathy: Lack of feeling or emotion; indifference. [EU] Aqueous: Having to do with water. [NIH] Aromatic: Having a spicy odour. [EU] Arrhythmia: Any variation from the normal rhythm or rate of the heart beat. [NIH] Arterial: Pertaining to an artery or to the arteries. [EU] Arteries: The vessels carrying blood away from the heart. [NIH] Arteriovenous: Both arterial and venous; pertaining to or affecting an artery and a vein. [EU] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Astrocytes: The largest and most numerous neuroglial cells in the brain and spinal cord. Astrocytes (from "star" cells) are irregularly shaped with many long processes, including those with "end feet" which form the glial (limiting) membrane and directly and indirectly contribute to the blood brain barrier. They regulate the extracellular ionic and chemical environment, and "reactive astrocytes" (along with microglia) respond to injury. Astrocytes have high- affinity transmitter uptake systems, voltage-dependent and transmitter-gated ion channels, and can release transmitter, but their role in signaling (as in many other functions) is not well understood. [NIH] Atrial: Pertaining to an atrium. [EU] Atrioventricular: Pertaining to an atrium of the heart and to a ventricle. [EU] Atrium: A chamber; used in anatomical nomenclature to designate a chamber affording entrance to another structure or organ. Usually used alone to designate an atrium of the heart. [EU] Atrophy: Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. [NIH] Attenuated: Strain with weakened or reduced virulence. [NIH] Atypical: Irregular; not conformable to the type; in microbiology, applied specifically to strains of unusual type. [EU] Auditory: Pertaining to the sense of hearing. [EU] Autonomic: Self-controlling; functionally independent. [EU] Autonomic Nervous System: The enteric, parasympathetic, and sympathetic nervous systems taken together. Generally speaking, the autonomic nervous system regulates the internal environment during both peaceful activity and physical or emotional stress. Autonomic activity is controlled and integrated by the central nervous system, especially the hypothalamus and the solitary nucleus, which receive information relayed from visceral afferents; these and related central and sensory structures are sometimes (but not here)

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considered to be part of the autonomic nervous system itself. [NIH] Autonomic Neuropathy: A disease of the nerves affecting mostly the internal organs such as the bladder muscles, the cardiovascular system, the digestive tract, and the genital organs. These nerves are not under a person's conscious control and function automatically. Also called visceral neuropathy. [NIH] Autopsy: Postmortem examination of the body. [NIH] Autoradiography: A process in which radioactive material within an object produces an image when it is in close proximity to a radiation sensitive emulsion. [NIH] Autoreceptors: Transmitter receptors on or near presynaptic terminals (or varicosities) which are sensitive to the transmitter(s) released by the terminal itself. Receptors for the hormones released by hormone-releasing cells are also included. [NIH] Autosuggestion: Suggestion coming from the subject himself. [NIH] Axilla: The underarm or armpit. [NIH] Axonal: Condition associated with metabolic derangement of the entire neuron and is manifest by degeneration of the distal portion of the nerve fiber. [NIH] Axons: Nerve fibers that are capable of rapidly conducting impulses away from the neuron cell body. [NIH] Baclofen: A GABA derivative that is a specific agonist at GABA-B receptors. It is used in the treatment of spasticity, especially that due to spinal cord damage. Its therapeutic effects result from actions at spinal and supraspinal sites, generally the reduction of excitatory transmission. [NIH] Bacteremia: The presence of viable bacteria circulating in the blood. Fever, chills, tachycardia, and tachypnea are common acute manifestations of bacteremia. The majority of cases are seen in already hospitalized patients, most of whom have underlying diseases or procedures which render their bloodstreams susceptible to invasion. [NIH] Bacteria: Unicellular prokaryotic microorganisms which generally possess rigid cell walls, multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or bacillary, and spiral or spirochetal. [NIH] Bacterial Physiology: Physiological processes and activities of bacteria. [NIH] Bactericidal: Substance lethal to bacteria; substance capable of killing bacteria. [NIH] Bacteriophage: A virus whose host is a bacterial cell; A virus that exclusively infects bacteria. It generally has a protein coat surrounding the genome (DNA or RNA). One of the coliphages most extensively studied is the lambda phage, which is also one of the most important. [NIH] Barbiturate: A drug with sedative and hypnotic effects. Barbiturates have been used as sedatives and anesthetics, and they have been used to treat the convulsions associated with epilepsy. [NIH] Basal Ganglia: Large subcortical nuclear masses derived from the telencephalon and located in the basal regions of the cerebral hemispheres. [NIH] Basal Ganglia Diseases: Diseases of the basal ganglia including the putamen; globus pallidus; claustrum; amygdala; and caudate nucleus. Dyskinesias (most notably involuntary movements and alterations of the rate of movement) represent the primary clinical manifestations of these disorders. Common etiologies include cerebrovascular disease; neurodegenerative diseases; and craniocerebral trauma. [NIH] Base: In chemistry, the nonacid part of a salt; a substance that combines with acids to form salts; a substance that dissociates to give hydroxide ions in aqueous solutions; a substance

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whose molecule or ion can combine with a proton (hydrogen ion); a substance capable of donating a pair of electrons (to an acid) for the formation of a coordinate covalent bond. [EU] Behavior Therapy: The application of modern theories of learning and conditioning in the treatment of behavior disorders. [NIH] Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [NIH]

Benzene: Toxic, volatile, flammable liquid hydrocarbon biproduct of coal distillation. It is used as an industrial solvent in paints, varnishes, lacquer thinners, gasoline, etc. Benzene causes central nervous system damage acutely and bone marrow damage chronically and is carcinogenic. It was formerly used as parasiticide. [NIH] Benzodiazepines: A two-ring heterocyclic compound consisting of a benzene ring fused to a diazepine ring. Permitted is any degree of hydrogenation, any substituents and any Hisomer. [NIH] Beta-Endorphin: A peptide consisting of amino acid sequence 61-91 of the endogenous pituitary hormone beta-lipotropin. The first four amino acids show a common tetrapeptide sequence with methionine- and leucine enkephalin. The compound shows opiate-like activity. Injection of beta-endorphin induces a profound analgesia of the whole body for several hours. This action is reversed after administration of naloxone. [NIH] Bicuculline: Isoquinoline alkaloid from Dicentra cucullaria and other plants that is a competitive antagonist at GABA-A receptors and thus causes convulsions. [NIH] Bile: An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts, cholesterol, and electrolytes. It aids digestion of fats in the duodenum. [NIH] Bilirubin: A bile pigment that is a degradation product of heme. [NIH] Bioavailability: The degree to which a drug or other substance becomes available to the target tissue after administration. [EU] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biological Factors: Compounds made by living organisms that contribute to or influence a phenomenon or process. They have biological or physiological activities. [NIH] Biological response modifier: BRM. A substance that stimulates the body's response to infection and disease. [NIH] Biological therapy: Treatment to stimulate or restore the ability of the immune system to fight infection and disease. Also used to lessen side effects that may be caused by some cancer treatments. Also known as immunotherapy, biotherapy, or biological response modifier (BRM) therapy. [NIH] Biomolecular: A scientific field at the interface between advanced computing and biotechnology. [NIH] Biopsy: Removal and pathologic examination of specimens in the form of small pieces of tissue from the living body. [NIH] Biosynthesis: The building up of a chemical compound in the physiologic processes of a living organism. [EU] Biotechnology: Body of knowledge related to the use of organisms, cells or cell-derived constituents for the purpose of developing products which are technically, scientifically and clinically useful. Alteration of biologic function at the molecular level (i.e., genetic engineering) is a central focus; laboratory methods used include transfection and cloning

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technologies, sequence and structure analysis algorithms, computer databases, and gene and protein structure function analysis and prediction. [NIH] Biotransformation: The chemical alteration of an exogenous substance by or in a biological system. The alteration may inactivate the compound or it may result in the production of an active metabolite of an inactive parent compound. The alteration may be either nonsynthetic (oxidation-reduction, hydrolysis) or synthetic (glucuronide formation, sulfate conjugation, acetylation, methylation). This also includes metabolic detoxication and clearance. [NIH] Bipolar Disorder: A major affective disorder marked by severe mood swings (manic or major depressive episodes) and a tendency to remission and recurrence. [NIH] Bladder: The organ that stores urine. [NIH] Blastocyst: The mammalian embryo in the post-morula stage in which a fluid-filled cavity, enclosed primarily by trophoblast, contains an inner cell mass which becomes the embryonic disc. [NIH] Bloating: Fullness or swelling in the abdomen that often occurs after meals. [NIH] Blood Cell Count: A count of the number of leukocytes and erythrocytes per unit volume in a sample of venous blood. A complete blood count (CBC) also includes measurement of the hemoglobin, hematocrit, and erythrocyte indices. [NIH] Blood Coagulation: The process of the interaction of blood coagulation factors that results in an insoluble fibrin clot. [NIH] Blood Glucose: Glucose in blood. [NIH] Blood Platelets: Non-nucleated disk-shaped cells formed in the megakaryocyte and found in the blood of all mammals. They are mainly involved in blood coagulation. [NIH] Blood pressure: The pressure of blood against the walls of a blood vessel or heart chamber. Unless there is reference to another location, such as the pulmonary artery or one of the heart chambers, it refers to the pressure in the systemic arteries, as measured, for example, in the forearm. [NIH] Blood transfusion: The administration of blood or blood products into a blood vessel. [NIH] Blood vessel: A tube in the body through which blood circulates. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins. [NIH] Blood-Borne Pathogens: Infectious organisms in the blood, of which the predominant medical interest is their contamination of blood-soiled linens, towels, gowns, bandages, other items from individuals in risk categories, needles and other sharp objects, and medical and dental waste, all of which health workers are exposed to. This concept is differentiated from the clinical conditions of bacteremia, viremia, and fungemia where the organism is present in the blood of a patient as the result of a natural infectious process. [NIH] Blood-Brain Barrier: Specialized non-fenestrated tightly-joined endothelial cells (tight junctions) that form a transport barrier for certain substances between the cerebral capillaries and the brain tissue. [NIH] Blushing: Involuntary reddening, especially of the face, associated with feelings of embarrassment, confusion, or shame. [NIH] Body Fluids: Liquid components of living organisms. [NIH] Bone Marrow: The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up

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of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. [NIH] Bowel: The long tube-shaped organ in the abdomen that completes the process of digestion. There is both a small and a large bowel. Also called the intestine. [NIH] Brachial: All the nerves from the arm are ripped from the spinal cord. [NIH] Brachial Plexus: The large network of nerve fibers which distributes the innervation of the upper extremity. The brachial plexus extends from the neck into the axilla. In humans, the nerves of the plexus usually originate from the lower cervical and the first thoracic spinal cord segments (C5-C8 and T1), but variations are not uncommon. [NIH] Bradycardia: Excessive slowness in the action of the heart, usually with a heart rate below 60 beats per minute. [NIH] Bradykinin: A nonapeptide messenger that is enzymatically produced from kallidin in the blood where it is a potent but short-lived agent of arteriolar dilation and increased capillary permeability. Bradykinin is also released from mast cells during asthma attacks, from gut walls as a gastrointestinal vasodilator, from damaged tissues as a pain signal, and may be a neurotransmitter. [NIH] Brain Ischemia: Localized reduction of blood flow to brain tissue due to arterial obtruction or systemic hypoperfusion. This frequently occurs in conjuction with brain hypoxia. Prolonged ischemia is associated with brain infarction. [NIH] Brain Stem: The part of the brain that connects the cerebral hemispheres with the spinal cord. It consists of the mesencephalon, pons, and medulla oblongata. [NIH] Branch: Most commonly used for branches of nerves, but applied also to other structures. [NIH]

Buccopharyngeal: Pertaining to the mouth and pharynx. [EU] Bulimia: Episodic binge eating. The episodes may be associated with the fear of not being able to stop eating, depressed mood, or self-deprecating thoughts (binge-eating disorder) and may frequently be terminated by self-induced vomiting (bulimia nervosa). [NIH] Buprenorphine: A derivative of the opioid alkaloid thebaine that is a more potent and longer lasting analgesic than morphine. It appears to act as a partial agonist at mu and kappa opioid receptors and as an antagonist at delta receptors. The lack of delta-agonist activity has been suggested to account for the observation that buprenorphine tolerance may not develop with chronic use. [NIH] Bupropion: A unicyclic, aminoketone antidepressant. The mechanism of its therapeutic actions is not well understood, but it does appear to block dopamine uptake. The hydrochloride is available as an aid to smoking cessation treatment. [NIH] Calcium: A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. [NIH] Calmodulin: A heat-stable, low-molecular-weight activator protein found mainly in the brain and heart. The binding of calcium ions to this protein allows this protein to bind to cyclic nucleotide phosphodiesterases and to adenyl cyclase with subsequent activation. Thereby this protein modulates cyclic AMP and cyclic GMP levels. [NIH] Cannabidiol: Compound isolated from Cannabis sativa extract. [NIH] Cannabinoids: Compounds extracted from Cannabis sativa L. and metabolites having the

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cannabinoid structure. The most active constituents are tetrahydrocannabinol, cannabinol, and cannabidiol. [NIH] Cannabinol: A physiologically inactive constituent of Cannabis sativa L. [NIH] Capillary: Any one of the minute vessels that connect the arterioles and venules, forming a network in nearly all parts of the body. Their walls act as semipermeable membranes for the interchange of various substances, including fluids, between the blood and tissue fluid; called also vas capillare. [EU] Capsules: Hard or soft soluble containers used for the oral administration of medicine. [NIH] Carbohydrate: An aldehyde or ketone derivative of a polyhydric alcohol, particularly of the pentahydric and hexahydric alcohols. They are so named because the hydrogen and oxygen are usually in the proportion to form water, (CH2O)n. The most important carbohydrates are the starches, sugars, celluloses, and gums. They are classified into mono-, di-, tri-, polyand heterosaccharides. [EU] Carbon Dioxide: A colorless, odorless gas that can be formed by the body and is necessary for the respiration cycle of plants and animals. [NIH] Carcinogenic: Producing carcinoma. [EU] Cardiac: Having to do with the heart. [NIH] Cardioselective: Having greater activity on heart tissue than on other tissue. [EU] Cardiovascular: Having to do with the heart and blood vessels. [NIH] Cardiovascular disease: Any abnormal condition characterized by dysfunction of the heart and blood vessels. CVD includes atherosclerosis (especially coronary heart disease, which can lead to heart attacks), cerebrovascular disease (e.g., stroke), and hypertension (high blood pressure). [NIH] Cardiovascular System: The heart and the blood vessels by which blood is pumped and circulated through the body. [NIH] Carrier Proteins: Transport proteins that carry specific substances in the blood or across cell membranes. [NIH] Catecholamine: A group of chemical substances manufactured by the adrenal medulla and secreted during physiological stress. [NIH] Catheters: A small, flexible tube that may be inserted into various parts of the body to inject or remove liquids. [NIH] Caudal: Denoting a position more toward the cauda, or tail, than some specified point of reference; same as inferior, in human anatomy. [EU] Caudate Nucleus: Elongated gray mass of the neostriatum located adjacent to the lateral ventricle of the brain. [NIH] Cell: The individual unit that makes up all of the tissues of the body. All living things are made up of one or more cells. [NIH] Cell Cycle: The complex series of phenomena, occurring between the end of one cell division and the end of the next, by which cellular material is divided between daughter cells. [NIH] Cell Death: The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. [NIH] Cell Differentiation: Progressive restriction of the developmental potential and increasing specialization of function which takes place during the development of the embryo and leads to the formation of specialized cells, tissues, and organs. [NIH]

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Cell Division: The fission of a cell. [NIH] Cell membrane: Cell membrane = plasma membrane. The structure enveloping a cell, enclosing the cytoplasm, and forming a selective permeability barrier; it consists of lipids, proteins, and some carbohydrates, the lipids thought to form a bilayer in which integral proteins are embedded to varying degrees. [EU] Cell proliferation: An increase in the number of cells as a result of cell growth and cell division. [NIH] Cell Respiration: The metabolic process of all living cells (animal and plant) in which oxygen is used to provide a source of energy for the cell. [NIH] Cell Survival: The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. [NIH] Cellobiose: A disaccharide consisting of two glucose units in beta (1-4) glycosidic linkage. Obtained from the partial hydrolysis of cellulose. [NIH] Cellulose: A polysaccharide with glucose units linked as in cellobiose. It is the chief constituent of plant fibers, cotton being the purest natural form of the substance. As a raw material, it forms the basis for many derivatives used in chromatography, ion exchange materials, explosives manufacturing, and pharmaceutical preparations. [NIH] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Central Nervous System Infections: Pathogenic infections of the brain, spinal cord, and meninges. DNA virus infections; RNA virus infections; bacterial infections; mycoplasma infections; Spirochaetales infections; fungal infections; protozoan infections; helminthiasis; and prion diseases may involve the central nervous system as a primary or secondary process. [NIH] Centrifugation: A method of separating organelles or large molecules that relies upon differential sedimentation through a preformed density gradient under the influence of a gravitational field generated in a centrifuge. [NIH] Cerebellum: Part of the metencephalon that lies in the posterior cranial fossa behind the brain stem. It is concerned with the coordination of movement. [NIH] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] Cerebral Infarction: The formation of an area of necrosis in the cerebrum caused by an insufficiency of arterial or venous blood flow. Infarcts of the cerebrum are generally classified by hemisphere (i.e., left vs. right), lobe (e.g., frontal lobe infarction), arterial distribution (e.g., infarction, anterior cerebral artery), and etiology (e.g., embolic infarction). [NIH]

Cerebrospinal: Pertaining to the brain and spinal cord. [EU] Cerebrospinal fluid: CSF. The fluid flowing around the brain and spinal cord. Cerebrospinal fluid is produced in the ventricles in the brain. [NIH] Cerebrovascular: Pertaining to the blood vessels of the cerebrum, or brain. [EU] Cerebrovascular Disorders: A broad category of disorders characterized by impairment of blood flow in the arteries and veins which supply the brain. These include cerebral infarction; brain ischemia; hypoxia, brain; intracranial embolism and thrombosis; intracranial arteriovenous malformations; and vasculitis, central nervous system. In common usage, the term cerebrovascular disorders is not limited to conditions that affect the cerebrum, but refers to vascular disorders of the entire brain including the diencephalon; brain stem; and cerebellum. [NIH]

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Cerebrum: The largest part of the brain. It is divided into two hemispheres, or halves, called the cerebral hemispheres. The cerebrum controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. [NIH] Cervical: Relating to the neck, or to the neck of any organ or structure. Cervical lymph nodes are located in the neck; cervical cancer refers to cancer of the uterine cervix, which is the lower, narrow end (the "neck") of the uterus. [NIH] Character: In current usage, approximately equivalent to personality. The sum of the relatively fixed personality traits and habitual modes of response of an individual. [NIH] Chemoreceptor: A receptor adapted for excitation by chemical substances, e.g., olfactory and gustatory receptors, or a sense organ, as the carotid body or the aortic (supracardial) bodies, which is sensitive to chemical changes in the blood stream, especially reduced oxygen content, and reflexly increases both respiration and blood pressure. [EU] Chemotactic Factors: Chemical substances that attract or repel cells or organisms. The concept denotes especially those factors released as a result of tissue injury, invasion, or immunologic activity, that attract leukocytes, macrophages, or other cells to the site of infection or insult. [NIH] Chemotherapy: Treatment with anticancer drugs. [NIH] Child Custody: The formally authorized guardianship or care of a child. [NIH] Child Welfare: Organized efforts by communities or organizations to improve the health and well-being of the child. [NIH] Cholesterol: The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. [NIH] Cholinergic: Resembling acetylcholine in pharmacological action; stimulated by or releasing acetylcholine or a related compound. [EU] Chorea: Involuntary, forcible, rapid, jerky movements that may be subtle or become confluent, markedly altering normal patterns of movement. Hypotonia and pendular reflexes are often associated. Conditions which feature recurrent or persistent episodes of chorea as a primary manifestation of disease are referred to as choreatic disorders. Chorea is also a frequent manifestation of basal ganglia diseases. [NIH] Choreatic Disorders: Acquired and hereditary conditions which feature chorea as a primary manifestation of the disease process. [NIH] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. [NIH] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Chronic Disease: Disease or ailment of long duration. [NIH] Circadian: Repeated more or less daily, i. e. on a 23- to 25-hour cycle. [NIH] Civil Rights: Legal guarantee protecting the individual from attack on personal liberties, right to fair trial, right to vote, and freedom from discrimination on the basis of race, religion, national origin, age, or gender. [NIH] Clamp: A u-shaped steel rod used with a pin or wire for skeletal traction in the treatment of certain fractures. [NIH] Clinical Medicine: The study and practice of medicine by direct examination of the patient. [NIH]

Clinical trial: A research study that tests how well new medical treatments or other interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis, or treatment of a disease. [NIH]

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Cloning: The production of a number of genetically identical individuals; in genetic engineering, a process for the efficient replication of a great number of identical DNA molecules. [NIH] Coagulation: 1. The process of clot formation. 2. In colloid chemistry, the solidification of a sol into a gelatinous mass; an alteration of a disperse phase or of a dissolved solid which causes the separation of the system into a liquid phase and an insoluble mass called the clot or curd. Coagulation is usually irreversible. 3. In surgery, the disruption of tissue by physical means to form an amorphous residuum, as in electrocoagulation and photocoagulation. [EU] Coca: Any of several South American shrubs of the Erythroxylon genus (and family) that yield cocaine; the leaves are chewed with alum for CNS stimulation. [NIH] Cocaine: An alkaloid ester extracted from the leaves of plants including coca. It is a local anesthetic and vasoconstrictor and is clinically used for that purpose, particularly in the eye, ear, nose, and throat. It also has powerful central nervous system effects similar to the amphetamines and is a drug of abuse. Cocaine, like amphetamines, acts by multiple mechanisms on brain catecholaminergic neurons; the mechanism of its reinforcing effects is thought to involve inhibition of dopamine uptake. [NIH] Codeine: An opioid analgesic related to morphine but with less potent analgesic properties and mild sedative effects. It also acts centrally to suppress cough. [NIH] Coenzymes: Substances that are necessary for the action or enhancement of action of an enzyme. Many vitamins are coenzymes. [NIH] Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [NIH] Cognition: Intellectual or mental process whereby an organism becomes aware of or obtains knowledge. [NIH] Colitis: Inflammation of the colon. [NIH] Collagen: A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin, connective tissue, and the organic substance of bones and teeth. Different forms of collagen are produced in the body but all consist of three alpha-polypeptide chains arranged in a triple helix. Collagen is differentiated from other fibrous proteins, such as elastin, by the content of proline, hydroxyproline, and hydroxylysine; by the absence of tryptophan; and particularly by the high content of polar groups which are responsible for its swelling properties. [NIH] Collagen disease: A term previously used to describe chronic diseases of the connective tissue (e.g., rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis), but now is thought to be more appropriate for diseases associated with defects in collagen, which is a component of the connective tissue. [NIH] Collapse: 1. A state of extreme prostration and depression, with failure of circulation. 2. Abnormal falling in of the walls of any part of organ. [EU] Colloidal: Of the nature of a colloid. [EU] Combination Therapy: Association of 3 drugs to treat AIDS (AZT + DDC or DDI + protease inhibitor). [NIH] Combinatorial: A cut-and-paste process that churns out thousands of potentially valuable compounds at once. [NIH] Communication Disorders: Disorders of verbal and nonverbal communication caused by receptive or expressive language disorders, cognitive dysfunction (e.g., mental retardation), psychiatric conditions, and hearing disorders. [NIH]

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Community Health Services: Diagnostic, therapeutic and preventive health services provided for individuals in the community. [NIH] Comorbidity: The presence of co-existing or additional diseases with reference to an initial diagnosis or with reference to the index condition that is the subject of study. Comorbidity may affect the ability of affected individuals to function and also their survival; it may be used as a prognostic indicator for length of hospital stay, cost factors, and outcome or survival. [NIH] Compacta: Part of substantia nigra. [NIH] Complement: A term originally used to refer to the heat-labile factor in serum that causes immune cytolysis, the lysis of antibody-coated cells, and now referring to the entire functionally related system comprising at least 20 distinct serum proteins that is the effector not only of immune cytolysis but also of other biologic functions. Complement activation occurs by two different sequences, the classic and alternative pathways. The proteins of the classic pathway are termed 'components of complement' and are designated by the symbols C1 through C9. C1 is a calcium-dependent complex of three distinct proteins C1q, C1r and C1s. The proteins of the alternative pathway (collectively referred to as the properdin system) and complement regulatory proteins are known by semisystematic or trivial names. Fragments resulting from proteolytic cleavage of complement proteins are designated with lower-case letter suffixes, e.g., C3a. Inactivated fragments may be designated with the suffix 'i', e.g. C3bi. Activated components or complexes with biological activity are designated by a bar over the symbol e.g. C1 or C4b,2a. The classic pathway is activated by the binding of C1 to classic pathway activators, primarily antigen-antibody complexes containing IgM, IgG1, IgG3; C1q binds to a single IgM molecule or two adjacent IgG molecules. The alternative pathway can be activated by IgA immune complexes and also by nonimmunologic materials including bacterial endotoxins, microbial polysaccharides, and cell walls. Activation of the classic pathway triggers an enzymatic cascade involving C1, C4, C2 and C3; activation of the alternative pathway triggers a cascade involving C3 and factors B, D and P. Both result in the cleavage of C5 and the formation of the membrane attack complex. Complement activation also results in the formation of many biologically active complement fragments that act as anaphylatoxins, opsonins, or chemotactic factors. [EU] Complementary and alternative medicine: CAM. Forms of treatment that are used in addition to (complementary) or instead of (alternative) standard treatments. These practices are not considered standard medical approaches. CAM includes dietary supplements, megadose vitamins, herbal preparations, special teas, massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complementary medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used to enhance or complement the standard treatments. Complementary medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Compulsion: In psychology, an irresistible urge, sometimes amounting to obsession to perform a particular act which usually is carried out against the performer's will or better judgment. [NIH] Compulsive Behavior: The behavior of performing an act persistently and repetitively without it leading to reward or pleasure. The act is usually a small, circumscribed behavior, almost ritualistic, yet not pathologically disturbing. Examples of compulsive behavior include twirling of hair, checking something constantly, not wanting pennies in change, straightening tilted pictures, etc. [NIH] Computational Biology: A field of biology concerned with the development of techniques

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for the collection and manipulation of biological data, and the use of such data to make biological discoveries or predictions. This field encompasses all computational methods and theories applicable to molecular biology and areas of computer-based techniques for solving biological problems including manipulation of models and datasets. [NIH] Computer Graphics: The process of pictorial communication, between human and computers, in which the computer input and output have the form of charts, drawings, or other appropriate pictorial representation. [NIH] Computer Simulation: Computer-based representation of physical systems and phenomena such as chemical processes. [NIH] Conception: The onset of pregnancy, marked by implantation of the blastocyst; the formation of a viable zygote. [EU] Concomitant: Accompanying; accessory; joined with another. [EU] Conditioned stimulus: A situation in which one signal, or stimulus, is given just before another signal. After this happens several times, the first signal alone can cause the response that would usually need the second signal. [NIH] Condoms: A sheath that is worn over the penis during sexual behavior in order to prevent pregnancy or spread of sexually transmitted disease. [NIH] Conduction: The transfer of sound waves, heat, nervous impulses, or electricity. [EU] Confusion: A mental state characterized by bewilderment, emotional disturbance, lack of clear thinking, and perceptual disorientation. [NIH] Congestion: Excessive or abnormal accumulation of blood in a part. [EU] Conjugated: Acting or operating as if joined; simultaneous. [EU] Consciousness: Sense of awareness of self and of the environment. [NIH] Constipation: Infrequent or difficult evacuation of feces. [NIH] Constitutional: 1. Affecting the whole constitution of the body; not local. 2. Pertaining to the constitution. [EU] Constriction: The act of constricting. [NIH] Constriction, Pathologic: The condition of an anatomical structure's being constricted beyond normal dimensions. [NIH] Consultation: A deliberation between two or more physicians concerning the diagnosis and the proper method of treatment in a case. [NIH] Consumption: Pulmonary tuberculosis. [NIH] Contamination: The soiling or pollution by inferior material, as by the introduction of organisms into a wound, or sewage into a stream. [EU] Continuous infusion: The administration of a fluid into a blood vessel, usually over a prolonged period of time. [NIH] Continuum: An area over which the vegetation or animal population is of constantly changing composition so that homogeneous, separate communities cannot be distinguished. [NIH]

Contraindications: Any factor or sign that it is unwise to pursue a certain kind of action or treatment, e. g. giving a general anesthetic to a person with pneumonia. [NIH] Control group: In a clinical trial, the group that does not receive the new treatment being studied. This group is compared to the group that receives the new treatment, to see if the new treatment works. [NIH]

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Controlled study: An experiment or clinical trial that includes a comparison (control) group. [NIH]

Convulsions: A general term referring to sudden and often violent motor activity of cerebral or brainstem origin. Convulsions may also occur in the absence of an electrical cerebral discharge (e.g., in response to hypotension). [NIH] Coordination: Muscular or motor regulation or the harmonious cooperation of muscles or groups of muscles, in a complex action or series of actions. [NIH] Cor: The muscular organ that maintains the circulation of the blood. c. adiposum a heart that has undergone fatty degeneration or that has an accumulation of fat around it; called also fat or fatty, heart. c. arteriosum the left side of the heart, so called because it contains oxygenated (arterial) blood. c. biloculare a congenital anomaly characterized by failure of formation of the atrial and ventricular septums, the heart having only two chambers, a single atrium and a single ventricle, and a common atrioventricular valve. c. bovinum (L. 'ox heart') a greatly enlarged heart due to a hypertrophied left ventricle; called also c. taurinum and bucardia. c. dextrum (L. 'right heart') the right atrium and ventricle. c. hirsutum, c. villosum. c. mobile (obs.) an abnormally movable heart. c. pendulum a heart so movable that it seems to be hanging by the great blood vessels. c. pseudotriloculare biatriatum a congenital cardiac anomaly in which the heart functions as a three-chambered heart because of tricuspid atresia, the right ventricle being extremely small or rudimentary and the right atrium greatly dilated. Blood passes from the right to the left atrium and thence disease due to pulmonary hypertension secondary to disease of the lung, or its blood vessels, with hypertrophy of the right ventricle. [EU] Corneum: The superficial layer of the epidermis containing keratinized cells. [NIH] Coronary: Encircling in the manner of a crown; a term applied to vessels; nerves, ligaments, etc. The term usually denotes the arteries that supply the heart muscle and, by extension, a pathologic involvement of them. [EU] Coronary heart disease: A type of heart disease caused by narrowing of the coronary arteries that feed the heart, which needs a constant supply of oxygen and nutrients carried by the blood in the coronary arteries. When the coronary arteries become narrowed or clogged by fat and cholesterol deposits and cannot supply enough blood to the heart, CHD results. [NIH] Coronary Thrombosis: Presence of a thrombus in a coronary artery, often causing a myocardial infarction. [NIH] Cortex: The outer layer of an organ or other body structure, as distinguished from the internal substance. [EU] Cortical: Pertaining to or of the nature of a cortex or bark. [EU] Corticosteroid: Any of the steroids elaborated by the adrenal cortex (excluding the sex hormones of adrenal origin) in response to the release of corticotrophin (adrenocorticotropic hormone) by the pituitary gland, to any of the synthetic equivalents of these steroids, or to angiotensin II. They are divided, according to their predominant biological activity, into three major groups: glucocorticoids, chiefly influencing carbohydrate, fat, and protein metabolism; mineralocorticoids, affecting the regulation of electrolyte and water balance; and C19 androgens. Some corticosteroids exhibit both types of activity in varying degrees, and others exert only one type of effect. The corticosteroids are used clinically for hormonal replacement therapy, for suppression of ACTH secretion by the anterior pituitary, as antineoplastic, antiallergic, and anti-inflammatory agents, and to suppress the immune response. Called also adrenocortical hormone and corticoid. [EU] Corticotropin-Releasing Hormone: A neuropeptide released by the hypothalamus that

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stimulates the release of corticotropin by the anterior pituitary gland. [NIH] Cortisol: A steroid hormone secreted by the adrenal cortex as part of the body's response to stress. [NIH] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] Craniocerebral Trauma: Traumatic injuries involving the cranium and intracranial structures (i.e., brain; cranial nerves; meninges; and other structures). Injuries may be classified by whether or not the skull is penetrated (i.e., penetrating vs. nonpenetrating) or whether there is an associated hemorrhage. [NIH] Crossing-over: The exchange of corresponding segments between chromatids of homologous chromosomes during meiosia, forming a chiasma. [NIH] Cues: Signals for an action; that specific portion of a perceptual field or pattern of stimuli to which a subject has learned to respond. [NIH] Curative: Tending to overcome disease and promote recovery. [EU] Cutaneous: Having to do with the skin. [NIH] Cyclic: Pertaining to or occurring in a cycle or cycles; the term is applied to chemical compounds that contain a ring of atoms in the nucleus. [EU] Cyclin: Molecule that regulates the cell cycle. [NIH] Cytochrome: Any electron transfer hemoprotein having a mode of action in which the transfer of a single electron is effected by a reversible valence change of the central iron atom of the heme prosthetic group between the +2 and +3 oxidation states; classified as cytochromes a in which the heme contains a formyl side chain, cytochromes b, which contain protoheme or a closely similar heme that is not covalently bound to the protein, cytochromes c in which protoheme or other heme is covalently bound to the protein, and cytochromes d in which the iron-tetrapyrrole has fewer conjugated double bonds than the hemes have. Well-known cytochromes have been numbered consecutively within groups and are designated by subscripts (beginning with no subscript), e.g. cytochromes c, c1, C2, . New cytochromes are named according to the wavelength in nanometres of the absorption maximum of the a-band of the iron (II) form in pyridine, e.g., c-555. [EU] Cytokine: Small but highly potent protein that modulates the activity of many cell types, including T and B cells. [NIH] Cytotoxic: Cell-killing. [NIH] Data Collection: Systematic gathering of data for a particular purpose from various sources, including questionnaires, interviews, observation, existing records, and electronic devices. The process is usually preliminary to statistical analysis of the data. [NIH] Databases, Bibliographic: Extensive collections, reputedly complete, of references and citations to books, articles, publications, etc., generally on a single subject or specialized subject area. Databases can operate through automated files, libraries, or computer disks. The concept should be differentiated from factual databases which is used for collections of data and facts apart from bibliographic references to them. [NIH] Decision Making: The process of making a selective intellectual judgment when presented with several complex alternatives consisting of several variables, and usually defining a course of action or an idea. [NIH] Decongestant: An agent that reduces congestion or swelling. [EU] Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU]

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Deletion: A genetic rearrangement through loss of segments of DNA (chromosomes), bringing sequences, which are normally separated, into close proximity. [NIH] Delirium: (DSM III-R) an acute, reversible organic mental disorder characterized by reduced ability to maintain attention to external stimuli and disorganized thinking as manifested by rambling, irrelevant, or incoherent speech; there are also a reduced level of consciousness, sensory misperceptions, disturbance of the sleep-wakefulness cycle and level of psychomotor activity, disorientation to time, place, or person, and memory impairment. Delirium may be caused by a large number of conditions resulting in derangement of cerebral metabolism, including systemic infection, poisoning, drug intoxication or withdrawal, seizures or head trauma, and metabolic disturbances such as hypoxia, hypoglycaemia, fluid, electrolyte, or acid-base imbalances, or hepatic or renal failure. Called also acute confusional state and acute brain syndrome. [EU] Delusion: A false belief, not susceptible to argument or reason, and determined, pathologically, by some form of mental disorder. [NIH] Dementia: An acquired organic mental disorder with loss of intellectual abilities of sufficient severity to interfere with social or occupational functioning. The dysfunction is multifaceted and involves memory, behavior, personality, judgment, attention, spatial relations, language, abstract thought, and other executive functions. The intellectual decline is usually progressive, and initially spares the level of consciousness. [NIH] Denaturation: Rupture of the hydrogen bonds by heating a DNA solution and then cooling it rapidly causes the two complementary strands to separate. [NIH] Dendrites: Extensions of the nerve cell body. They are short and branched and receive stimuli from other neurons. [NIH] Dendritic: 1. Branched like a tree. 2. Pertaining to or possessing dendrites. [EU] Density: The logarithm to the base 10 of the opacity of an exposed and processed film. [NIH] Dental Care: The total of dental diagnostic, preventive, and restorative services provided to meet the needs of a patient (from Illustrated Dictionary of Dentistry, 1982). [NIH] Dental Caries: Localized destruction of the tooth surface initiated by decalcification of the enamel followed by enzymatic lysis of organic structures and leading to cavity formation. If left unchecked, the cavity may penetrate the enamel and dentin and reach the pulp. The three most prominent theories used to explain the etiology of the disase are that acids produced by bacteria lead to decalcification; that micro-organisms destroy the enamel protein; or that keratolytic micro-organisms produce chelates that lead to decalcification. [NIH]

Dental Waste: Any waste product generated by a dental office, surgery, clinic, or laboratory including amalgams, saliva, and rinse water. [NIH] Dentate Gyrus: Gray matter situated above the gyrus hippocampi. It is composed of three layers. The molecular layer is continuous with the hippocampus in the hippocampal fissure. The granular layer consists of closely arranged spherical or oval neurons, called granule cells, whose axons pass through the polymorphic layer ending on the dendrites of pyramidal cells in the hippocampus. [NIH] Depersonalization: Alteration in the perception of the self so that the usual sense of one's own reality is lost, manifested in a sense of unreality or self-estrangement, in changes of body image, or in a feeling that one does not control his own actions and speech; seen in depersonalization disorder, schizophrenic disorders, and schizotypal personality disorder. Some do not draw a distinction between depersonalization and derealization, using depersonalization to include both. [EU] Depolarization: The process or act of neutralizing polarity. In neurophysiology, the reversal

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of the resting potential in excitable cell membranes when stimulated, i.e., the tendency of the cell membrane potential to become positive with respect to the potential outside the cell. [EU] Deprivation: Loss or absence of parts, organs, powers, or things that are needed. [EU] Derealization: Is characterized by the loss of the sense of reality concerning one's surroundings. [NIH] Desensitization: The prevention or reduction of immediate hypersensitivity reactions by administration of graded doses of allergen; called also hyposensitization and immunotherapy. [EU] Detoxification: Treatment designed to free an addict from his drug habit. [EU] Deuterium: Deuterium. The stable isotope of hydrogen. It has one neutron and one proton in the nucleus. [NIH] Developed Countries: Countries that have reached a level of economic achievement through an increase of production, per capita income and consumption, and utilization of natural and human resources. [NIH] Developing Countries: Countries in the process of change directed toward economic growth, that is, an increase in production, per capita consumption, and income. The process of economic growth involves better utilization of natural and human resources, which results in a change in the social, political, and economic structures. [NIH] Dexmedetomidine: A selective inhibitor of receptors, adrenergic alpha-2 that has analgesic and sedative properties. Medetomidine is the other racemic form. [NIH] Dextroamphetamine: The d-form of amphetamine. It is a central nervous system stimulant and a sympathomimetic. It has also been used in the treatment of narcolepsy and of attention deficit disorders and hyperactivity in children. Dextroamphetamine has multiple mechanisms of action including blocking uptake of adrenergics and dopamine, stimulating release of monamines, and inhibiting monoamine oxidase. It is also a drug of abuse and a psychotomimetic. [NIH] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH] Diagnostic procedure: A method used to identify a disease. [NIH] Dialyzer: A part of the hemodialysis machine. (See hemodialysis under dialysis.) The dialyzer has two sections separated by a membrane. One section holds dialysate. The other holds the patient's blood. [NIH] Diaphoresis: Perspiration, especially profuse perspiration. Called also sudoresis. [EU] Diarrhea: Passage of excessively liquid or excessively frequent stools. [NIH] Diastolic: Of or pertaining to the diastole. [EU] Diencephalon: The paired caudal parts of the prosencephalon from which the thalamus, hypothalamus, epithalamus, and subthalamus are derived. [NIH] Digestion: The process of breakdown of food for metabolism and use by the body. [NIH] Digestive system: The organs that take in food and turn it into products that the body can use to stay healthy. Waste products the body cannot use leave the body through bowel movements. The digestive system includes the salivary glands, mouth, esophagus, stomach, liver, pancreas, gallbladder, small and large intestines, and rectum. [NIH] Digestive tract: The organs through which food passes when food is eaten. These organs are the mouth, esophagus, stomach, small and large intestines, and rectum. [NIH] Dilatation: The act of dilating. [NIH]

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Dimethyl: A volatile metabolite of the amino acid methionine. [NIH] Direct: 1. Straight; in a straight line. 2. Performed immediately and without the intervention of subsidiary means. [EU] Discrimination: The act of qualitative and/or quantitative differentiation between two or more stimuli. [NIH] Disease Progression: The worsening of a disease over time. This concept is most often used for chronic and incurable diseases where the stage of the disease is an important determinant of therapy and prognosis. [NIH] Disinfectant: An agent that disinfects; applied particularly to agents used on inanimate objects. [EU] Disorientation: The loss of proper bearings, or a state of mental confusion as to time, place, or identity. [EU] Disparity: Failure of the two retinal images of an object to fall on corresponding retinal points. [NIH] Disposition: A tendency either physical or mental toward certain diseases. [EU] Dissociation: 1. The act of separating or state of being separated. 2. The separation of a molecule into two or more fragments (atoms, molecules, ions, or free radicals) produced by the absorption of light or thermal energy or by solvation. 3. In psychology, a defense mechanism in which a group of mental processes are segregated from the rest of a person's mental activity in order to avoid emotional distress, as in the dissociative disorders (q.v.), or in which an idea or object is segregated from its emotional significance; in the first sense it is roughly equivalent to splitting, in the second, to isolation. 4. A defect of mental integration in which one or more groups of mental processes become separated off from normal consciousness and, thus separated, function as a unitary whole. [EU] Distal: Remote; farther from any point of reference; opposed to proximal. In dentistry, used to designate a position on the dental arch farther from the median line of the jaw. [EU] Disulfiram: A carbamate derivative used as an alcohol deterrent. It is a relatively nontoxic substance when administered alone, but markedly alters the intermediary metabolism of alcohol. When alcohol is ingested after administration of disulfiram, blood acetaldehyde concentrations are increased, followed by flushing, systemic vasodilation, respiratory difficulties, nausea, hypotension, and other symptoms (acetaldehyde syndrome). It acts by inhibiting aldehyde dehydrogenase. [NIH] Diuresis: Increased excretion of urine. [EU] Dizziness: An imprecise term which may refer to a sense of spatial disorientation, motion of the environment, or lightheadedness. [NIH] Domestic Violence: Deliberate, often repetitive, physical abuse by one family member against another: marital partners, parents, children, siblings, or any other member of a household. [NIH] Dopamine: An endogenous catecholamine and prominent neurotransmitter in several systems of the brain. In the synthesis of catecholamines from tyrosine, it is the immediate precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. A family of dopaminergic receptor subtypes mediate its action. Dopamine is used pharmacologically for its direct (beta adrenergic agonist) and indirect (adrenergic releasing) sympathomimetic effects including its actions as an inotropic agent and as a renal vasodilator. [NIH] Dopamine Agonists: Drugs that bind to and activate dopamine receptors. [NIH]

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Dorsal: 1. Pertaining to the back or to any dorsum. 2. Denoting a position more toward the back surface than some other object of reference; same as posterior in human anatomy; superior in the anatomy of quadrupeds. [EU] Dorsum: A plate of bone which forms the posterior boundary of the sella turcica. [NIH] Dosage Forms: Completed forms of the pharmaceutical preparation in which prescribed doses of medication are included. They are designed to resist action by gastric fluids, prevent vomiting and nausea, reduce or alleviate the undesirable taste and smells associated with oral administration, achieve a high concentration of drug at target site, or produce a delayed or long-acting drug effect. They include capsules, liniments, ointments, pharmaceutical solutions, powders, tablets, etc. [NIH] Dose-dependent: Refers to the effects of treatment with a drug. If the effects change when the dose of the drug is changed, the effects are said to be dose dependent. [NIH] Drive: A state of internal activity of an organism that is a necessary condition before a given stimulus will elicit a class of responses; e.g., a certain level of hunger (drive) must be present before food will elicit an eating response. [NIH] Drug Delivery Systems: Systems of administering drugs through controlled delivery so that an optimum amount reaches the target site. Drug delivery systems encompass the carrier, route, and target. [NIH] Drug Design: The molecular designing of drugs for specific purposes (such as DNAbinding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include pharmacokinetics, dosage analysis, or drug administration analysis. [NIH] Drug Interactions: The action of a drug that may affect the activity, metabolism, or toxicity of another drug. [NIH] Drug Resistance: Diminished or failed response of an organism, disease or tissue to the intended effectiveness of a chemical or drug. It should be differentiated from drug tolerance which is the progressive diminution of the susceptibility of a human or animal to the effects of a drug, as a result of continued administration. [NIH] Drug Tolerance: Progressive diminution of the susceptibility of a human or animal to the effects of a drug, resulting from its continued administration. It should be differentiated from drug resistance wherein an organism, disease, or tissue fails to respond to the intended effectiveness of a chemical or drug. It should also be differentiated from maximum tolerated dose and no-observed-adverse-effect level. [NIH] Duct: A tube through which body fluids pass. [NIH] Duodenum: The first part of the small intestine. [NIH] Dynorphins: A class of opioid peptides including dynorphin A, dynorphin B, and smaller fragments of these peptides. Dynorphins prefer kappa-opioid receptors (receptors, opioid, kappa) and have been shown to play a role as central nervous system transmitters. [NIH] Dyskinesia: Impairment of the power of voluntary movement, resulting in fragmentary or incomplete movements. [EU] Dyspnea: Difficult or labored breathing. [NIH] Dystonia: Disordered tonicity of muscle. [EU] Eating Disorders: A group of disorders characterized by physiological and psychological disturbances in appetite or food intake. [NIH]

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Ectopic: Pertaining to or characterized by ectopia. [EU] Edema: Excessive amount of watery fluid accumulated in the intercellular spaces, most commonly present in subcutaneous tissue. [NIH] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] Effector cell: A cell that performs a specific function in response to a stimulus; usually used to describe cells in the immune system. [NIH] Efficacy: The extent to which a specific intervention, procedure, regimen, or service produces a beneficial result under ideal conditions. Ideally, the determination of efficacy is based on the results of a randomized control trial. [NIH] Elasticity: Resistance and recovery from distortion of shape. [NIH] Elective: Subject to the choice or decision of the patient or physician; applied to procedures that are advantageous to the patient but not urgent. [EU] Electrode: Component of the pacing system which is at the distal end of the lead. It is the interface with living cardiac tissue across which the stimulus is transmitted. [NIH] Electroencephalography: Recording of electric currents developed in the brain by means of electrodes applied to the scalp, to the surface of the brain, or placed within the substance of the brain. [NIH] Electrolyte: A substance that dissociates into ions when fused or in solution, and thus becomes capable of conducting electricity; an ionic solute. [EU] Electrons: Stable elementary particles having the smallest known negative charge, present in all elements; also called negatrons. Positively charged electrons are called positrons. The numbers, energies and arrangement of electrons around atomic nuclei determine the chemical identities of elements. Beams of electrons are called cathode rays or beta rays, the latter being a high-energy biproduct of nuclear decay. [NIH] Electrophoresis: An electrochemical process in which macromolecules or colloidal particles with a net electric charge migrate in a solution under the influence of an electric current. [NIH]

Electrophysiological: Pertaining to electrophysiology, that is a branch of physiology that is concerned with the electric phenomena associated with living bodies and involved in their functional activity. [EU] Electroporation: A technique in which electric pulses of intensity in kilovolts per centimeter and of microsecond-to-millisecond duration cause a temporary loss of the semipermeability of cell membranes, thus leading to ion leakage, escape of metabolites, and increased uptake by cells of drugs, molecular probes, and DNA. Some applications of electroporation include introduction of plasmids or foreign DNA into living cells for transfection, fusion of cells to prepare hybridomas, and insertion of proteins into cell membranes. [NIH] Embryo: The prenatal stage of mammalian development characterized by rapid morphological changes and the differentiation of basic structures. [NIH] Empirical: A treatment based on an assumed diagnosis, prior to receiving confirmatory laboratory test results. [NIH] Emulsion: A preparation of one liquid distributed in small globules throughout the body of a second liquid. The dispersed liquid is the discontinuous phase, and the dispersion medium is the continuous phase. When oil is the dispersed liquid and an aqueous solution is the continuous phase, it is known as an oil-in-water emulsion, whereas when water or aqueous solution is the dispersed phase and oil or oleaginous substance is the continuous phase, it is known as a water-in-oil emulsion. Pharmaceutical emulsions for which official

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standards have been promulgated include cod liver oil emulsion, cod liver oil emulsion with malt, liquid petrolatum emulsion, and phenolphthalein in liquid petrolatum emulsion. [EU] Encapsulated: Confined to a specific, localized area and surrounded by a thin layer of tissue. [NIH]

Endocarditis: Exudative and proliferative inflammatory alterations of the endocardium, characterized by the presence of vegetations on the surface of the endocardium or in the endocardium itself, and most commonly involving a heart valve, but sometimes affecting the inner lining of the cardiac chambers or the endocardium elsewhere. It may occur as a primary disorder or as a complication of or in association with another disease. [EU] Endocardium: The innermost layer of the heart, comprised of endothelial cells. [NIH] Endocrine System: The system of glands that release their secretions (hormones) directly into the circulatory system. In addition to the endocrine glands, included are the chromaffin system and the neurosecretory systems. [NIH] Endopeptidases: A subclass of peptide hydrolases. They are classified primarily by their catalytic mechanism. Specificity is used only for identification of individual enzymes. They comprise the serine endopeptidases, EC 3.4.21; cysteine endopeptidases, EC 3.4.22; aspartic endopeptidases, EC 3.4.23, metalloendopeptidases, EC 3.4.24; and a group of enzymes yet to be assigned to any of the above sub-classes, EC 3.4.99. EC 3.4.-. [NIH] Endorphin: Opioid peptides derived from beta-lipotropin. Endorphin is the most potent naturally occurring analgesic agent. It is present in pituitary, brain, and peripheral tissues. [NIH]

Endoscope: A thin, lighted tube used to look at tissues inside the body. [NIH] Endoscopic: A technique where a lateral-view endoscope is passed orally to the duodenum for visualization of the ampulla of Vater. [NIH] Endothelial cell: The main type of cell found in the inside lining of blood vessels, lymph vessels, and the heart. [NIH] Endotoxins: Toxins closely associated with the living cytoplasm or cell wall of certain microorganisms, which do not readily diffuse into the culture medium, but are released upon lysis of the cells. [NIH] End-stage renal: Total chronic kidney failure. When the kidneys fail, the body retains fluid and harmful wastes build up. A person with ESRD needs treatment to replace the work of the failed kidneys. [NIH] Enhancers: Transcriptional element in the virus genome. [NIH] Enkephalin: A natural opiate painkiller, in the hypothalamus. [NIH] Entorhinal Cortex: Cortex where the signals are combined with those from other sensory systems. [NIH] Environmental Health: The science of controlling or modifying those conditions, influences, or forces surrounding man which relate to promoting, establishing, and maintaining health. [NIH]

Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Enzyme Inhibitors: Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. [NIH] Epidemic: Occurring suddenly in numbers clearly in excess of normal expectancy; said especially of infectious diseases but applied also to any disease, injury, or other healthrelated event occurring in such outbreaks. [EU]

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Epidemiological: Relating to, or involving epidemiology. [EU] Epidermis: Nonvascular layer of the skin. It is made up, from within outward, of five layers: 1) basal layer (stratum basale epidermidis); 2) spinous layer (stratum spinosum epidermidis); 3) granular layer (stratum granulosum epidermidis); 4) clear layer (stratum lucidum epidermidis); and 5) horny layer (stratum corneum epidermidis). [NIH] Epinephrine: The active sympathomimetic hormone from the adrenal medulla in most species. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. It is used in asthma and cardiac failure and to delay absorption of local anesthetics. [NIH] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Escalation: Progressive use of more harmful drugs. [NIH] Esophagus: The muscular tube through which food passes from the throat to the stomach. [NIH]

Estradiol: The most potent mammalian estrogenic hormone. It is produced in the ovary, placenta, testis, and possibly the adrenal cortex. [NIH] Estrogen: One of the two female sex hormones. [NIH] Ethanol: A clear, colorless liquid rapidly absorbed from the gastrointestinal tract and distributed throughout the body. It has bactericidal activity and is used often as a topical disinfectant. It is widely used as a solvent and preservative in pharmaceutical preparations as well as serving as the primary ingredient in alcoholic beverages. [NIH] Ethnic Groups: A group of people with a common cultural heritage that sets them apart from others in a variety of social relationships. [NIH] Eukaryotic Cells: Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane. [NIH] Euphoria: An exaggerated feeling of physical and emotional well-being not consonant with apparent stimuli or events; usually of psychologic origin, but also seen in organic brain disease and toxic states. [NIH] Evacuation: An emptying, as of the bowels. [EU] Evoke: The electric response recorded from the cerebral cortex after stimulation of a peripheral sense organ. [NIH] Excipients: Usually inert substances added to a prescription in order to provide suitable consistency to the dosage form; a binder, matrix, base or diluent in pills, tablets, creams, salves, etc. [NIH] Excitability: Property of a cardiac cell whereby, when the cell is depolarized to a critical level (called threshold), the membrane becomes permeable and a regenerative inward current causes an action potential. [NIH] Excitation: An act of irritation or stimulation or of responding to a stimulus; the addition of energy, as the excitation of a molecule by absorption of photons. [EU] Excitatory: When cortical neurons are excited, their output increases and each new input they receive while they are still excited raises their output markedly. [NIH] Excitatory Amino Acids: Endogenous amino acids released by neurons as excitatory neurotransmitters. Glutamic acid is the most common excitatory neurotransmitter in the brain. Aspartic acid has been regarded as an excitatory transmitter for many years, but the extent of its role as a transmitter is unclear. [NIH]

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Exhaustion: The feeling of weariness of mind and body. [NIH] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Expiration: The act of breathing out, or expelling air from the lungs. [EU] Extracellular: Outside a cell or cells. [EU] Extracellular Space: Interstitial space between cells, occupied by fluid as well as amorphous and fibrous substances. [NIH] Extraction: The process or act of pulling or drawing out. [EU] Extrapyramidal: Outside of the pyramidal tracts. [EU] Extremity: A limb; an arm or leg (membrum); sometimes applied specifically to a hand or foot. [EU] Exudate: Material, such as fluid, cells, or cellular debris, which has escaped from blood vessels and has been deposited in tissues or on tissue surfaces, usually as a result of inflammation. An exudate, in contrast to a transudate, is characterized by a high content of protein, cells, or solid materials derived from cells. [EU] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Fat: Total lipids including phospholipids. [NIH] Fatigue: The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. [NIH]

Fatty acids: A major component of fats that are used by the body for energy and tissue development. [NIH] Feces: The excrement discharged from the intestines, consisting of bacteria, cells exfoliated from the intestines, secretions, chiefly of the liver, and a small amount of food residue. [EU] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [NIH] Fibrinogen: Plasma glycoprotein clotted by thrombin, composed of a dimer of three nonidentical pairs of polypeptide chains (alpha, beta, gamma) held together by disulfide bonds. Fibrinogen clotting is a sol-gel change involving complex molecular arrangements: whereas fibrinogen is cleaved by thrombin to form polypeptides A and B, the proteolytic action of other enzymes yields different fibrinogen degradation products. [NIH] Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [NIH] Fissure: Any cleft or groove, normal or otherwise; especially a deep fold in the cerebral cortex which involves the entire thickness of the brain wall. [EU] Fixation: 1. The act or operation of holding, suturing, or fastening in a fixed position. 2. The condition of being held in a fixed position. 3. In psychiatry, a term with two related but distinct meanings : (1) arrest of development at a particular stage, which like regression (return to an earlier stage), if temporary is a normal reaction to setbacks and difficulties but if protracted or frequent is a cause of developmental failures and emotional problems, and (2) a close and suffocating attachment to another person, especially a childhood figure, such as one's mother or father. Both meanings are derived from psychoanalytic theory and refer to 'fixation' of libidinal energy either in a specific erogenous zone, hence fixation at the oral, anal, or phallic stage, or in a specific object, hence mother or father fixation. 4. The use of a fixative (q.v.) to preserve histological or cytological specimens. 5. In chemistry, the process whereby a substance is removed from the gaseous or solution phase and localized, as in carbon dioxide fixation or nitrogen fixation. 6. In ophthalmology, direction of the gaze so

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that the visual image of the object falls on the fovea centralis. 7. In film processing, the chemical removal of all undeveloped salts of the film emulsion, leaving only the developed silver to form a permanent image. [EU] Fluid Therapy: Therapy whose basic objective is to restore the volume and composition of the body fluids to normal with respect to water-electrolyte balance. Fluids may be administered intravenously, orally, by intermittent gavage, or by hypodermoclysis. [NIH] Fluorescence: The property of emitting radiation while being irradiated. The radiation emitted is usually of longer wavelength than that incident or absorbed, e.g., a substance can be irradiated with invisible radiation and emit visible light. X-ray fluorescence is used in diagnosis. [NIH] Fluorine: A nonmetallic, diatomic gas that is a trace element and member of the halogen family. It is used in dentistry as flouride to prevent dental caries. [NIH] Flushing: A transient reddening of the face that may be due to fever, certain drugs, exertion, stress, or a disease process. [NIH] Focus Groups: A method of data collection and a qualitative research tool in which a small group of individuals are brought together and allowed to interact in a discussion of their opinions about topics, issues, or questions. [NIH] Fold: A plication or doubling of various parts of the body. [NIH] Forearm: The part between the elbow and the wrist. [NIH] Forensic Medicine: The application of medical knowledge to questions of law. [NIH] Frontal Lobe: The anterior part of the cerebral hemisphere. [NIH] Fructose: A type of sugar found in many fruits and vegetables and in honey. Fructose is used to sweeten some diet foods. It is considered a nutritive sweetener because it has calories. [NIH] Functional magnetic resonance imaging: A noninvasive tool used to observe functioning in the brain or other organs by detecting changes in chemical composition, blood flow, or both. [NIH]

Fungemia: The presence of fungi circulating in the blood. Opportunistic fungal sepsis is seen most often in immunosuppressed patients with severe neutropenia or in postoperative patients with intravenous catheters and usually follows prolonged antibiotic therapy. [NIH] Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. [NIH] Gamma Rays: Very powerful and penetrating, high-energy electromagnetic radiation of shorter wavelength than that of x-rays. They are emitted by a decaying nucleus, usually between 0.01 and 10 MeV. They are also called nuclear x-rays. [NIH] Gamma-hydroxybutyrate: Anxiolytic. [NIH] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [NIH] Ganglionic Blockers: Agents having as their major action the interruption of neural transmission at nicotinic receptors on postganglionic autonomic neurons. Because their actions are so broad, including blocking of sympathetic and parasympathetic systems, their therapeutic use has been largely supplanted by more specific drugs. They may still be used in the control of blood pressure in patients with acute dissecting aortic aneurysm and for the induction of hypotension in surgery. [NIH] Gangliosides: Protein kinase C's inhibitor which reduces ischemia-related brain damage. [NIH]

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Gap Junctions: Connections between cells which allow passage of small molecules and electric current. Gap junctions were first described anatomically as regions of close apposition between cells with a narrow (1-2 nm) gap between cell membranes. The variety in the properties of gap junctions is reflected in the number of connexins, the family of proteins which form the junctions. [NIH] Gas: Air that comes from normal breakdown of food. The gases are passed out of the body through the rectum (flatus) or the mouth (burp). [NIH] Gas exchange: Primary function of the lungs; transfer of oxygen from inhaled air into the blood and of carbon dioxide from the blood into the lungs. [NIH] Gastric: Having to do with the stomach. [NIH] Gastric Emptying: The evacuation of food from the stomach into the duodenum. [NIH] Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [NIH]

Gastroenterology: A subspecialty of internal medicine concerned with the study of the physiology and diseases of the digestive system and related structures (esophagus, liver, gallbladder, and pancreas). [NIH] Gastrointestinal: Refers to the stomach and intestines. [NIH] Gastrointestinal tract: The stomach and intestines. [NIH] Gastroparesis: Nerve or muscle damage in the stomach. Causes slow digestion and emptying, vomiting, nausea, or bloating. Also called delayed gastric emptying. [NIH] Gene: The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein. [NIH]

Gene Expression: The phenotypic manifestation of a gene or genes by the processes of gene action. [NIH] Gene Targeting: The integration of exogenous DNA into the genome of an organism at sites where its expression can be suitably controlled. This integration occurs as a result of homologous recombination. [NIH] Genetic Engineering: Directed modification of the gene complement of a living organism by such techniques as altering the DNA, substituting genetic material by means of a virus, transplanting whole nuclei, transplanting cell hybrids, etc. [NIH] Genetic Markers: A phenotypically recognizable genetic trait which can be used to identify a genetic locus, a linkage group, or a recombination event. [NIH] Genetic testing: Analyzing DNA to look for a genetic alteration that may indicate an increased risk for developing a specific disease or disorder. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genital: Pertaining to the genitalia. [EU] Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Geriatric: Pertaining to the treatment of the aged. [EU] Gestation: The period of development of the young in viviparous animals, from the time of fertilization of the ovum until birth. [EU] Gland: An organ that produces and releases one or more substances for use in the body. Some glands produce fluids that affect tissues or organs. Others produce hormones or participate in blood production. [NIH]

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Globus Pallidus: The representation of the phylogenetically oldest part of the corpus striatum called the paleostriatum. It forms the smaller, more medial part of the lentiform nucleus. [NIH] Glomerular: Pertaining to or of the nature of a glomerulus, especially a renal glomerulus. [EU]

Glomerular Filtration Rate: The volume of water filtered out of plasma through glomerular capillary walls into Bowman's capsules per unit of time. It is considered to be equivalent to inulin clearance. [NIH] Glomerulus: A tiny set of looping blood vessels in the nephron where blood is filtered in the kidney. [NIH] Glucocorticoid: A compound that belongs to the family of compounds called corticosteroids (steroids). Glucocorticoids affect metabolism and have anti-inflammatory and immunosuppressive effects. They may be naturally produced (hormones) or synthetic (drugs). [NIH] Glucose: D-Glucose. A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. [NIH] Glucose Intolerance: A pathological state in which the fasting plasma glucose level is less than 140 mg per deciliter and the 30-, 60-, or 90-minute plasma glucose concentration following a glucose tolerance test exceeds 200 mg per deciliter. This condition is seen frequently in diabetes mellitus but also occurs with other diseases. [NIH] Glutamate: Excitatory neurotransmitter of the brain. [NIH] Glycoprotein: A protein that has sugar molecules attached to it. [NIH] Glycoside: Any compound that contains a carbohydrate molecule (sugar), particularly any such natural product in plants, convertible, by hydrolytic cleavage, into sugar and a nonsugar component (aglycone), and named specifically for the sugar contained, as glucoside (glucose), pentoside (pentose), fructoside (fructose) etc. [EU] Gonadal: Pertaining to a gonad. [EU] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [NIH] Grafting: The operation of transfer of tissue from one site to another. [NIH] Granulocytes: Leukocytes with abundant granules in the cytoplasm. They are divided into three groups: neutrophils, eosinophils, and basophils. [NIH] Gravis: Eruption of watery blisters on the skin among those handling animals and animal products. [NIH] Growth: The progressive development of a living being or part of an organism from its earliest stage to maturity. [NIH] Growth factors: Substances made by the body that function to regulate cell division and cell survival. Some growth factors are also produced in the laboratory and used in biological therapy. [NIH] Habituation: Decline in response of an organism to environmental or other stimuli with repeated or maintained exposure. [NIH] Haematoma: A localized collection of blood, usually clotted, in an organ, space, or tissue, due to a break in the wall of a blood vessel. [EU] Haemorrhage: The escape of blood from the vessels; bleeding. Small haemorrhages are classified according to size as petechiae (very small), purpura (up to 1 cm), and ecchymoses

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(larger). The massive accumulation of blood within a tissue is called a haematoma. [EU] Half-Life: The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. [NIH] Hallucination: A sense perception without a source in the external world; a perception of an external stimulus object in the absence of such an object. [EU] Haptens: Small antigenic determinants capable of eliciting an immune response only when coupled to a carrier. Haptens bind to antibodies but by themselves cannot elicit an antibody response. [NIH] Headache: Pain in the cranial region that may occur as an isolated and benign symptom or as a manifestation of a wide variety of conditions including subarachnoid hemorrhage; craniocerebral trauma; central nervous system infections; intracranial hypertension; and other disorders. In general, recurrent headaches that are not associated with a primary disease process are referred to as headache disorders (e.g., migraine). [NIH] Headache Disorders: Common conditions characterized by persistent or recurrent headaches. Headache syndrome classification systems may be based on etiology (e.g., vascular headache, post-traumatic headaches, etc.), temporal pattern (e.g., cluster headache, paroxysmal hemicrania, etc.), and precipitating factors (e.g., cough headache). [NIH] Health Education: Education that increases the awareness and favorably influences the attitudes and knowledge relating to the improvement of health on a personal or community basis. [NIH] Health Services: Services for the diagnosis and treatment of disease and the maintenance of health. [NIH] Health Status: The level of health of the individual, group, or population as subjectively assessed by the individual or by more objective measures. [NIH] Hearing Disorders: Conditions that impair the transmission or perception of auditory impulses and information from the level of the ear to the temporal cortices, including the sensorineural pathways. [NIH] Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH] Heart failure: Loss of pumping ability by the heart, often accompanied by fatigue, breathlessness, and excess fluid accumulation in body tissues. [NIH] Hematocrit: Measurement of the volume of packed red cells in a blood specimen by centrifugation. The procedure is performed using a tube with graduated markings or with automated blood cell counters. It is used as an indicator of erythrocyte status in disease. For example, anemia shows a low hematocrit, polycythemia, high values. [NIH] Hematoxylin: A dye obtained from the heartwood of logwood (Haematoxylon campechianum Linn., Leguminosae) used as a stain in microscopy and in the manufacture of ink. [NIH] Heme: The color-furnishing portion of hemoglobin. It is found free in tissues and as the prosthetic group in many hemeproteins. [NIH] Hemodialysis: The use of a machine to clean wastes from the blood after the kidneys have failed. The blood travels through tubes to a dialyzer, which removes wastes and extra fluid. The cleaned blood then flows through another set of tubes back into the body. [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Hemostasis: The process which spontaneously arrests the flow of blood from vessels carrying blood under pressure. It is accomplished by contraction of the vessels, adhesion and aggregation of formed blood elements, and the process of blood or plasma coagulation.

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[NIH]

Hepatic: Refers to the liver. [NIH] Hepatitis: Inflammation of the liver and liver disease involving degenerative or necrotic alterations of hepatocytes. [NIH] Hepatocytes: The main structural component of the liver. They are specialized epithelial cells that are organized into interconnected plates called lobules. [NIH] Hepatology: The field of medicine concerned with the functions and disorders of the liver. [NIH]

Hereditary: Of, relating to, or denoting factors that can be transmitted genetically from one generation to another. [NIH] Heredity: 1. The genetic transmission of a particular quality or trait from parent to offspring. 2. The genetic constitution of an individual. [EU] Heterogeneity: The property of one or more samples or populations which implies that they are not identical in respect of some or all of their parameters, e. g. heterogeneity of variance. [NIH]

Hippocampus: A curved elevation of gray matter extending the entire length of the floor of the temporal horn of the lateral ventricle (Dorland, 28th ed). The hippocampus, subiculum, and dentate gyrus constitute the hippocampal formation. Sometimes authors include the entorhinal cortex in the hippocampal formation. [NIH] Histamine: 1H-Imidazole-4-ethanamine. A depressor amine derived by enzymatic decarboxylation of histidine. It is a powerful stimulant of gastric secretion, a constrictor of bronchial smooth muscle, a vasodilator, and also a centrally acting neurotransmitter. [NIH] Homeless Persons: Persons who have no permanent residence. The concept excludes nomadic peoples. [NIH] Homeostasis: The processes whereby the internal environment of an organism tends to remain balanced and stable. [NIH] Homicide: The killing of one person by another. [NIH] Homogeneous: Consisting of or composed of similar elements or ingredients; of a uniform quality throughout. [EU] Homologous: Corresponding in structure, position, origin, etc., as (a) the feathers of a bird and the scales of a fish, (b) antigen and its specific antibody, (c) allelic chromosomes. [EU] Homosexuality: Sexual attraction or relationship between members of the same sex. [NIH] Hormonal: Pertaining to or of the nature of a hormone. [EU] Hormone: A substance in the body that regulates certain organs. Hormones such as gastrin help in breaking down food. Some hormones come from cells in the stomach and small intestine. [NIH] Horny layer: The superficial layer of the epidermis containing keratinized cells. [NIH] Host: Any animal that receives a transplanted graft. [NIH] Hybridomas: Cells artificially created by fusion of activated lymphocytes with neoplastic cells. The resulting hybrid cells are cloned and produce pure or "monoclonal" antibodies or T-cell products, identical to those produced by the immunologically competent parent, and continually grow and divide as the neoplastic parent. [NIH] Hydrocortisone: The main glucocorticoid secreted by the adrenal cortex. Its synthetic counterpart is used, either as an injection or topically, in the treatment of inflammation, allergy, collagen diseases, asthma, adrenocortical deficiency, shock, and some neoplastic

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conditions. [NIH] Hydrogen: The first chemical element in the periodic table. It has the atomic symbol H, atomic number 1, and atomic weight 1. It exists, under normal conditions, as a colorless, odorless, tasteless, diatomic gas. Hydrogen ions are protons. Besides the common H1 isotope, hydrogen exists as the stable isotope deuterium and the unstable, radioactive isotope tritium. [NIH] Hydromorphone: An opioid analgesic made from morphine and used mainly as an analgesic. It has a shorter duration of action than morphine. [NIH] Hyperglycaemia: Abnormally increased content of sugar in the blood. [EU] Hyperlipidaemia: A general term for elevated concentrations of any or all of the lipids in the plasma, including hyperlipoproteinaemia, hypercholesterolaemia, etc. [EU] Hypersensitivity: Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen. [NIH] Hypertension: Persistently high arterial blood pressure. Currently accepted threshold levels are 140 mm Hg systolic and 90 mm Hg diastolic pressure. [NIH] Hyperthyroidism: Excessive functional activity of the thyroid gland. [NIH] Hypertrophy: General increase in bulk of a part or organ, not due to tumor formation, nor to an increase in the number of cells. [NIH] Hypnotic: A drug that acts to induce sleep. [EU] Hypoglycaemia: An abnormally diminished concentration of glucose in the blood, which may lead to tremulousness, cold sweat, piloerection, hypothermia, and headache, accompanied by irritability, confusion, hallucinations, bizarre behaviour, and ultimately, convulsions and coma. [EU] Hypoglycemia: Abnormally low blood sugar [NIH] Hypotension: Abnormally low blood pressure. [NIH] Hypothalamic: Of or involving the hypothalamus. [EU] Hypothalamus: Ventral part of the diencephalon extending from the region of the optic chiasm to the caudal border of the mammillary bodies and forming the inferior and lateral walls of the third ventricle. [NIH] Hypoxia: Reduction of oxygen supply to tissue below physiological levels despite adequate perfusion of the tissue by blood. [EU] Iatrogenic: Resulting from the activity of physicians. Originally applied to disorders induced in the patient by autosuggestion based on the physician's examination, manner, or discussion, the term is now applied to any adverse condition in a patient occurring as the result of treatment by a physician or surgeon, especially to infections acquired by the patient during the course of treatment. [EU] Ibogaine: One of several indole alkaloids extracted from Tabernanthe iboga, Baill. It has a complex pharmacological profile and interacts with multiple systems of neurotransmission. Ibogaine has psychoactive properties and appears to modulate tolerance to opiates. [NIH] Id: The part of the personality structure which harbors the unconscious instinctive desires and strivings of the individual. [NIH] Imaging procedures: Methods of producing pictures of areas inside the body. [NIH] Immune function: Production and action of cells that fight disease or infection. [NIH] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]

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Immune Sera: Serum that contains antibodies. It is obtained from an animal that has been immunized either by antigen injection or infection with microorganisms containing the antigen. [NIH] Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] Immunization: Deliberate stimulation of the host's immune response. Active immunization involves administration of antigens or immunologic adjuvants. Passive immunization involves administration of immune sera or lymphocytes or their extracts (e.g., transfer factor, immune RNA) or transplantation of immunocompetent cell producing tissue (thymus or bone marrow). [NIH] Immunodeficiency: The decreased ability of the body to fight infection and disease. [NIH] Immunodeficiency syndrome: The inability of the body to produce an immune response. [NIH]

Immunoglobulins: Glycoproteins present in the blood (antibodies) and in other tissue. They are classified by structure and activity into five classes (IgA, IgD, IgE, IgG, IgM). [NIH] Immunologic: The ability of the antibody-forming system to recall a previous experience with an antigen and to respond to a second exposure with the prompt production of large amounts of antibody. [NIH] Immunology: The study of the body's immune system. [NIH] Immunosuppressive: Describes the ability to lower immune system responses. [NIH] Immunotherapy: Manipulation of the host's immune system in treatment of disease. It includes both active and passive immunization as well as immunosuppressive therapy to prevent graft rejection. [NIH] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] Impulsive Behavior: An act performed without delay, reflection, voluntary direction, or obvious control in response to a stimulus. [NIH] In vitro: In the laboratory (outside the body). The opposite of in vivo (in the body). [NIH] In vivo: In the body. The opposite of in vitro (outside the body or in the laboratory). [NIH] Incontinence: Inability to control the flow of urine from the bladder (urinary incontinence) or the escape of stool from the rectum (fecal incontinence). [NIH] Incubated: Grown in the laboratory under controlled conditions. (For instance, white blood cells can be grown in special conditions so that they attack specific cancer cells when returned to the body.) [NIH] Incubation: The development of an infectious disease from the entrance of the pathogen to the appearance of clinical symptoms. [EU] Indicative: That indicates; that points out more or less exactly; that reveals fairly clearly. [EU] Induction: The act or process of inducing or causing to occur, especially the production of a specific morphogenetic effect in the developing embryo through the influence of evocators or organizers, or the production of anaesthesia or unconsciousness by use of appropriate agents. [EU] Infarction: A pathological process consisting of a sudden insufficient blood supply to an area, which results in necrosis of that area. It is usually caused by a thrombus, an embolus, or a vascular torsion. [NIH] Infection: 1. Invasion and multiplication of microorganisms in body tissues, which may be

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clinically unapparent or result in local cellular injury due to competitive metabolism, toxins, intracellular replication, or antigen-antibody response. The infection may remain localized, subclinical, and temporary if the body's defensive mechanisms are effective. A local infection may persist and spread by extension to become an acute, subacute, or chronic clinical infection or disease state. A local infection may also become systemic when the microorganisms gain access to the lymphatic or vascular system. 2. An infectious disease. [EU]

Infertility: The diminished or absent ability to conceive or produce an offspring while sterility is the complete inability to conceive or produce an offspring. [NIH] Inflammation: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. [NIH] Inflammatory bowel disease: A general term that refers to the inflammation of the colon and rectum. Inflammatory bowel disease includes ulcerative colitis and Crohn's disease. [NIH]

Infusion: A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion. [NIH] Ingestion: Taking into the body by mouth [NIH] Inhalation: The drawing of air or other substances into the lungs. [EU] Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a step in a carcinogenic process. [NIH] Innervation: 1. The distribution or supply of nerves to a part. 2. The supply of nervous energy or of nerve stimulus sent to a part. [EU] Inositol: An isomer of glucose that has traditionally been considered to be a B vitamin although it has an uncertain status as a vitamin and a deficiency syndrome has not been identified in man. (From Martindale, The Extra Pharmacopoeia, 30th ed, p1379) Inositol phospholipids are important in signal transduction. [NIH] Inotropic: Affecting the force or energy of muscular contractions. [EU] Insight: The capacity to understand one's own motives, to be aware of one's own psychodynamics, to appreciate the meaning of symbolic behavior. [NIH] Insomnia: Difficulty in going to sleep or getting enough sleep. [NIH] Insulin: A protein hormone secreted by beta cells of the pancreas. Insulin plays a major role in the regulation of glucose metabolism, generally promoting the cellular utilization of glucose. It is also an important regulator of protein and lipid metabolism. Insulin is used as a drug to control insulin-dependent diabetes mellitus. [NIH] Insulin-dependent diabetes mellitus: A disease characterized by high levels of blood glucose resulting from defects in insulin secretion, insulin action, or both. Autoimmune, genetic, and environmental factors are involved in the development of type I diabetes. [NIH] Interferon: A biological response modifier (a substance that can improve the body's natural response to disease). Interferons interfere with the division of cancer cells and can slow tumor growth. There are several types of interferons, including interferon-alpha, -beta, and gamma. These substances are normally produced by the body. They are also made in the laboratory for use in treating cancer and other diseases. [NIH] Interferon-alpha: One of the type I interferons produced by peripheral blood leukocytes or lymphoblastoid cells when exposed to live or inactivated virus, double-stranded RNA, or bacterial products. It is the major interferon produced by virus-induced leukocyte cultures and, in addition to its pronounced antiviral activity, it causes activation of NK cells. [NIH]

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Intermittent: Occurring at separated intervals; having periods of cessation of activity. [EU] Internal Medicine: A medical specialty concerned with the diagnosis and treatment of diseases of the internal organ systems of adults. [NIH] International Cooperation: The interaction of persons or groups of persons representing various nations in the pursuit of a common goal or interest. [NIH] Intestinal: Having to do with the intestines. [NIH] Intestine: A long, tube-shaped organ in the abdomen that completes the process of digestion. There is both a large intestine and a small intestine. Also called the bowel. [NIH] Intoxication: Poisoning, the state of being poisoned. [EU] Intracellular: Inside a cell. [NIH] Intracellular Membranes: Membranes of subcellular structures. [NIH] Intracranial Embolism: The sudden obstruction of a blood vessel by an embolus. [NIH] Intracranial Embolism and Thrombosis: Embolism or thrombosis involving blood vessels which supply intracranial structures. Emboli may originate from extracranial or intracranial sources. Thrombosis may occur in arterial or venous structures. [NIH] Intramuscular: IM. Within or into muscle. [NIH] Intraocular: Within the eye. [EU] Intraocular pressure: Pressure of the fluid inside the eye; normal IOP varies among individuals. [NIH] Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] Inulin: A starch found in the tubers and roots of many plants. Since it is hydrolyzable to fructose, it is classified as a fructosan. It has been used in physiologic investigation for determination of the rate of glomerular function. [NIH] Involuntary: Reaction occurring without intention or volition. [NIH] Ion Channels: Gated, ion-selective glycoproteins that traverse membranes. The stimulus for channel gating can be a membrane potential, drug, transmitter, cytoplasmic messenger, or a mechanical deformation. Ion channels which are integral parts of ionotropic neurotransmitter receptors are not included. [NIH] Ionizing: Radiation comprising charged particles, e. g. electrons, protons, alpha-particles, etc., having sufficient kinetic energy to produce ionization by collision. [NIH] Ions: An atom or group of atoms that have a positive or negative electric charge due to a gain (negative charge) or loss (positive charge) of one or more electrons. Atoms with a positive charge are known as cations; those with a negative charge are anions. [NIH] Irritable Bowel Syndrome: A disorder that comes and goes. Nerves that control the muscles in the GI tract are too active. The GI tract becomes sensitive to food, stool, gas, and stress. Causes abdominal pain, bloating, and constipation or diarrhea. Also called spastic colon or mucous colitis. [NIH] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Isradipine: 4-(4-Benzofurazanyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid methyl 1-methyl ethyl ester. A potent calcium channel antagonist that is highly selective for vascular smooth muscle. It is effective in the treatment of chronic stable angina pectoris, hypertension, and congestive cardiac failure. [NIH]

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Joint: The point of contact between elements of an animal skeleton with the parts that surround and support it. [NIH] Kainate: Glutamate receptor. [NIH] Kb: A measure of the length of DNA fragments, 1 Kb = 1000 base pairs. The largest DNA fragments are up to 50 kilobases long. [NIH] Kidney Failure: The inability of a kidney to excrete metabolites at normal plasma levels under conditions of normal loading, or the inability to retain electrolytes under conditions of normal intake. In the acute form (kidney failure, acute), it is marked by uremia and usually by oliguria or anuria, with hyperkalemia and pulmonary edema. The chronic form (kidney failure, chronic) is irreversible and requires hemodialysis. [NIH] Kinetic: Pertaining to or producing motion. [EU] Labile: 1. Gliding; moving from point to point over the surface; unstable; fluctuating. 2. Chemically unstable. [EU] Language Disorders: Conditions characterized by deficiencies of comprehension or expression of written and spoken forms of language. These include acquired and developmental disorders. [NIH] Large Intestine: The part of the intestine that goes from the cecum to the rectum. The large intestine absorbs water from stool and changes it from a liquid to a solid form. The large intestine is 5 feet long and includes the appendix, cecum, colon, and rectum. Also called colon. [NIH] Latent: Phoria which occurs at one distance or another and which usually has no troublesome effect. [NIH] Lectin: A complex molecule that has both protein and sugars. Lectins are able to bind to the outside of a cell and cause biochemical changes in it. Lectins are made by both animals and plants. [NIH] Lens: The transparent, double convex (outward curve on both sides) structure suspended between the aqueous and vitreous; helps to focus light on the retina. [NIH] Lesion: An area of abnormal tissue change. [NIH] Lethal: Deadly, fatal. [EU] Leucine: An essential branched-chain amino acid important for hemoglobin formation. [NIH] Leukopenia: A condition in which the number of leukocytes (white blood cells) in the blood is reduced. [NIH] Library Services: Services offered to the library user. They include reference and circulation. [NIH]

Lice: A general name for small, wingless, parasitic insects, previously of the order Phthiraptera. Though exact taxonomy is still controversial, they can be grouped in the orders Anoplura (sucking lice), Mallophaga (biting lice), and Rhynchophthirina (elephant lice). [NIH] Lie detector: An instrument for making a graphic record of the changes in blood pressure and pulse and respiration rate of someone being questioned under or as if under suspicion of guilt. [NIH] Life Expectancy: A figure representing the number of years, based on known statistics, to which any person of a given age may reasonably expect to live. [NIH] Ligaments: Shiny, flexible bands of fibrous tissue connecting together articular extremities of bones. They are pliant, tough, and inextensile. [NIH]

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Ligands: A RNA simulation method developed by the MIT. [NIH] Limbic: Pertaining to a limbus, or margin; forming a border around. [EU] Limbic System: A set of forebrain structures common to all mammals that is defined functionally and anatomically. It is implicated in the higher integration of visceral, olfactory, and somatic information as well as homeostatic responses including fundamental survival behaviors (feeding, mating, emotion). For most authors, it includes the amygdala, epithalamus, gyrus cinguli, hippocampal formation (see hippocampus), hypothalamus, parahippocampal gyrus, septal nuclei, anterior nuclear group of thalamus, and portions of the basal ganglia. (Parent, Carpenter's Human Neuroanatomy, 9th ed, p744; NeuroNames, http://rprcsgi.rprc.washington.edu/neuronames/index.html (September 2, 1998)). [NIH] Linkage: The tendency of two or more genes in the same chromosome to remain together from one generation to the next more frequently than expected according to the law of independent assortment. [NIH] Lipid: Fat. [NIH] Lipophilic: Having an affinity for fat; pertaining to or characterized by lipophilia. [EU] Lithium: An element in the alkali metals family. It has the atomic symbol Li, atomic number 3, and atomic weight 6.94. Salts of lithium are used in treating manic-depressive disorders. [NIH]

Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] Lobe: A portion of an organ such as the liver, lung, breast, or brain. [NIH] Lobeline: An alkaloid that has actions similar to nicotine on nicotinic cholinergic receptors but is less potent. It has been proposed for a variety of therapeutic uses including in respiratory disorders, peripheral vascular disorders, insomnia, and smoking cessation. [NIH] Localization: The process of determining or marking the location or site of a lesion or disease. May also refer to the process of keeping a lesion or disease in a specific location or site. [NIH] Localized: Cancer which has not metastasized yet. [NIH] Locomotion: Movement or the ability to move from one place or another. It can refer to humans, vertebrate or invertebrate animals, and microorganisms. [NIH] Locomotor: Of or pertaining to locomotion; pertaining to or affecting the locomotive apparatus of the body. [EU] Longitudinal Studies: Studies in which variables relating to an individual or group of individuals are assessed over a period of time. [NIH] Longitudinal study: Also referred to as a "cohort study" or "prospective study"; the analytic method of epidemiologic study in which subsets of a defined population can be identified who are, have been, or in the future may be exposed or not exposed, or exposed in different degrees, to a factor or factors hypothesized to influence the probability of occurrence of a given disease or other outcome. The main feature of this type of study is to observe large numbers of subjects over an extended time, with comparisons of incidence rates in groups that differ in exposure levels. [NIH] Lymphatic: The tissues and organs, including the bone marrow, spleen, thymus, and lymph nodes, that produce and store cells that fight infection and disease. [NIH] Lymphatic system: The tissues and organs that produce, store, and carry white blood cells that fight infection and other diseases. This system includes the bone marrow, spleen, thymus, lymph nodes and a network of thin tubes that carry lymph and white blood cells.

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These tubes branch, like blood vessels, into all the tissues of the body. [NIH] Lymphocyte: A white blood cell. Lymphocytes have a number of roles in the immune system, including the production of antibodies and other substances that fight infection and diseases. [NIH] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] Magnetic Resonance Imaging: Non-invasive method of demonstrating internal anatomy based on the principle that atomic nuclei in a strong magnetic field absorb pulses of radiofrequency energy and emit them as radiowaves which can be reconstructed into computerized images. The concept includes proton spin tomographic techniques. [NIH] Magnetoencephalography: The measurement of magnetic fields over the head generated by electric currents in the brain. As in any electrical conductor, electric fields in the brain are accompanied by orthogonal magnetic fields. The measurement of these fields provides information about the localization of brain activity which is complementary to that provided by electroencephalography. Magnetoencephalography may be used alone or together with electroencephalography, for measurement of spontaneous or evoked activity, and for research or clinical purposes. [NIH] Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malingering: Simulation of symptoms of illness or injury with intent to deceive in order to obtain a goal, e.g., a claim of physical illness to avoid jury duty. [NIH] Malnutrition: A condition caused by not eating enough food or not eating a balanced diet. [NIH]

Manic: Affected with mania. [EU] Manic-depressive psychosis: One of a group of psychotic reactions, fundamentally marked by severe mood swings and a tendency to remission and recurrence. [NIH] Manifest: Being the part or aspect of a phenomenon that is directly observable : concretely expressed in behaviour. [EU] Marital Status: A demographic parameter indicating a person's status with respect to marriage, divorce, widowhood, singleness, etc. [NIH] Marital Therapy: A form of psychotherapy involving the husband and wife and directed to improving the marital relationship. [NIH] Masturbation: Sexual stimulation or gratification of the self. [NIH] Maximum Tolerated Dose: The highest dose level eliciting signs of toxicity without having major effects on survival relative to the test in which it is used. [NIH] Mecamylamine: A nicotinic antagonist that is well absorbed from the gastrointestinal tract and crosses the blood-brain barrier. Mecamylamine has been used as a ganglionic blocker in treating hypertension, but, like most ganglionic blockers, is more often used now as a research tool. [NIH] Medetomidine: An agonist of receptors, adrenergic alpha-2 that is used in veterinary medicine for its analgesic and sedative properties. It is the racemate of dexmedetomidine. [NIH]

Medial: Lying near the midsaggital plane of the body; opposed to lateral. [NIH] Mediate: Indirect; accomplished by the aid of an intervening medium. [EU] Mediator: An object or substance by which something is mediated, such as (1) a structure of the nervous system that transmits impulses eliciting a specific response; (2) a chemical

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substance (transmitter substance) that induces activity in an excitable tissue, such as nerve or muscle; or (3) a substance released from cells as the result of the interaction of antigen with antibody or by the action of antigen with a sensitized lymphocyte. [EU] MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] Medullary: Pertaining to the marrow or to any medulla; resembling marrow. [EU] Meiosis: A special method of cell division, occurring in maturation of the germ cells, by means of which each daughter nucleus receives half the number of chromosomes characteristic of the somatic cells of the species. [NIH] Melanin: The substance that gives the skin its color. [NIH] Memantine: Amantadine derivative that has some dopaminergic effects. It has been proposed as an antiparkinson agent. [NIH] Membrane: A very thin layer of tissue that covers a surface. [NIH] Membrane Glycoproteins: Glycoproteins found on the membrane or surface of cells. [NIH] Membrane Proteins: Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors. [NIH] Memory: Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. [NIH] Meninges: The three membranes that cover and protect the brain and spinal cord. [NIH] Menopause: Permanent cessation of menstruation. [NIH] Mental Disorders: Psychiatric illness or diseases manifested by breakdowns in the adaptational process expressed primarily as abnormalities of thought, feeling, and behavior producing either distress or impairment of function. [NIH] Mental Health: The state wherein the person is well adjusted. [NIH] Mental Processes: Conceptual functions or thinking in all its forms. [NIH] Mental Retardation: Refers to sub-average general intellectual functioning which originated during the developmental period and is associated with impairment in adaptive behavior. [NIH]

Mentors: Senior professionals who provide guidance, direction and support to those persons desirous of improvement in academic positions, administrative positions or other career development situations. [NIH] Mesoderm: The middle germ layer of the embryo. [NIH] Mesolimbic: Inner brain region governing emotion and drives. [NIH] Metabolic disorder: A condition in which normal metabolic processes are disrupted, usually because of a missing enzyme. [NIH] Metabolite: Any substance produced by metabolism or by a metabolic process. [EU] Metabotropic: A glutamate receptor which triggers an increase in production of 2 intracellular messengers: diacylglycerol and inositol 1, 4, 5-triphosphate. [NIH] Methamphetamine: A central nervous system stimulant and sympathomimetic with actions and uses similar to dextroamphetamine. The smokable form is a drug of abuse and is referred to as crank, crystal, crystal meth, ice, and speed. [NIH]

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Methanol: A colorless, flammable liquid used in the manufacture of formaldehyde and acetic acid, in chemical synthesis, antifreeze, and as a solvent. Ingestion of methanol is toxic and may cause blindness. [NIH] Methionine: A sulfur containing essential amino acid that is important in many body functions. It is a chelating agent for heavy metals. [NIH] MI: Myocardial infarction. Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Microbe: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microbiology: The study of microorganisms such as fungi, bacteria, algae, archaea, and viruses. [NIH] Microdialysis: A technique for measuring extracellular concentrations of substances in tissues, usually in vivo, by means of a small probe equipped with a semipermeable membrane. Substances may also be introduced into the extracellular space through the membrane. [NIH] Microorganism: An organism that can be seen only through a microscope. Microorganisms include bacteria, protozoa, algae, and fungi. Although viruses are not considered living organisms, they are sometimes classified as microorganisms. [NIH] Microscopy: The application of microscope magnification to the study of materials that cannot be properly seen by the unaided eye. [NIH] Mineralization: The action of mineralizing; the state of being mineralized. [EU] Mineralocorticoids: A group of corticosteroids primarily associated with the regulation of water and electrolyte balance. This is accomplished through the effect on ion transport in renal tubules, resulting in retention of sodium and loss of potassium. Mineralocorticoid secretion is itself regulated by plasma volume, serum potassium, and angiotensin II. [NIH] Modeling: A treatment procedure whereby the therapist presents the target behavior which the learner is to imitate and make part of his repertoire. [NIH] Modification: A change in an organism, or in a process in an organism, that is acquired from its own activity or environment. [NIH] Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Molecular Probes: A group of atoms or molecules attached to other molecules or cellular structures and used in studying the properties of these molecules and structures. Radioactive DNA or RNA sequences are used in molecular genetics to detect the presence of a complementary sequence by molecular hybridization. [NIH] Molecule: A chemical made up of two or more atoms. The atoms in a molecule can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms. [NIH] Monitor: An apparatus which automatically records such physiological signs as respiration, pulse, and blood pressure in an anesthetized patient or one undergoing surgical or other procedures. [NIH] Monoamine: Enzyme that breaks down dopamine in the astrocytes and microglia. [NIH] Monoamine Oxidase: An enzyme that catalyzes the oxidative deamination of naturally occurring monoamines. It is a flavin-containing enzyme that is localized in mitochondrial membranes, whether in nerve terminals, the liver, or other organs. Monoamine oxidase is

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important in regulating the metabolic degradation of catecholamines and serotonin in neural or target tissues. Hepatic monoamine oxidase has a crucial defensive role in inactivating circulating monoamines or those, such as tyramine, that originate in the gut and are absorbed into the portal circulation. (From Goodman and Gilman's, The Pharmacological Basis of Therapeutics, 8th ed, p415) EC 1.4.3.4. [NIH] Morals: Standards of conduct as right or wrong. [NIH] Morphine: The principal alkaloid in opium and the prototype opiate analgesic and narcotic. Morphine has widespread effects in the central nervous system and on smooth muscle. [NIH] Morphological: Relating to the configuration or the structure of live organs. [NIH] Morphology: The science of the form and structure of organisms (plants, animals, and other forms of life). [NIH] Morula: The early embryo at the developmental stage in which the blastomeres, resulting from repeated mitotic divisions of the fertilized ovum, form a compact mass. [NIH] Mother-Child Relations: Interaction between the mother and the child. [NIH] Motility: The ability to move spontaneously. [EU] Movement Disorders: Syndromes which feature dyskinesias as a cardinal manifestation of the disease process. Included in this category are degenerative, hereditary, post-infectious, medication-induced, post-inflammatory, and post-traumatic conditions. [NIH] Mutagenesis: Process of generating genetic mutations. It may occur spontaneously or be induced by mutagens. [NIH] Mutagens: Chemical agents that increase the rate of genetic mutation by interfering with the function of nucleic acids. A clastogen is a specific mutagen that causes breaks in chromosomes. [NIH] Myasthenia: Muscular debility; any constitutional anomaly of muscle. [EU] Myocardial infarction: Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [NIH] Naive: Used to describe an individual who has never taken a certain drug or class of drugs (e. g., AZT-naive, antiretroviral-naive), or to refer to an undifferentiated immune system cell. [NIH] Naloxone: A specific opiate antagonist that has no agonist activity. It is a competitive antagonist at mu, delta, and kappa opioid receptors. [NIH] Naltrexone: Derivative of noroxymorphone that is the N-cyclopropylmethyl congener of naloxone. It is a narcotic antagonist that is effective orally, longer lasting and more potent than naloxone, and has been proposed for the treatment of heroin addiction. The FDA has approved naltrexone for the treatment of alcohol dependence. [NIH] Naphazoline: An adrenergic vasoconstrictor agent used as a decongestant. [NIH] Narcolepsy: A condition of unknown cause characterized by a periodic uncontrollable tendency to fall asleep. [NIH] Narcosis: A general and nonspecific reversible depression of neuronal excitability, produced by a number of physical and chemical aspects, usually resulting in stupor. [NIH] Narcotic: 1. Pertaining to or producing narcosis. 2. An agent that produces insensibility or stupor, applied especially to the opioids, i.e. to any natural or synthetic drug that has

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morphine-like actions. [EU] Nausea: An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. [NIH] Necrosis: A pathological process caused by the progressive degradative action of enzymes that is generally associated with severe cellular trauma. It is characterized by mitochondrial swelling, nuclear flocculation, uncontrolled cell lysis, and ultimately cell death. [NIH] Need: A state of tension or dissatisfaction felt by an individual that impels him to action toward a goal he believes will satisfy the impulse. [NIH] Needle Sharing: Usage of a single needle among two or more people for injecting drugs. Needle sharing is a high-risk behavior for contracting infectious disease. [NIH] Neonatal: Pertaining to the first four weeks after birth. [EU] Neoplasm: A new growth of benign or malignant tissue. [NIH] Neoplastic: Pertaining to or like a neoplasm (= any new and abnormal growth); pertaining to neoplasia (= the formation of a neoplasm). [EU] Neostriatum: The phylogenetically newer part of the corpus striatum consisting of the caudate nucleus and putamen. It is often called simply the striatum. [NIH] Nerve: A cordlike structure of nervous tissue that connects parts of the nervous system with other tissues of the body and conveys nervous impulses to, or away from, these tissues. [NIH] Nerve Fibers: Slender processes of neurons, especially the prolonged axons that conduct nerve impulses. [NIH] Nerve Growth Factor: Nerve growth factor is the first of a series of neurotrophic factors that were found to influence the growth and differentiation of sympathetic and sensory neurons. It is comprised of alpha, beta, and gamma subunits. The beta subunit is responsible for its growth stimulating activity. [NIH] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and ganglia. [NIH] Networks: Pertaining to a nerve or to the nerves, a meshlike structure of interlocking fibers or strands. [NIH] Neural: 1. Pertaining to a nerve or to the nerves. 2. Situated in the region of the spinal axis, as the neutral arch. [EU] Neurodegenerative Diseases: Hereditary and sporadic conditions which are characterized by progressive nervous system dysfunction. These disorders are often associated with atrophy of the affected central or peripheral nervous system structures. [NIH] Neuroendocrine: Having to do with the interactions between the nervous system and the endocrine system. Describes certain cells that release hormones into the blood in response to stimulation of the nervous system. [NIH] Neuroleptic: A term coined to refer to the effects on cognition and behaviour of antipsychotic drugs, which produce a state of apathy, lack of initiative, and limited range of emotion and in psychotic patients cause a reduction in confusion and agitation and normalization of psychomotor activity. [EU] Neuromuscular: Pertaining to muscles and nerves. [EU] Neuromuscular Junction: The synapse between a neuron and a muscle. [NIH] Neuronal: Pertaining to a neuron or neurons (= conducting cells of the nervous system). [EU] Neuronal Plasticity: The capacity of the nervous system to change its reactivity as the result

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of successive activations. [NIH] Neurons: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. [NIH] Neuropathy: A problem in any part of the nervous system except the brain and spinal cord. Neuropathies can be caused by infection, toxic substances, or disease. [NIH] Neuropeptide: A member of a class of protein-like molecules made in the brain. Neuropeptides consist of short chains of amino acids, with some functioning as neurotransmitters and some functioning as hormones. [NIH] Neuroprotective Agents: Drugs intended to prevent damage to the brain or spinal cord from ischemia, stroke, convulsions, or trauma. Some must be administered before the event, but others may be effective for some time after. They act by a variety of mechanisms, but often directly or indirectly minimize the damage produced by endogenous excitatory amino acids. [NIH] Neurosis: Functional derangement due to disorders of the nervous system which does not affect the psychic personality of the patient. [NIH] Neurotic: 1. Pertaining to or characterized by neurosis. 2. A person affected with a neurosis. [EU]

Neurotic Disorders: Disorders in which the symptoms are distressing to the individual and recognized by him or her as being unacceptable. Social relationships may be greatly affected but usually remain within acceptable limits. The disturbance is relatively enduring or recurrent without treatment. [NIH] Neurotoxicity: The tendency of some treatments to cause damage to the nervous system. [NIH]

Neurotoxin: A substance that is poisonous to nerve tissue. [NIH] Neurotransmitters: Endogenous signaling molecules that alter the behavior of neurons or effector cells. Neurotransmitter is used here in its most general sense, including not only messengers that act directly to regulate ion channels, but also those that act through second messenger systems, and those that act at a distance from their site of release. Included are neuromodulators, neuroregulators, neuromediators, and neurohumors, whether or not acting at synapses. [NIH] Neurotrophins: A nerve growth factor. [NIH] Neutrons: Electrically neutral elementary particles found in all atomic nuclei except light hydrogen; the mass is equal to that of the proton and electron combined and they are unstable when isolated from the nucleus, undergoing beta decay. Slow, thermal, epithermal, and fast neutrons refer to the energy levels with which the neutrons are ejected from heavier nuclei during their decay. [NIH] Niacin: Water-soluble vitamin of the B complex occurring in various animal and plant tissues. Required by the body for the formation of coenzymes NAD and NADP. Has pellagra-curative, vasodilating, and antilipemic properties. [NIH] Nicotine: Nicotine is highly toxic alkaloid. It is the prototypical agonist at nicotinic cholinergic receptors where it dramatically stimulates neurons and ultimately blocks synaptic transmission. Nicotine is also important medically because of its presence in tobacco smoke. [NIH] Nicotinic Antagonists: Drugs that bind to nicotinic cholinergic receptors (receptors, nicotinic) and block the actions of acetylcholine or cholinergic agonists. Nicotinic antagonists block synaptic transmission at autonomic ganglia, the skeletal neuromuscular junction, and

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at central nervous system nicotinic synapses. [NIH] Nitrogen: An element with the atomic symbol N, atomic number 7, and atomic weight 14. Nitrogen exists as a diatomic gas and makes up about 78% of the earth's atmosphere by volume. It is a constituent of proteins and nucleic acids and found in all living cells. [NIH] Nonverbal Communication: Transmission of emotions, ideas, and attitudes between individuals in ways other than the spoken language. [NIH] Norepinephrine: Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers and of the diffuse projection system in the brain arising from the locus ceruleus. It is also found in plants and is used pharmacologically as a sympathomimetic. [NIH] Notochord: The rod-shaped body, composed of cells derived from the mesoblast and defining the primitive axis of the embryo. In lower vertebrates, it persists throughout life as the main axial support of the body, but in higher vertebrates it is replaced by the vertebral column. [NIH] Nuclear: A test of the structure, blood flow, and function of the kidneys. The doctor injects a mildly radioactive solution into an arm vein and uses x-rays to monitor its progress through the kidneys. [NIH] Nuclei: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nucleic acid: Either of two types of macromolecule (DNA or RNA) formed by polymerization of nucleotides. Nucleic acids are found in all living cells and contain the information (genetic code) for the transfer of genetic information from one generation to the next. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nucleus Accumbens: Collection of pleomorphic cells in the caudal part of the anterior horn of the lateral ventricle, in the region of the olfactory tubercle, lying between the head of the caudate nucleus and the anterior perforated substance. It is part of the so-called ventral striatum, a composite structure considered part of the basal ganglia. [NIH] Nutritional Support: The administration of nutrients for assimilation and utilization by a patient by means other than normal eating. It does not include fluid therapy which normalizes body fluids to restore water-electrolyte balance. [NIH] Obsession: A recurrent, persistent thought, image, or impulse that is unwanted and distressing (ego-dystonic) and comes involuntarily to mind despite attempts to ignore or suppress it. Common obsessions involve thoughts of violence, contamination, and selfdoubt. [EU] Ocular: 1. Of, pertaining to, or affecting the eye. 2. Eyepiece. [EU] Odour: A volatile emanation that is perceived by the sense of smell. [EU] Ointments: Semisolid preparations used topically for protective emollient effects or as a vehicle for local administration of medications. Ointment bases are various mixtures of fats, waxes, animal and plant oils and solid and liquid hydrocarbons. [NIH] Opacity: Degree of density (area most dense taken for reading). [NIH] Opioid Peptides: The endogenous peptides with opiate-like activity. The three major classes currently recognized are the enkephalins, the dynorphins, and the endorphins. Each of these families derives from different precursors, proenkephalin, prodynorphin, and pro-

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opiomelanocortin, respectively. There are also at least three classes of opioid receptors, but the peptide families do not map to the receptors in a simple way. [NIH] Opium: The air-dried exudate from the unripe seed capsule of the opium poppy, Papaver somniferum, or its variant, P. album. It contains a number of alkaloids, but only a few morphine, codeine, and papaverine - have clinical significance. Opium has been used as an analgesic, antitussive, antidiarrheal, and antispasmodic. [NIH] Opportunistic Infections: An infection caused by an organism which becomes pathogenic under certain conditions, e.g., during immunosuppression. [NIH] Oral Health: The optimal state of the mouth and normal functioning of the organs of the mouth without evidence of disease. [NIH] Orbit: One of the two cavities in the skull which contains an eyeball. Each eye is located in a bony socket or orbit. [NIH] Orbital: Pertaining to the orbit (= the bony cavity that contains the eyeball). [EU] Orderly: A male hospital attendant. [NIH] Orthostatic: Pertaining to or caused by standing erect. [EU] Osmotic: Pertaining to or of the nature of osmosis (= the passage of pure solvent from a solution of lesser to one of greater solute concentration when the two solutions are separated by a membrane which selectively prevents the passage of solute molecules, but is permeable to the solvent). [EU] Osteomalacia: A condition marked by softening of the bones (due to impaired mineralization, with excess accumulation of osteoid), with pain, tenderness, muscular weakness, anorexia, and loss of weight, resulting from deficiency of vitamin D and calcium. [EU]

Osteomyelitis: Inflammation of bone caused by a pyogenic organism. It may remain localized or may spread through the bone to involve the marrow, cortex, cancellous tissue, and periosteum. [EU] Osteoporosis: Reduction of bone mass without alteration in the composition of bone, leading to fractures. Primary osteoporosis can be of two major types: postmenopausal osteoporosis and age-related (or senile) osteoporosis. [NIH] Outpatient: A patient who is not an inmate of a hospital but receives diagnosis or treatment in a clinic or dispensary connected with the hospital. [NIH] Ovariectomy: The surgical removal of one or both ovaries. [NIH] Ovaries: The pair of female reproductive glands in which the ova, or eggs, are formed. The ovaries are located in the pelvis, one on each side of the uterus. [NIH] Ovary: Either of the paired glands in the female that produce the female germ cells and secrete some of the female sex hormones. [NIH] Overdose: An accidental or deliberate dose of a medication or street drug that is in excess of what is normally used. [NIH] Oxidation: The act of oxidizing or state of being oxidized. Chemically it consists in the increase of positive charges on an atom or the loss of negative charges. Most biological oxidations are accomplished by the removal of a pair of hydrogen atoms (dehydrogenation) from a molecule. Such oxidations must be accompanied by reduction of an acceptor molecule. Univalent o. indicates loss of one electron; divalent o., the loss of two electrons. [EU]

Oxygen Consumption: The oxygen consumption is determined by calculating the difference between the amount of oxygen inhaled and exhaled. [NIH]

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Oxygenation: The process of supplying, treating, or mixing with oxygen. No:1245 oxygenation the process of supplying, treating, or mixing with oxygen. [EU] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] Palsy: Disease of the peripheral nervous system occurring usually after many years of increased lead absorption. [NIH] Pancreas: A mixed exocrine and endocrine gland situated transversely across the posterior abdominal wall in the epigastric and hypochondriac regions. The endocrine portion is comprised of the Islets of Langerhans, while the exocrine portion is a compound acinar gland that secretes digestive enzymes. [NIH] Panic: A state of extreme acute, intense anxiety and unreasoning fear accompanied by disorganization of personality function. [NIH] Panic Disorder: A type of anxiety disorder characterized by unexpected panic attacks that last minutes or, rarely, hours. Panic attacks begin with intense apprehension, fear or terror and, often, a feeling of impending doom. Symptoms experienced during a panic attack include dyspnea or sensations of being smothered; dizziness, loss of balance or faintness; choking sensations; palpitations or accelerated heart rate; shakiness; sweating; nausea or other form of abdominal distress; depersonalization or derealization; paresthesias; hot flashes or chills; chest discomfort or pain; fear of dying and fear of not being in control of oneself or going crazy. Agoraphobia may also develop. Similar to other anxiety disorders, it may be inherited as an autosomal dominant trait. [NIH] Papaverine: An alkaloid found in opium but not closely related to the other opium alkaloids in its structure or pharmacological actions. It is a direct-acting smooth muscle relaxant used in the treatment of impotence and as a vasodilator, especially for cerebral vasodilation. The mechanism of its pharmacological actions is not clear, but it apparently can inhibit phosphodiesterases and it may have direct actions on calcium channels. [NIH] Paralysis: Loss of ability to move all or part of the body. [NIH] Parasitic: Having to do with or being a parasite. A parasite is an animal or a plant that lives on or in an organism of another species and gets at least some of its nutrients from it. [NIH] Parenteral: Not through the alimentary canal but rather by injection through some other route, as subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, intravenous, etc. [EU] Paresthesias: Abnormal touch sensations, such as burning or prickling, that occur without an outside stimulus. [NIH] Parkinsonism: A group of neurological disorders characterized by hypokinesia, tremor, and muscular rigidity. [EU] Particle: A tiny mass of material. [EU] Patch: A piece of material used to cover or protect a wound, an injured part, etc.: a patch over the eye. [NIH] Pathogen: Any disease-producing microorganism. [EU] Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (= branch of medicine that treats the essential nature of the disease, especially the structural and functional changes in tissues and organs of the body caused by the disease). [EU] Pathophysiology: Altered functions in an individual or an organ due to disease. [NIH] Patient Education: The teaching or training of patients concerning their own health needs. [NIH]

Penicillin: An antibiotic drug used to treat infection. [NIH]

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Penis: The external reproductive organ of males. It is composed of a mass of erectile tissue enclosed in three cylindrical fibrous compartments. Two of the three compartments, the corpus cavernosa, are placed side-by-side along the upper part of the organ. The third compartment below, the corpus spongiosum, houses the urethra. [NIH] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Perception: The ability quickly and accurately to recognize similarities and differences among presented objects, whether these be pairs of words, pairs of number series, or multiple sets of these or other symbols such as geometric figures. [NIH] Perfusion: Bathing an organ or tissue with a fluid. In regional perfusion, a specific area of the body (usually an arm or a leg) receives high doses of anticancer drugs through a blood vessel. Such a procedure is performed to treat cancer that has not spread. [NIH] Perinatal: Pertaining to or occurring in the period shortly before and after birth; variously defined as beginning with completion of the twentieth to twenty-eighth week of gestation and ending 7 to 28 days after birth. [EU] Peripheral Nervous System: The nervous system outside of the brain and spinal cord. The peripheral nervous system has autonomic and somatic divisions. The autonomic nervous system includes the enteric, parasympathetic, and sympathetic subdivisions. The somatic nervous system includes the cranial and spinal nerves and their ganglia and the peripheral sensory receptors. [NIH] Personality Disorders: A major deviation from normal patterns of behavior. [NIH] Perspiration: Sweating; the functional secretion of sweat. [EU] Petechiae: Pinpoint, unraised, round red spots under the skin caused by bleeding. [NIH] PH: The symbol relating the hydrogen ion (H+) concentration or activity of a solution to that of a given standard solution. Numerically the pH is approximately equal to the negative logarithm of H+ concentration expressed in molarity. pH 7 is neutral; above it alkalinity increases and below it acidity increases. [EU] Pharmaceutical Preparations: Drugs intended for human or veterinary use, presented in their finished dosage form. Included here are materials used in the preparation and/or formulation of the finished dosage form. [NIH] Pharmaceutical Solutions: Homogeneous liquid preparations that contain one or more chemical substances dissolved, i.e., molecularly dispersed, in a suitable solvent or mixture of mutually miscible solvents. For reasons of their ingredients, method of preparation, or use, they do not fall into another group of products. [NIH] Pharmacist: A person trained to prepare and distribute medicines and to give information about them. [NIH] Pharmacodynamic: Is concerned with the response of living tissues to chemical stimuli, that is, the action of drugs on the living organism in the absence of disease. [NIH] Pharmacogenetics: A branch of genetics which deals with the genetic components of variability in individual responses to and metabolism (biotransformation) of drugs. [NIH] Pharmacokinetic: The mathematical analysis of the time courses of absorption, distribution, and elimination of drugs. [NIH] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Pharmacotherapy: A regimen of using appetite suppressant medications to manage obesity by decreasing appetite or increasing the feeling of satiety. These medications decrease appetite by increasing serotonin or catecholamine—two brain chemicals that affect mood

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and appetite. [NIH] Pharynx: The hollow tube about 5 inches long that starts behind the nose and ends at the top of the trachea (windpipe) and esophagus (the tube that goes to the stomach). [NIH] Phenotype: The outward appearance of the individual. It is the product of interactions between genes and between the genotype and the environment. This includes the killer phenotype, characteristic of yeasts. [NIH] Phenoxybenzamine: An alpha-adrenergic anatagonist with long duration of action. It has been used to treat hypertension and as a peripheral vasodilator. [NIH] Phenyl: Ingredient used in cold and flu remedies. [NIH] Phenylalanine: An aromatic amino acid that is essential in the animal diet. It is a precursor of melanin, dopamine, noradrenalin, and thyroxine. [NIH] Phobias: An exaggerated and invariably pathological dread of some specific type of stimulus or situation. [NIH] Phospholipases: A class of enzymes that catalyze the hydrolysis of phosphoglycerides or glycerophosphatidates. EC 3.1.-. [NIH] Phospholipids: Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides; glycerophospholipids) or sphingosine (sphingolipids). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system. [NIH] Phosphorus: A non-metallic element that is found in the blood, muscles, nevers, bones, and teeth, and is a component of adenosine triphosphate (ATP; the primary energy source for the body's cells.) [NIH] Phosphorylate: Attached to a phosphate group. [NIH] Phosphorylated: Attached to a phosphate group. [NIH] Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. [NIH] Physiologic: Having to do with the functions of the body. When used in the phrase "physiologic age," it refers to an age assigned by general health, as opposed to calendar age. [NIH]

Physiology: The science that deals with the life processes and functions of organismus, their cells, tissues, and organs. [NIH] Pilot Projects: Small-scale tests of methods and procedures to be used on a larger scale if the pilot study demonstrates that these methods and procedures can work. [NIH] Pilot study: The initial study examining a new method or treatment. [NIH] Pituitary Gland: A small, unpaired gland situated in the sella turcica tissue. It is connected to the hypothalamus by a short stalk. [NIH] Placenta: A highly vascular fetal organ through which the fetus absorbs oxygen and other nutrients and excretes carbon dioxide and other wastes. It begins to form about the eighth day of gestation when the blastocyst adheres to the decidua. [NIH] Plants: Multicellular, eukaryotic life forms of the kingdom Plantae. They are characterized by a mainly photosynthetic mode of nutrition; essentially unlimited growth at localized regions of cell divisions (meristems); cellulose within cells providing rigidity; the absence of organs of locomotion; absense of nervous and sensory systems; and an alteration of haploid and diploid generations. [NIH]

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Plasma: The clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma. [NIH] Plasma cells: A type of white blood cell that produces antibodies. [NIH] Plasma protein: One of the hundreds of different proteins present in blood plasma, including carrier proteins ( such albumin, transferrin, and haptoglobin), fibrinogen and other coagulation factors, complement components, immunoglobulins, enzyme inhibitors, precursors of substances such as angiotension and bradykinin, and many other types of proteins. [EU] Plasmids: Any extrachromosomal hereditary determinant. Plasmids are self-replicating circular molecules of DNA that are found in a variety of bacterial, archaeal, fungal, algal, and plant species. [NIH] Plasticity: In an individual or a population, the capacity for adaptation: a) through gene changes (genetic plasticity) or b) through internal physiological modifications in response to changes of environment (physiological plasticity). [NIH] Platelet Activation: A series of progressive, overlapping events triggered by exposure of the platelets to subendothelial tissue. These events include shape change, adhesiveness, aggregation, and release reactions. When carried through to completion, these events lead to the formation of a stable hemostatic plug. [NIH] Pleomorphic: Occurring in various distinct forms. In terms of cells, having variation in the size and shape of cells or their nuclei. [NIH] Plexus: A network or tangle; a general term for a network of lymphatic vessels, nerves, or veins. [EU] Poisoning: A condition or physical state produced by the ingestion, injection or inhalation of, or exposure to a deleterious agent. [NIH] Polygraph: An instrument for making a graphic record of the changes in blood pressure and pulse and respiration rate of someone being questioned under or as if under suspicion of guilt. [NIH] Polymerase: An enzyme which catalyses the synthesis of DNA using a single DNA strand as a template. The polymerase copies the template in the 5'-3'direction provided that sufficient quantities of free nucleotides, dATP and dTTP are present. [NIH] Polymerase Chain Reaction: In vitro method for producing large amounts of specific DNA or RNA fragments of defined length and sequence from small amounts of short oligonucleotide flanking sequences (primers). The essential steps include thermal denaturation of the double-stranded target molecules, annealing of the primers to their complementary sequences, and extension of the annealed primers by enzymatic synthesis with DNA polymerase. The reaction is efficient, specific, and extremely sensitive. Uses for the reaction include disease diagnosis, detection of difficult-to-isolate pathogens, mutation analysis, genetic testing, DNA sequencing, and analyzing evolutionary relationships. [NIH] Polymers: Compounds formed by the joining of smaller, usually repeating, units linked by covalent bonds. These compounds often form large macromolecules (e.g., polypeptides, proteins, plastics). [NIH] Polymorphism: The occurrence together of two or more distinct forms in the same population. [NIH] Polysaccharide: A type of carbohydrate. It contains sugar molecules that are linked together chemically. [NIH] Posterior: Situated in back of, or in the back part of, or affecting the back or dorsal surface of the body. In lower animals, it refers to the caudal end of the body. [EU]

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Postherpetic Neuralgia: Variety of neuralgia associated with migraine in which pain is felt in or behind the eye. [NIH] Postmenopausal: Refers to the time after menopause. Menopause is the time in a woman's life when menstrual periods stop permanently; also called "change of life." [NIH] Postnatal: Occurring after birth, with reference to the newborn. [EU] Postsynaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Post-synaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Post-translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Post-traumatic: Occurring as a result of or after injury. [EU] Post-traumatic stress disorder: A psychological disorder that develops in some individuals after a major traumatic experience such as war, rape, domestic violence, or accident. [NIH] Postural: Pertaining to posture or position. [EU] Potassium: An element that is in the alkali group of metals. It has an atomic symbol K, atomic number 19, and atomic weight 39.10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte and it plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. [NIH] Potassium Channels: Cell membrane glycoproteins selective for potassium ions. [NIH] Potentiate: A degree of synergism which causes the exposure of the organism to a harmful substance to worsen a disease already contracted. [NIH] Potentiation: An overall effect of two drugs taken together which is greater than the sum of the effects of each drug taken alone. [NIH] Practicability: A non-standard characteristic of an analytical procedure. It is dependent on the scope of the method and is determined by requirements such as sample throughout and costs. [NIH] Practice Guidelines: Directions or principles presenting current or future rules of policy for the health care practitioner to assist him in patient care decisions regarding diagnosis, therapy, or related clinical circumstances. The guidelines may be developed by government agencies at any level, institutions, professional societies, governing boards, or by the convening of expert panels. The guidelines form a basis for the evaluation of all aspects of health care and delivery. [NIH] Prazosin: A selective adrenergic alpha-1 antagonist used in the treatment of heart failure, hypertension, pheochromocytoma, Raynaud's syndrome, prostatic hypertrophy, and urinary retention. [NIH] Precursor: Something that precedes. In biological processes, a substance from which another, usually more active or mature substance is formed. In clinical medicine, a sign or symptom that heralds another. [EU] Predisposition: A latent susceptibility to disease which may be activated under certain conditions, as by stress. [EU] Prefrontal Cortex: The rostral part of the frontal lobe, bounded by the inferior precentral fissure in humans, which receives projection fibers from the mediodorsal nucleus of the thalamus. The prefrontal cortex receives afferent fibers from numerous structures of the diencephalon, mesencephalon, and limbic system as well as cortical afferents of visual, auditory, and somatic origin. [NIH] Presbyopia: The normal decreasing elasticity of the crystalline lens that leads to loss of accommodation. [NIH]

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Prescription drug abuse: Using two or more drugs interchangeably in an attempt to counteract the adverse effects of one with the other or to potentiate the effects of one with the other, so that an interdependent habit requiring both is formed. [NIH] Presynaptic: Situated proximal to a synapse, or occurring before the synapse is crossed. [EU] Presynaptic Terminals: The distal terminations of axons which are specialized for the release of neurotransmitters. Also included are varicosities along the course of axons which have similar specializations and also release transmitters. Presynaptic terminals in both the central and peripheral nervous systems are included. [NIH] Prevalence: The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. [NIH] Preventive Health Services: Services designed for promotion of health and prevention of disease. [NIH] Probe: An instrument used in exploring cavities, or in the detection and dilatation of strictures, or in demonstrating the potency of channels; an elongated instrument for exploring or sounding body cavities. [NIH] Problem Solving: A learning situation involving more than one alternative from which a selection is made in order to attain a specific goal. [NIH] Prodrug: A substance that gives rise to a pharmacologically active metabolite, although not itself active (i. e. an inactive precursor). [NIH] Progesterone: Pregn-4-ene-3,20-dione. The principal progestational hormone of the body, secreted by the corpus luteum, adrenal cortex, and placenta. Its chief function is to prepare the uterus for the reception and development of the fertilized ovum. It acts as an antiovulatory agent when administered on days 5-25 of the menstrual cycle. [NIH] Progression: Increase in the size of a tumor or spread of cancer in the body. [NIH] Progressive: Advancing; going forward; going from bad to worse; increasing in scope or severity. [EU] Projection: A defense mechanism, operating unconsciously, whereby that which is emotionally unacceptable in the self is rejected and attributed (projected) to others. [NIH] Prone: Having the front portion of the body downwards. [NIH] Pro-Opiomelanocortin: A precursor protein, MW 30,000, synthesized mainly in the anterior pituitary gland but also found in the hypothalamus, brain, and several peripheral tissues. It incorporates the amino acid sequences of ACTH and beta-lipotropin. These two hormones, in turn, contain the biologically active peptides MSH, corticotropin-like intermediate lobe peptide, alpha-lipotropin, endorphins, and methionine enkephalin. [NIH] Prophase: The first phase of cell division, in which the chromosomes become visible, the nucleus starts to lose its identity, the spindle appears, and the centrioles migrate toward opposite poles. [NIH] Prophylaxis: An attempt to prevent disease. [NIH] Propranolol: A widely used non-cardioselective beta-adrenergic antagonist. Propranolol is used in the treatment or prevention of many disorders including acute myocardial infarction, arrhythmias, angina pectoris, hypertension, hypertensive emergencies, hyperthyroidism, migraine, pheochromocytoma, menopause, and anxiety. [NIH] Prospective study: An epidemiologic study in which a group of individuals (a cohort), all free of a particular disease and varying in their exposure to a possible risk factor, is followed over a specific amount of time to determine the incidence rates of the disease in the exposed

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and unexposed groups. [NIH] Prosthesis: An artificial replacement of a part of the body. [NIH] Prostitution: The practice of indulging in promiscuous sexual relations for money. [NIH] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] Protease Inhibitors: Compounds which inhibit or antagonize biosynthesis or actions of proteases (endopeptidases). [NIH] Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein S: The vitamin K-dependent cofactor of activated protein C. Together with protein C, it inhibits the action of factors VIIIa and Va. A deficiency in protein S can lead to recurrent venous and arterial thrombosis. [NIH] Proteins: Polymers of amino acids linked by peptide bonds. The specific sequence of amino acids determines the shape and function of the protein. [NIH] Proteolytic: 1. Pertaining to, characterized by, or promoting proteolysis. 2. An enzyme that promotes proteolysis (= the splitting of proteins by hydrolysis of the peptide bonds with formation of smaller polypeptides). [EU] Protocol: The detailed plan for a clinical trial that states the trial's rationale, purpose, drug or vaccine dosages, length of study, routes of administration, who may participate, and other aspects of trial design. [NIH] Protons: Stable elementary particles having the smallest known positive charge, found in the nuclei of all elements. The proton mass is less than that of a neutron. A proton is the nucleus of the light hydrogen atom, i.e., the hydrogen ion. [NIH] Proximal: Nearest; closer to any point of reference; opposed to distal. [EU] Psychiatric: Pertaining to or within the purview of psychiatry. [EU] Psychiatry: The medical science that deals with the origin, diagnosis, prevention, and treatment of mental disorders. [NIH] Psychic: Pertaining to the psyche or to the mind; mental. [EU] Psychology: The science dealing with the study of mental processes and behavior in man and animals. [NIH] Psychomotor: Pertaining to motor effects of cerebral or psychic activity. [EU] Psychopathology: The study of significant causes and processes in the development of mental illness. [NIH] Psychosis: A mental disorder characterized by gross impairment in reality testing as evidenced by delusions, hallucinations, markedly incoherent speech, or disorganized and agitated behaviour without apparent awareness on the part of the patient of the incomprehensibility of his behaviour; the term is also used in a more general sense to refer to mental disorders in which mental functioning is sufficiently impaired as to interfere grossly with the patient's capacity to meet the ordinary demands of life. Historically, the term has been applied to many conditions, e.g. manic-depressive psychosis, that were first described in psychotic patients, although many patients with the disorder are not judged psychotic. [EU] Psychotherapy: A generic term for the treatment of mental illness or emotional disturbances primarily by verbal or nonverbal communication. [NIH]

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Psychotomimetic: Psychosis miming. [NIH] Psychotropic: Exerting an effect upon the mind; capable of modifying mental activity; usually applied to drugs that effect the mental state. [EU] Public Health: Branch of medicine concerned with the prevention and control of disease and disability, and the promotion of physical and mental health of the population on the international, national, state, or municipal level. [NIH] Public Opinion: The attitude of a significant portion of a population toward any given proposition, based upon a measurable amount of factual evidence, and involving some degree of reflection, analysis, and reasoning. [NIH] Public Policy: A course or method of action selected, usually by a government, from among alternatives to guide and determine present and future decisions. [NIH] Publishing: "The business or profession of the commercial production and issuance of literature" (Webster's 3d). It includes the publisher, publication processes, editing and editors. Production may be by conventional printing methods or by electronic publishing. [NIH]

Pulmonary: Relating to the lungs. [NIH] Pulmonary Artery: The short wide vessel arising from the conus arteriosus of the right ventricle and conveying unaerated blood to the lungs. [NIH] Pulmonary Embolism: Embolism in the pulmonary artery or one of its branches. [NIH] Pulmonary hypertension: Abnormally high blood pressure in the arteries of the lungs. [NIH] Pulse: The rhythmical expansion and contraction of an artery produced by waves of pressure caused by the ejection of blood from the left ventricle of the heart as it contracts. [NIH]

Purpura: Purplish or brownish red discoloration, easily visible through the epidermis, caused by hemorrhage into the tissues. [NIH] Purulent: Consisting of or containing pus; associated with the formation of or caused by pus. [EU] Putamen: The largest and most lateral of the basal ganglia lying between the lateral medullary lamina of the globus pallidus and the external capsule. It is part of the neostriatum and forms part of the lentiform nucleus along with the globus pallidus. [NIH] Pyogenic: Producing pus; pyopoietic (= liquid inflammation product made up of cells and a thin fluid called liquor puris). [EU] Pyramidal Tracts: Fibers that arise from cells within the cerebral cortex, pass through the medullary pyramid, and descend in the spinal cord. Many authorities say the pyramidal tracts include both the corticospinal and corticobulbar tracts. [NIH] Quality of Life: A generic concept reflecting concern with the modification and enhancement of life attributes, e.g., physical, political, moral and social environment. [NIH] Race: A population within a species which exhibits general similarities within itself, but is both discontinuous and distinct from other populations of that species, though not sufficiently so as to achieve the status of a taxon. [NIH] Radiation: Emission or propagation of electromagnetic energy (waves/rays), or the waves/rays themselves; a stream of electromagnetic particles (electrons, neutrons, protons, alpha particles) or a mixture of these. The most common source is the sun. [NIH] Radioactive: Giving off radiation. [NIH] Radioactivity: The quality of emitting or the emission of corpuscular or electromagnetic radiations consequent to nuclear disintegration, a natural property of all chemical elements

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of atomic number above 83, and possible of induction in all other known elements. [EU] Radioimmunotherapy: Radiotherapy where cytotoxic radionuclides are linked to antibodies in order to deliver toxins directly to tumor targets. Therapy with targeted radiation rather than antibody-targeted toxins (immunotoxins) has the advantage that adjacent tumor cells, which lack the appropriate antigenic determinants, can be destroyed by radiation cross-fire. Radioimmunotherapy is sometimes called targeted radiotherapy, but this latter term can also refer to radionuclides linked to non-immune molecules (radiotherapy). [NIH] Radiolabeled: Any compound that has been joined with a radioactive substance. [NIH] Radiotherapy: The use of ionizing radiation to treat malignant neoplasms and other benign conditions. The most common forms of ionizing radiation used as therapy are x-rays, gamma rays, and electrons. A special form of radiotherapy, targeted radiotherapy, links a cytotoxic radionuclide to a molecule that targets the tumor. When this molecule is an antibody or other immunologic molecule, the technique is called radioimmunotherapy. [NIH] Randomized: Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments. [NIH] Randomized clinical trial: A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best. It is the patient's choice to be in a randomized trial. [NIH] Rape: Unlawful sexual intercourse without consent of the victim. [NIH] Reality Testing: The individual's objective evaluation of the external world and the ability to differentiate adequately between it and the internal world; considered to be a primary ego function. [NIH] Reassurance: A procedure in psychotherapy that seeks to give the client confidence in a favorable outcome. It makes use of suggestion, of the prestige of the therapist. [NIH] Receptor: A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific physiologic effect in the cell. [NIH] Receptors, Adrenergic: Cell-surface proteins that bind epinephrine and/or norepinephrine with high affinity and trigger intracellular changes. The two major classes of adrenergic receptors, alpha and beta, were originally discriminated based on their cellular actions but now are distinguished by their relative affinity for characteristic synthetic ligands. Adrenergic receptors may also be classified according to the subtypes of G-proteins with which they bind; this scheme does not respect the alpha-beta distinction. [NIH] Receptors, Nicotinic: One of the two major classes of cholinergic receptors. Nicotinic receptors were originally distinguished by their preference for nicotine over muscarine. They are generally divided into muscle-type and neuronal-type (previously ganglionic) based on pharmacology, molecular biology, and biophysical properties of the channels. [NIH] Receptors, Serotonin: Cell-surface proteins that bind serotonin and trigger intracellular changes which influence the behavior of cells. Several types of serotonin receptors have been recognized which differ in their pharmacology, molecular biology, and mode of action. [NIH] Recombinant: A cell or an individual with a new combination of genes not found together in either parent; usually applied to linked genes. [EU] Recombination: The formation of new combinations of genes as a result of segregation in crosses between genetically different parents; also the rearrangement of linked genes due to crossing-over. [NIH]

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Rectal: By or having to do with the rectum. The rectum is the last 8 to 10 inches of the large intestine and ends at the anus. [NIH] Rectum: The last 8 to 10 inches of the large intestine. [NIH] Recurrence: The return of a sign, symptom, or disease after a remission. [NIH] Red Nucleus: A pinkish-yellow portion of the midbrain situated in the rostral mesencephalic tegmentum. It receives a large projection from the contralateral half of the cerebellum via the superior cerebellar peduncle and a projection from the ipsilateral motor cortex. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [NIH] Refraction: A test to determine the best eyeglasses or contact lenses to correct a refractive error (myopia, hyperopia, or astigmatism). [NIH] Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of treatment. [NIH] Rehabilitative: Instruction of incapacitated individuals or of those affected with some mental disorder, so that some or all of their lost ability may be regained. [NIH] Relapse: The return of signs and symptoms of cancer after a period of improvement. [NIH] Reliability: Used technically, in a statistical sense, of consistency of a test with itself, i. e. the extent to which we can assume that it will yield the same result if repeated a second time. [NIH]

Remission: A decrease in or disappearance of signs and symptoms of cancer. In partial remission, some, but not all, signs and symptoms of cancer have disappeared. In complete remission, all signs and symptoms of cancer have disappeared, although there still may be cancer in the body. [NIH] Renal failure: Progressive renal insufficiency and uremia, due to irreversible and progressive renal glomerular tubular or interstitial disease. [NIH] Respiration: The act of breathing with the lungs, consisting of inspiration, or the taking into the lungs of the ambient air, and of expiration, or the expelling of the modified air which contains more carbon dioxide than the air taken in (Blakiston's Gould Medical Dictionary, 4th ed.). This does not include tissue respiration (= oxygen consumption) or cell respiration (= cell respiration). [NIH] Respiratory Paralysis: Complete or severe weakness of the muscles of respiration. This condition may be associated with motor neuron diseases; peripheral nerve disorders; neuromuscular junction diseases; spinal cord diseases; injury to the phrenic nerve; and other disorders. [NIH] Respiratory Physiology: Functions and activities of the respiratory tract as a whole or of any of its parts. [NIH] Retinal: 1. Pertaining to the retina. 2. The aldehyde of retinol, derived by the oxidative enzymatic splitting of absorbed dietary carotene, and having vitamin A activity. In the retina, retinal combines with opsins to form visual pigments. One isomer, 11-cis retinal combines with opsin in the rods (scotopsin) to form rhodopsin, or visual purple. Another, all-trans retinal (trans-r.); visual yellow; xanthopsin) results from the bleaching of rhodopsin by light, in which the 11-cis form is converted to the all-trans form. Retinal also combines with opsins in the cones (photopsins) to form the three pigments responsible for colour vision. Called also retinal, and retinene1. [EU] Rheumatism: A group of disorders marked by inflammation or pain in the connective tissue structures of the body. These structures include bone, cartilage, and fat. [NIH]

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Rheumatoid: Resembling rheumatism. [EU] Rheumatoid arthritis: A form of arthritis, the cause of which is unknown, although infection, hypersensitivity, hormone imbalance and psychologic stress have been suggested as possible causes. [NIH] Ribavirin: 1-beta-D-Ribofuranosyl-1H-1,2,4-triazole-3-carboxamide. A nucleoside antimetabolite antiviral agent that blocks nucleic acid synthesis and is used against both RNA and DNA viruses. [NIH] Rigidity: Stiffness or inflexibility, chiefly that which is abnormal or morbid; rigor. [EU] Risk factor: A habit, trait, condition, or genetic alteration that increases a person's chance of developing a disease. [NIH] Risk-Taking: Undertaking a task involving a challenge for achievement or a desirable goal in which there is a lack of certainty or a fear of failure. It may also include the exhibiting of certain behaviors whose outcomes may present a risk to the individual or to those associated with him or her. [NIH] Rod: A reception for vision, located in the retina. [NIH] Role-play: In this method, a conflict is artificially constructed, and the trainee is given a strategic position in it. [NIH] Saline: A solution of salt and water. [NIH] Saliva: The clear, viscous fluid secreted by the salivary glands and mucous glands of the mouth. It contains mucins, water, organic salts, and ptylin. [NIH] Salivary: The duct that convey saliva to the mouth. [NIH] Saponins: Sapogenin glycosides. A type of glycoside widely distributed in plants. Each consists of a sapogenin as the aglycon moiety, and a sugar. The sapogenin may be a steroid or a triterpene and the sugar may be glucose, galactose, a pentose, or a methylpentose. Sapogenins are poisonous towards the lower forms of life and are powerful hemolytics when injected into the blood stream able to dissolve red blood cells at even extreme dilutions. [NIH] Schizoid: Having qualities resembling those found in greater degree in schizophrenics; a person of schizoid personality. [NIH] Schizophrenia: A mental disorder characterized by a special type of disintegration of the personality. [NIH] Schizophrenia, Catatonic: A type of schizophrenia characterized by abnormality of motor behavior which may involve particular forms of stupor, rigidity, excitement or inappropriate posture. [NIH] Schizotypal Personality Disorder: A personality disorder in which there are oddities of thought (magical thinking, paranoid ideation, suspiciousness), perception (illusions, depersonalization), speech (digressive, vague, overelaborate), and behavior (inappropriate affect in social interactions, frequently social isolation) that are not severe enough to characterize schizophrenia. [NIH] Sclerosis: A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. [NIH] Screening: Checking for disease when there are no symptoms. [NIH] Second Messenger Systems: Systems in which an intracellular signal is generated in response to an intercellular primary messenger such as a hormone or neurotransmitter. They are intermediate signals in cellular processes such as metabolism, secretion, contraction, phototransduction, and cell growth. Examples of second messenger systems are

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the adenyl cyclase-cyclic AMP system, the phosphatidylinositol diphosphate-inositol triphosphate system, and the cyclic GMP system. [NIH] Secretion: 1. The process of elaborating a specific product as a result of the activity of a gland; this activity may range from separating a specific substance of the blood to the elaboration of a new chemical substance. 2. Any substance produced by secretion. [EU] Secretory: Secreting; relating to or influencing secretion or the secretions. [NIH] Sedative: 1. Allaying activity and excitement. 2. An agent that allays excitement. [EU] Segregation: The separation in meiotic cell division of homologous chromosome pairs and their contained allelomorphic gene pairs. [NIH] Seizures: Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as epilepsy or "seizure disorder." [NIH] Self-Help Groups: Organizations which provide an environment encouraging social interactions through group activities or individual relationships especially for the purpose of rehabilitating or supporting patients, individuals with common health problems, or the elderly. They include therapeutic social clubs. [NIH] Sella: A deep depression in the shape of a Turkish saddle in the upper surface of the body of the sphenoid bone in the deepest part of which is lodged the hypophysis cerebri. [NIH] Senile: Relating or belonging to old age; characteristic of old age; resulting from infirmity of old age. [NIH] Sensitization: 1. Administration of antigen to induce a primary immune response; priming; immunization. 2. Exposure to allergen that results in the development of hypersensitivity. 3. The coating of erythrocytes with antibody so that they are subject to lysis by complement in the presence of homologous antigen, the first stage of a complement fixation test. [EU] Septal: An abscess occurring at the root of the tooth on the proximal surface. [NIH] Septicemia: Systemic disease associated with the presence and persistence of pathogenic microorganisms or their toxins in the blood. Called also blood poisoning. [EU] Septum: A dividing wall or partition; a general term for such a structure. The term is often used alone to refer to the septal area or to the septum pellucidum. [EU] Septum Pellucidum: A triangular double membrane separating the anterior horns of the lateral ventricles of the brain. It is situated in the median plane and bounded by the corpus callosum and the body and columns of the fornix. [NIH] Sequencing: The determination of the order of nucleotides in a DNA or RNA chain. [NIH] Serotonin: A biochemical messenger and regulator, synthesized from the essential amino acid L-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Multiple receptor families (receptors, serotonin) explain the broad physiological actions and distribution of this biochemical mediator. [NIH] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Sex Characteristics: Those characteristics that distinguish one sex from the other. The primary sex characteristics are the ovaries and testes and their related hormones. Secondary sex characteristics are those which are masculine or feminine but not directly related to reproduction. [NIH]

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Sexual Abstinence: Refraining from sexual intercourse. [NIH] Sexual Harassment: A form of discrimination in the workplace which violates the Civil Rights Act of 1964. Sexual harassment takes two forms: quid pro quo, where the employee must submit to sexual advances in exchange for job benefits or be penalized for refusing; or a hostile environment, where the atmosphere of the workplace is offensive and affects the employee's well-being. Offensive sexual conduct may include unwelcome advances, comments, touching, questions about marital status and sex practices, etc. Both men and women may be aggressors or victims. (Slee and Slee, Health Care Terms, 2d ed, p.404). While civil rights legislation deals with sexual harassment in the workplace, the behavior is not restricted to this; it may take place outside the work environment: in schools and colleges, athletics, and other social milieus and activities. [NIH] Sexual Partners: Married or single individuals who share sexual relations. [NIH] Sexually Transmitted Diseases: Diseases due to or propagated by sexual contact. [NIH] Shame: An emotional attitude excited by realization of a shortcoming or impropriety. [NIH] Shock: The general bodily disturbance following a severe injury; an emotional or moral upset occasioned by some disturbing or unexpected experience; disruption of the circulation, which can upset all body functions: sometimes referred to as circulatory shock. [NIH]

Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU] Signal Transduction: The intercellular or intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GABA-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptormediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. [NIH] Signs and Symptoms: Clinical manifestations that can be either objective when observed by a physician, or subjective when perceived by the patient. [NIH] Skeletal: Having to do with the skeleton (boney part of the body). [NIH] Skeleton: The framework that supports the soft tissues of vertebrate animals and protects many of their internal organs. The skeletons of vertebrates are made of bone and/or cartilage. [NIH] Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH] Sleep Deprivation: The state of being deprived of sleep under experimental conditions, due to life events, or from a wide variety of pathophysiologic causes such as medication effect, chronic illness, psychiatric illness, or sleep disorder. [NIH] Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [NIH]

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Smooth muscle: Muscle that performs automatic tasks, such as constricting blood vessels. [NIH]

Social Environment: The aggregate of social and cultural institutions, forms, patterns, and processes that influence the life of an individual or community. [NIH] Social Problems: Situations affecting a significant number of people, that are believed to be sources of difficulty or threaten the stability of the community, and that require programs of amelioration. [NIH] Social Support: Support systems that provide assistance and encouragement to individuals with physical or emotional disabilities in order that they may better cope. Informal social support is usually provided by friends, relatives, or peers, while formal assistance is provided by churches, groups, etc. [NIH] Social Work: The use of community resources, individual case work, or group work to promote the adaptive capacities of individuals in relation to their social and economic environments. It includes social service agencies. [NIH] Sodium: An element that is a member of the alkali group of metals. It has the atomic symbol Na, atomic number 11, and atomic weight 23. With a valence of 1, it has a strong affinity for oxygen and other nonmetallic elements. Sodium provides the chief cation of the extracellular body fluids. Its salts are the most widely used in medicine. (From Dorland, 27th ed) Physiologically the sodium ion plays a major role in blood pressure regulation, maintenance of fluid volume, and electrolyte balance. [NIH] Solitary Nucleus: Gray matter located in the dorsomedial part of the medulla oblongata associated with the solitary tract. The solitary nucleus receives inputs from most organ systems including the terminations of the facial, glossopharyngeal, and vagus nerves. It is a major coordinator of autonomic nervous system regulation of cardiovascular, respiratory, gustatory, gastrointestinal, and chemoreceptive aspects of homeostasis. The solitary nucleus is also notable for the large number of neurotransmitters which are found therein. [NIH] Solvent: 1. Dissolving; effecting a solution. 2. A liquid that dissolves or that is capable of dissolving; the component of a solution that is present in greater amount. [EU] Somatic: 1. Pertaining to or characteristic of the soma or body. 2. Pertaining to the body wall in contrast to the viscera. [EU] Sound wave: An alteration of properties of an elastic medium, such as pressure, particle displacement, or density, that propagates through the medium, or a superposition of such alterations. [NIH] Spastic: 1. Of the nature of or characterized by spasms. 2. Hypertonic, so that the muscles are stiff and the movements awkward. 3. A person exhibiting spasticity, such as occurs in spastic paralysis or in cerebral palsy. [EU] Spasticity: A state of hypertonicity, or increase over the normal tone of a muscle, with heightened deep tendon reflexes. [EU] Specialist: In medicine, one who concentrates on 1 special branch of medical science. [NIH] Species: A taxonomic category subordinate to a genus (or subgenus) and superior to a subspecies or variety, composed of individuals possessing common characters distinguishing them from other categories of individuals of the same taxonomic level. In taxonomic nomenclature, species are designated by the genus name followed by a Latin or Latinized adjective or noun. [EU] Specificity: Degree of selectivity shown by an antibody with respect to the number and types of antigens with which the antibody combines, as well as with respect to the rates and the extents of these reactions. [NIH]

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Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of a disease. [EU] Spike: The activation of synapses causes changes in the permeability of the dendritic membrane leading to changes in the membrane potential. This difference of the potential travels along the axon of the neuron and is called spike. [NIH] Spinal cord: The main trunk or bundle of nerves running down the spine through holes in the spinal bone (the vertebrae) from the brain to the level of the lower back. [NIH] Spinous: Like a spine or thorn in shape; having spines. [NIH] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Stabilization: The creation of a stable state. [EU] Standard therapy: A currently accepted and widely used treatment for a certain type of cancer, based on the results of past research. [NIH] Steel: A tough, malleable, iron-based alloy containing up to, but no more than, two percent carbon and often other metals. It is used in medicine and dentistry in implants and instrumentation. [NIH] Stereotactic: Radiotherapy that treats brain tumors by using a special frame affixed directly to the patient's cranium. By aiming the X-ray source with respect to the rigid frame, technicians can position the beam extremely precisely during each treatment. [NIH] Sterile: Unable to produce children. [NIH] Sterility: 1. The inability to produce offspring, i.e., the inability to conceive (female s.) or to induce conception (male s.). 2. The state of being aseptic, or free from microorganisms. [EU] Steroid: A group name for lipids that contain a hydrogenated cyclopentanoperhydrophenanthrene ring system. Some of the substances included in this group are progesterone, adrenocortical hormones, the gonadal hormones, cardiac aglycones, bile acids, sterols (such as cholesterol), toad poisons, saponins, and some of the carcinogenic hydrocarbons. [EU] Stimulant: 1. Producing stimulation; especially producing stimulation by causing tension on muscle fibre through the nervous tissue. 2. An agent or remedy that produces stimulation. [EU]

Stimulus: That which can elicit or evoke action (response) in a muscle, nerve, gland or other excitable issue, or cause an augmenting action upon any function or metabolic process. [NIH] Stomach: An organ of digestion situated in the left upper quadrant of the abdomen between the termination of the esophagus and the beginning of the duodenum. [NIH] Stool: The waste matter discharged in a bowel movement; feces. [NIH] Strand: DNA normally exists in the bacterial nucleus in a helix, in which two strands are coiled together. [NIH] Stress: Forcibly exerted influence; pressure. Any condition or situation that causes strain or tension. Stress may be either physical or psychologic, or both. [NIH] Striatum: A higher brain's domain thus called because of its stripes. [NIH] Stroke: Sudden loss of function of part of the brain because of loss of blood flow. Stroke may be caused by a clot (thrombosis) or rupture (hemorrhage) of a blood vessel to the brain. [NIH] Structure-Activity Relationship: The relationship between the chemical structure of a

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compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Other factors contributing to structure-activity relationship include chemical reactivity, electronic effects, resonance, and inductive effects. [NIH] Stupor: Partial or nearly complete unconsciousness, manifested by the subject's responding only to vigorous stimulation. Also, in psychiatry, a disorder marked by reduced responsiveness. [EU] Subacute: Somewhat acute; between acute and chronic. [EU] Subarachnoid: Situated or occurring between the arachnoid and the pia mater. [EU] Subclinical: Without clinical manifestations; said of the early stage(s) of an infection or other disease or abnormality before symptoms and signs become apparent or detectable by clinical examination or laboratory tests, or of a very mild form of an infection or other disease or abnormality. [EU] Subcutaneous: Beneath the skin. [NIH] Subiculum: A region of the hippocampus that projects to other areas of the brain. [NIH] Sublingual: Located beneath the tongue. [EU] Subspecies: A category intermediate in rank between species and variety, based on a smaller number of correlated characters than are used to differentiate species and generally conditioned by geographical and/or ecological occurrence. [NIH] Substance P: An eleven-amino acid neurotransmitter that appears in both the central and peripheral nervous systems. It is involved in transmission of pain, causes rapid contractions of the gastrointestinal smooth muscle, and modulates inflammatory and immune responses. [NIH]

Substrate: A substance upon which an enzyme acts. [EU] Support group: A group of people with similar disease who meet to discuss how better to cope with their cancer and treatment. [NIH] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [NIH] Supraspinal: Above the spinal column or any spine. [NIH] Sweat: The fluid excreted by the sweat glands. It consists of water containing sodium chloride, phosphate, urea, ammonia, and other waste products. [NIH] Sympathetic Nervous System: The thoracolumbar division of the autonomic nervous system. Sympathetic preganglionic fibers originate in neurons of the intermediolateral column of the spinal cord and project to the paravertebral and prevertebral ganglia, which in turn project to target organs. The sympathetic nervous system mediates the body's response to stressful situations, i.e., the fight or flight reactions. It often acts reciprocally to the parasympathetic system. [NIH] Sympathomimetic: 1. Mimicking the effects of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. 2. An agent that produces effects similar to those of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. Called also adrenergic. [EU] Symptomatic: Having to do with symptoms, which are signs of a condition or disease. [NIH] Symptomatic treatment: Therapy that eases symptoms without addressing the cause of disease. [NIH] Symptomatology: 1. That branch of medicine with treats of symptoms; the systematic

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discussion of symptoms. 2. The combined symptoms of a disease. [EU] Synapses: Specialized junctions at which a neuron communicates with a target cell. At classical synapses, a neuron's presynaptic terminal releases a chemical transmitter stored in synaptic vesicles which diffuses across a narrow synaptic cleft and activates receptors on the postsynaptic membrane of the target cell. The target may be a dendrite, cell body, or axon of another neuron, or a specialized region of a muscle or secretory cell. Neurons may also communicate through direct electrical connections which are sometimes called electrical synapses; these are not included here but rather in gap junctions. [NIH] Synapsis: The pairing between homologous chromosomes of maternal and paternal origin during the prophase of meiosis, leading to the formation of gametes. [NIH] Synaptic: Pertaining to or affecting a synapse (= site of functional apposition between neurons, at which an impulse is transmitted from one neuron to another by electrical or chemical means); pertaining to synapsis (= pairing off in point-for-point association of homologous chromosomes from the male and female pronuclei during the early prophase of meiosis). [EU] Synaptic Transmission: The communication from a neuron to a target (neuron, muscle, or secretory cell) across a synapse. In chemical synaptic transmission, the presynaptic neuron releases a neurotransmitter that diffuses across the synaptic cleft and binds to specific synaptic receptors. These activated receptors modulate ion channels and/or secondmessenger systems to influence the postsynaptic cell. Electrical transmission is less common in the nervous system, and, as in other tissues, is mediated by gap junctions. [NIH] Synaptic Vesicles: Membrane-bound compartments which contain transmitter molecules. Synaptic vesicles are concentrated at presynaptic terminals. They actively sequester transmitter molecules from the cytoplasm. In at least some synapses, transmitter release occurs by fusion of these vesicles with the presynaptic membrane, followed by exocytosis of their contents. [NIH] Synergistic: Acting together; enhancing the effect of another force or agent. [EU] Systemic: Affecting the entire body. [NIH] Systolic: Indicating the maximum arterial pressure during contraction of the left ventricle of the heart. [EU] Tardive: Marked by lateness, late; said of a disease in which the characteristic lesion is late in appearing. [EU] Telencephalon: Paired anteriolateral evaginations of the prosencephalon plus the lamina terminalis. The cerebral hemispheres are derived from it. Many authors consider cerebrum a synonymous term to telencephalon, though a minority include diencephalon as part of the cerebrum (Anthoney, 1994). [NIH] Temporal: One of the two irregular bones forming part of the lateral surfaces and base of the skull, and containing the organs of hearing. [NIH] Temporal Lobe: Lower lateral part of the cerebral hemisphere. [NIH] Terminator: A DNA sequence sited at the end of a transcriptional unit that signals the end of transcription. [NIH] Testis: Either of the paired male reproductive glands that produce the male germ cells and the male hormones. [NIH] Tetracycline: An antibiotic originally produced by Streptomyces viridifaciens, but used mostly in synthetic form. It is an inhibitor of aminoacyl-tRNA binding during protein synthesis. [NIH]

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Tetrahydrocannabinol: A psychoactive compound extracted from the resin of Cannabis sativa (marihuana, hashish). The isomer delta-9-tetrahydrocannabinol (THC) is considered the most active form, producing characteristic mood and perceptual changes associated with this compound. Dronabinol is a synthetic form of delta-9-THC. [NIH] Thalamus: Paired bodies containing mostly gray substance and forming part of the lateral wall of the third ventricle of the brain. The thalamus represents the major portion of the diencephalon and is commonly divided into cellular aggregates known as nuclear groups. [NIH]

Therapeutic Community: Psychotherapeutic technique which emphasizes socioenvironmental and interpersonal influences in the resocialization and rehabilitation of the patient. The setting is usually a hospital unit or ward in which professional and nonprofessional staff interact with the patients. [NIH] Therapeutics: The branch of medicine which is concerned with the treatment of diseases, palliative or curative. [NIH] Thermal: Pertaining to or characterized by heat. [EU] Thiamine: 3-((4-Amino-2-methyl-5-pyrimidinyl)methyl)-5-(2methylthiazolium chloride. [NIH]

hydroxyethyl)-4-

Thoracic: Having to do with the chest. [NIH] Threshold: For a specified sensory modality (e. g. light, sound, vibration), the lowest level (absolute threshold) or smallest difference (difference threshold, difference limen) or intensity of the stimulus discernible in prescribed conditions of stimulation. [NIH] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin. (Dorland, 27th ed) EC 3.4.21.5. [NIH] Thrombomodulin: A cell surface glycoprotein of endothelial cells that binds thrombin and serves as a cofactor in the activation of protein C and its regulation of blood coagulation. [NIH]

Thrombosis: The formation or presence of a blood clot inside a blood vessel. [NIH] Thymus: An organ that is part of the lymphatic system, in which T lymphocytes grow and multiply. The thymus is in the chest behind the breastbone. [NIH] Thyroid: A gland located near the windpipe (trachea) that produces thyroid hormone, which helps regulate growth and metabolism. [NIH] Thyroxine: An amino acid of the thyroid gland which exerts a stimulating effect on thyroid metabolism. [NIH] Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [NIH] Token Economy: A practice whereby tokens representing money, toys, candy, etc., are given as secondary reinforcers contingent upon certain desired behaviors or performances. [NIH] Tolerance: 1. The ability to endure unusually large doses of a drug or toxin. 2. Acquired drug tolerance; a decreasing response to repeated constant doses of a drug or the need for increasing doses to maintain a constant response. [EU] Tomography: Imaging methods that result in sharp images of objects located on a chosen plane and blurred images located above or below the plane. [NIH] Tonicity: The normal state of muscular tension. [NIH] Tooth Preparation: Procedures carried out with regard to the teeth or tooth structures preparatory to specified dental therapeutic and surgical measures. [NIH] Topical: On the surface of the body. [NIH]

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Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Toxicology: The science concerned with the detection, chemical composition, and pharmacologic action of toxic substances or poisons and the treatment and prevention of toxic manifestations. [NIH] Toxins: Specific, characterizable, poisonous chemicals, often proteins, with specific biological properties, including immunogenicity, produced by microbes, higher plants, or animals. [NIH] Trace element: Substance or element essential to plant or animal life, but present in extremely small amounts. [NIH] Traction: The act of pulling. [NIH] Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. [NIH] Transdermal: Entering through the dermis, or skin, as in administration of a drug applied to the skin in ointment or patch form. [EU] Transduction: The transfer of genes from one cell to another by means of a viral (in the case of bacteria, a bacteriophage) vector or a vector which is similar to a virus particle (pseudovirion). [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH] Transfer Factor: Factor derived from leukocyte lysates of immune donors which can transfer both local and systemic cellular immunity to nonimmune recipients. [NIH] Transfusion: The infusion of components of blood or whole blood into the bloodstream. The blood may be donated from another person, or it may have been taken from the person earlier and stored until needed. [NIH] Translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Transmitter: A chemical substance which effects the passage of nerve impulses from one cell to the other at the synapse. [NIH] Transplantation: Transference of a tissue or organ, alive or dead, within an individual, between individuals of the same species, or between individuals of different species. [NIH] Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH] Treatment Outcome: Evaluation undertaken to assess the results or consequences of management and procedures used in combating disease in order to determine the efficacy, effectiveness, safety, practicability, etc., of these interventions in individual cases or series. [NIH]

Triad: Trivalent. [NIH] Tricuspid Atresia: Absence of the orifice between the right atrium and ventricle, with the presence of an atrial defect through which all the systemic venous return reaches the left heart. As a result, there is left ventricular hypertrophy because the right ventricle is absent or not functional. [NIH] Tricuspid Valve: The valve consisting of three cusps situated between the right atrium and right ventricle of the heart. [NIH]

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Trigger zone: Dolorogenic zone (= producing or causing pain). [EU] Trophoblast: The outer layer of cells of the blastocyst which works its way into the endometrium during ovum implantation and grows rapidly, later combining with mesoderm. [NIH] Tryptophan: An essential amino acid that is necessary for normal growth in infants and for nitrogen balance in adults. It is a precursor serotonin and niacin. [NIH] Tubercle: A rounded elevation on a bone or other structure. [NIH] Tuberculosis: Any of the infectious diseases of man and other animals caused by species of Mycobacterium. [NIH] Tyrosine: A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine, thyroid hormones, and melanin. [NIH] Ubiquitin: A highly conserved 76 amino acid-protein found in all eukaryotic cells. [NIH] Ulcer: A localized necrotic lesion of the skin or a mucous surface. [NIH] Unconscious: Experience which was once conscious, but was subsequently rejected, as the "personal unconscious". [NIH] Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [NIH]

Urinary: Having to do with urine or the organs of the body that produce and get rid of urine. [NIH] Urinary Retention: Inability to urinate. The etiology of this disorder includes obstructive, neurogenic, pharmacologic, and psychogenic causes. [NIH] Urine: Fluid containing water and waste products. Urine is made by the kidneys, stored in the bladder, and leaves the body through the urethra. [NIH] Urine Testing: Checking urine to see if it contains glucose (sugar) and ketones. Special strips of paper or tablets (called reagents) are put into a small amount of urine or urine plus water. Changes in the color of the strip show the amount of glucose or ketones in the urine. Urine testing is the only way to check for the presence of ketones, a sign of serious illness. However, urine testing is less desirable then blood testing for monitoring the level of glucose in the body. [NIH] Vaccine: A substance or group of substances meant to cause the immune system to respond to a tumor or to microorganisms, such as bacteria or viruses. [NIH] Varicose: The common ulcer in the lower third of the leg or near the ankle. [NIH] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vasculitis: Inflammation of a blood vessel. [NIH] Vasoconstriction: Narrowing of the blood vessels without anatomic change, for which constriction, pathologic is used. [NIH] Vasodilation: Physiological dilation of the blood vessels without anatomic change. For dilation with anatomic change, dilatation, pathologic or aneurysm (or specific aneurysm) is used. [NIH] Vasodilator: An agent that widens blood vessels. [NIH] VE: The total volume of gas either inspired or expired in one minute. [NIH] Vector: Plasmid or other self-replicating DNA molecule that transfers DNA between cells in nature or in recombinant DNA technology. [NIH] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH]

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Venlafaxine: An antidepressant drug that is being evaluated for the treatment of hot flashes in women who have breast cancer. [NIH] Venous: Of or pertaining to the veins. [EU] Ventilation: 1. In respiratory physiology, the process of exchange of air between the lungs and the ambient air. Pulmonary ventilation (usually measured in litres per minute) refers to the total exchange, whereas alveolar ventilation refers to the effective ventilation of the alveoli, in which gas exchange with the blood takes place. 2. In psychiatry, verbalization of one's emotional problems. [EU] Ventral: 1. Pertaining to the belly or to any venter. 2. Denoting a position more toward the belly surface than some other object of reference; same as anterior in human anatomy. [EU] Ventral Tegmental Area: A region in the mesencephalon which is dorsomedial to the substantia nigra and ventral to the red nucleus. The mesocortical and mesolimbic dopaminergic systems originate here, including an important projection to the nucleus accumbens. Overactivity of the cells in this area has been suspected to contribute to the positive symptoms of schizophrenia. [NIH] Ventricle: One of the two pumping chambers of the heart. The right ventricle receives oxygen-poor blood from the right atrium and pumps it to the lungs through the pulmonary artery. The left ventricle receives oxygen-rich blood from the left atrium and pumps it to the body through the aorta. [NIH] Ventricular: Pertaining to a ventricle. [EU] Vertebrae: A bony unit of the segmented spinal column. [NIH] Vertebral: Of or pertaining to a vertebra. [EU] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] Viral Hepatitis: Hepatitis caused by a virus. Five different viruses (A, B, C, D, and E) most commonly cause this form of hepatitis. Other rare viruses may also cause hepatitis. [NIH] Viral Load: The quantity of measurable virus in the blood. Change in viral load, measured in plasma, is used as a surrogate marker in HIV disease progression. [NIH] Viremia: The presence of viruses in the blood. [NIH] Virulence: The degree of pathogenicity within a group or species of microorganisms or viruses as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. [NIH] Virus: Submicroscopic organism that causes infectious disease. In cancer therapy, some viruses may be made into vaccines that help the body build an immune response to, and kill, tumor cells. [NIH] Visceral: , from viscus a viscus) pertaining to a viscus. [EU] Visceral Afferents: The sensory fibers innervating the viscera. [NIH] Vitro: Descriptive of an event or enzyme reaction under experimental investigation occurring outside a living organism. Parts of an organism or microorganism are used together with artificial substrates and/or conditions. [NIH] Vivo: Outside of or removed from the body of a living organism. [NIH] Volition: Voluntary activity without external compulsion. [NIH] Wakefulness: A state in which there is an enhanced potential for sensitivity and an efficient responsiveness to external stimuli. [NIH]

Dictionary 255

War: Hostile conflict between organized groups of people. [NIH] White blood cell: A type of cell in the immune system that helps the body fight infection and disease. White blood cells include lymphocytes, granulocytes, macrophages, and others. [NIH]

Withdrawal: 1. A pathological retreat from interpersonal contact and social involvement, as may occur in schizophrenia, depression, or schizoid avoidant and schizotypal personality disorders. 2. (DSM III-R) A substance-specific organic brain syndrome that follows the cessation of use or reduction in intake of a psychoactive substance that had been regularly used to induce a state of intoxication. [EU] Xenograft: The cells of one species transplanted to another species. [NIH] X-ray: High-energy radiation used in low doses to diagnose diseases and in high doses to treat cancer. [NIH] Yeasts: A general term for single-celled rounded fungi that reproduce by budding. Brewers' and bakers' yeasts are Saccharomyces cerevisiae; therapeutic dried yeast is dried yeast. [NIH] Zidovudine: A dideoxynucleoside compound in which the 3'-hydroxy group on the sugar moiety has been replaced by an azido group. This modification prevents the formation of phosphodiester linkages which are needed for the completion of nucleic acid chains. The compound is a potent inhibitor of HIV replication, acting as a chain-terminator of viral DNA during reverse transcription. It improves immunologic function, partially reverses the HIVinduced neurological dysfunction, and improves certain other clinical abnormalities associated with AIDS. Its principal toxic effect is dose-dependent suppression of bone marrow, resulting in anemia and leukopenia. [NIH] Zymogen: Inactive form of an enzyme which can then be converted to the active form, usually by excision of a polypeptide, e. g. trypsinogen is the zymogen of trypsin. [NIH]

257

INDEX A Abdominal, 70, 189, 223, 234 Abdominal Pain, 189, 223 Abscess, 97, 189, 245 Accidents, Radiation, 93, 189 Accommodation, 189, 238 Acetaldehyde, 126, 133, 152, 189, 209 Acetylcholine, 17, 189, 201, 231 Adaptability, 189, 199, 200 Adaptation, 33, 49, 189, 237 Adjustment, 189 Adolescence, 29, 100, 132, 189 Adrenal Cortex, 189, 205, 206, 213, 219, 239 Adrenal Medulla, 189, 199, 213, 232 Adrenergic, 147, 189, 193, 209, 213, 229, 236, 238, 239, 242, 249 Adverse Effect, 25, 146, 148, 190, 239, 246 Afferent, 31, 190, 238 Affinity, 22, 27, 47, 54, 128, 134, 140, 141, 145, 150, 190, 194, 225, 242, 247 Agonist, 47, 53, 58, 65, 127, 143, 147, 148, 190, 195, 198, 209, 226, 229, 231 Akathisia, 190, 193 Albumin, 5, 190, 237 Aldehyde Dehydrogenase, 190, 209 Algorithms, 190, 197 Alimentary, 190, 234 Alkaline, 190, 198 Alkaloid, 190, 196, 198, 202, 225, 229, 231, 234 Allergen, 190, 208, 245 Alpha Particles, 190, 241 Alpha-1, 190, 238 Alternative medicine, 167, 191 Alveoli, 191, 254 Amantadine, 40, 191, 227 Amenorrhea, 191, 192 Amino Acid Sequence, 191, 192, 196, 239 Amino Acids, 191, 196, 213, 231, 235, 240 Amphetamine, 14, 27, 48, 51, 57, 70, 178, 191, 208 Ampulla, 191, 212 Amygdala, 16, 19, 24, 34, 39, 52, 59, 81, 87, 106, 191, 195, 225 Anaesthesia, 70, 191, 221 Anaesthetic, 147, 191 Anal, 163, 191, 214, 225

Analgesic, 54, 66, 128, 132, 147, 149, 151, 191, 198, 202, 208, 212, 220, 226, 229, 233 Analog, 27, 128, 191 Analogous, 191, 210, 252 Anaphylatoxins, 191, 203 Anatomical, 14, 21, 41, 45, 192, 194, 204, 221, 244 Androgens, 189, 192, 205 Anemia, 192, 218, 255 Anesthesia, 105, 131, 132, 192 Anesthetics, 143, 192, 195, 213 Aneurysm, 102, 192, 215, 253 Angina, 192, 223, 239 Angina Pectoris, 192, 223, 239 Animal model, 7, 20, 23, 37, 39, 48, 54, 62, 66, 145, 192 Anions, 190, 192, 223 Ankle, 192, 253 Annealing, 192, 237 Anorexia, 122, 124, 134, 135, 136, 139, 140, 141, 150, 192, 233 Anorexia Nervosa, 134, 135, 136, 139, 192 Antagonism, 137, 145, 192 Antiallergic, 192, 205 Antibacterial, 192, 248 Antibiotic, 192, 215, 234, 248, 250 Antibodies, 4, 28, 62, 87, 144, 164, 192, 193, 218, 219, 221, 226, 237, 242 Antibody, 62, 144, 154, 162, 163, 190, 192, 193, 203, 218, 219, 221, 222, 227, 242, 245, 247 Anticoagulant, 193, 240 Antidepressant, 26, 138, 140, 141, 145, 193, 198, 254 Antiemetic, 193 Antigen, 4, 190, 192, 193, 203, 219, 220, 221, 222, 227, 245 Antigen-Antibody Complex, 193, 203 Antihypertensive, 148, 193 Anti-inflammatory, 193, 205, 217 Anti-Inflammatory Agents, 193, 205 Antimetabolite, 193, 244 Antimicrobial, 73, 193 Antineoplastic, 193, 205 Antipsychotic, 137, 193, 230 Antiserum, 128, 193 Antispasmodic, 194, 233 Antitussive, 194, 233

258 Drug Addiction

Antiviral, 191, 194, 222, 244 Anus, 191, 194, 243 Anxiety, 16, 101, 122, 123, 134, 136, 137, 138, 139, 141, 145, 149, 150, 190, 194, 234, 239 Anxiety Disorders, 145, 194, 234 Aorta, 194, 254 Apathy, 132, 194, 230 Aqueous, 132, 194, 195, 211, 224 Aromatic, 150, 194, 236 Arrhythmia, 150, 194 Arterial, 70, 87, 194, 198, 200, 205, 220, 223, 240, 250 Arteries, 194, 197, 200, 205, 228, 229, 241 Arteriovenous, 194, 200 Assay, 15, 27, 194 Astrocytes, 194, 228 Atrial, 194, 205, 252 Atrioventricular, 194, 205 Atrium, 194, 205, 252, 254 Atrophy, 194, 230 Attenuated, 27, 194 Atypical, 131, 132, 194 Auditory, 132, 194, 218, 238 Autonomic, 86, 130, 135, 136, 139, 189, 193, 194, 195, 215, 231, 232, 235, 247, 249 Autonomic Nervous System, 130, 194, 235, 247, 249 Autonomic Neuropathy, 86, 195 Autopsy, 90, 195 Autoradiography, 14, 195 Autoreceptors, 138, 195 Autosuggestion, 195, 220 Axilla, 195, 198 Axonal, 31, 195 Axons, 29, 195, 207, 230, 239 B Baclofen, 65, 195 Bacteremia, 195, 197 Bacteria, 192, 193, 195, 207, 214, 228, 248, 252, 253 Bacterial Physiology, 189, 195 Bactericidal, 195, 213 Bacteriophage, 195, 252 Barbiturate, 158, 195 Basal Ganglia, 43, 193, 195, 201, 225, 232, 241 Basal Ganglia Diseases, 195, 201 Base, 129, 147, 195, 207, 213, 224, 250 Behavior Therapy, 81, 196 Benign, 196, 218, 230, 242 Benzene, 196

Benzodiazepines, 15, 196 Beta-Endorphin, 47, 196 Bicuculline, 28, 196 Bile, 196, 215, 225, 248 Bilirubin, 190, 196 Bioavailability, 48, 196 Biochemical, 32, 35, 39, 41, 66, 70, 136, 140, 193, 196, 224, 245 Biological Factors, 47, 196 Biological response modifier, 196, 222 Biological therapy, 196, 217 Biomolecular, 21, 61, 196 Biopsy, 159, 196 Biosynthesis, 35, 196, 240 Biotechnology, 66, 67, 157, 167, 173, 196 Biotransformation, 11, 197, 235 Bipolar Disorder, 122, 123, 137, 145, 197 Bladder, 195, 197, 221, 253 Blastocyst, 46, 197, 204, 236, 253 Bloating, 197, 216, 223 Blood Cell Count, 197, 218 Blood Coagulation, 197, 198, 251 Blood Glucose, 5, 56, 197, 222 Blood Platelets, 197, 245 Blood pressure, 131, 193, 197, 199, 201, 215, 220, 224, 228, 237, 241, 247 Blood transfusion, 159, 197 Blood vessel, 197, 199, 200, 204, 205, 212, 214, 217, 223, 226, 235, 247, 248, 251, 253 Blood-Borne Pathogens, 6, 197 Blood-Brain Barrier, 123, 132, 197, 226 Blushing, 131, 197 Body Fluids, 197, 210, 215, 232, 247 Bone Marrow, 196, 197, 221, 225, 255 Bowel, 54, 191, 198, 208, 222, 223, 248 Brachial, 102, 198 Brachial Plexus, 102, 198 Bradycardia, 148, 198 Bradykinin, 198, 237 Brain Ischemia, 198, 200 Brain Stem, 198, 200 Branch, 185, 198, 211, 226, 234, 235, 241, 247, 249, 251 Buccopharyngeal, 4, 198 Bulimia, 124, 141, 198 Buprenorphine, 48, 50, 132, 198 Bupropion, 26, 198 C Calcium, 17, 35, 43, 58, 126, 198, 203, 223, 233, 234, 246 Calmodulin, 28, 198 Cannabidiol, 198, 199

Index 259

Cannabinoids, 31, 54, 198 Cannabinol, 199 Capillary, 198, 199, 217 Capsules, 199, 210, 217 Carbohydrate, 199, 205, 217, 237 Carbon Dioxide, 199, 214, 216, 236, 243 Carcinogenic, 196, 199, 222, 248 Cardiac, 75, 143, 199, 205, 211, 212, 213, 223, 229, 248 Cardioselective, 199, 239 Cardiovascular, 12, 85, 97, 124, 134, 135, 136, 150, 191, 195, 199, 245, 247 Cardiovascular disease, 12, 199 Cardiovascular System, 195, 199 Carrier Proteins, 199, 237 Catecholamine, 199, 209, 235 Catheters, 17, 65, 130, 199, 215 Caudal, 30, 199, 208, 220, 232, 237 Caudate Nucleus, 195, 199, 230, 232 Cell Cycle, 199, 206 Cell Death, 35, 199, 230 Cell Differentiation, 199, 246 Cell Division, 195, 199, 200, 217, 227, 236, 239, 245 Cell membrane, 199, 200, 208, 211, 216, 236, 238 Cell proliferation, 200, 246 Cell Respiration, 200, 243 Cell Survival, 200, 217 Cellobiose, 200 Cellulose, 5, 200, 236 Central Nervous System, 14, 21, 27, 50, 122, 134, 135, 136, 138, 139, 147, 149, 150, 189, 191, 194, 196, 200, 202, 208, 210, 215, 218, 227, 229, 232, 245 Central Nervous System Infections, 200, 218 Centrifugation, 200, 218 Cerebellum, 200, 243 Cerebral, 123, 141, 195, 197, 198, 200, 201, 205, 207, 213, 214, 215, 234, 240, 241, 247, 250 Cerebral Infarction, 200 Cerebrospinal, 145, 200 Cerebrospinal fluid, 145, 200 Cerebrovascular, 135, 150, 195, 199, 200 Cerebrovascular Disorders, 150, 200 Cerebrum, 200, 201, 250 Cervical, 198, 201 Character, 192, 201, 206 Chemoreceptor, 193, 201 Chemotactic Factors, 201, 203

Chemotherapy, 4, 91, 201 Child Custody, 154, 201 Child Welfare, 79, 201 Cholesterol, 196, 201, 205, 248 Cholinergic, 17, 193, 201, 225, 231, 242 Chorea, 123, 193, 201 Choreatic Disorders, 201 Chromosome, 201, 225, 245 Chronic Disease, 159, 201, 202 Circadian, 7, 201 Civil Rights, 201, 246 Clamp, 17, 57, 201 Clinical Medicine, 201, 238 Clinical trial, 7, 38, 40, 42, 43, 53, 62, 173, 201, 204, 205, 240, 242 Cloning, 22, 35, 123, 196, 202 Coagulation, 197, 202, 218, 237 Coca, 202 Codeine, 132, 202, 233 Coenzymes, 202, 231 Cofactor, 61, 202, 240, 251 Cognition, 40, 51, 123, 134, 138, 147, 202, 230 Colitis, 202, 222, 223 Collagen, 202, 219 Collagen disease, 202, 219 Collapse, 131, 202 Colloidal, 190, 202, 211 Combination Therapy, 159, 202 Combinatorial, 22, 202 Communication Disorders, 5, 172, 202 Community Health Services, 24, 203 Comorbidity, 29, 42, 61, 203 Compacta, 16, 43, 203 Complement, 22, 40, 54, 63, 66, 191, 203, 216, 237, 245 Complementary and alternative medicine, 113, 115, 203 Complementary medicine, 113, 203 Compulsion, 58, 148, 203, 254 Compulsive Behavior, 124, 154, 203 Computational Biology, 173, 203 Computer Graphics, 64, 204 Computer Simulation, 30, 204 Conception, 204, 214, 248 Concomitant, 51, 58, 204 Conditioned stimulus, 18, 204 Condoms, 155, 162, 163, 204 Conduction, 30, 204 Confusion, 197, 204, 209, 220, 230 Congestion, 193, 204, 206 Conjugated, 204, 206

260 Drug Addiction

Consciousness, 191, 204, 207, 209 Constipation, 150, 151, 193, 204, 223 Constitutional, 204, 229 Constriction, 56, 204, 223, 253 Constriction, Pathologic, 204, 253 Consultation, 57, 157, 204 Consumption, 12, 204, 208, 233 Contamination, 197, 204, 232 Continuous infusion, 16, 204 Continuum, 164, 168, 204 Contraindications, ii, 3, 204 Control group, 40, 204 Controlled study, 79, 94, 205 Convulsions, 195, 196, 205, 220, 231 Coordination, 40, 200, 205 Cor, 24, 102, 106, 135, 136, 139, 144, 145, 205, 239 Corneum, 205, 213 Coronary, 132, 192, 199, 205, 228, 229 Coronary heart disease, 199, 205 Coronary Thrombosis, 205, 228, 229 Cortex, 27, 30, 48, 49, 59, 99, 205, 212, 213, 214, 233, 238, 241, 243 Cortical, 31, 59, 149, 205, 213, 238, 245 Corticosteroid, 25, 205 Corticotropin-Releasing Hormone, 145, 205 Cortisol, 25, 56, 190, 206 Cranial, 200, 206, 218, 235 Craniocerebral Trauma, 195, 206, 218 Crossing-over, 206, 242 Cues, 18, 26, 41, 58, 64, 127, 147, 206 Curative, 206, 231, 251 Cutaneous, 77, 130, 206 Cyclic, 198, 206, 245 Cyclin, 61, 206 Cytochrome, 56, 206 Cytokine, 19, 206 Cytotoxic, 206, 242, 246 D Data Collection, 206, 215 Databases, Bibliographic, 173, 206 Decision Making, 39, 57, 163, 206 Decongestant, 206, 229 Degenerative, 36, 156, 206, 219, 229 Deletion, 62, 207 Delirium, 36, 193, 207 Delusion, 132, 207 Dementia, 130, 135, 136, 150, 193, 207 Denaturation, 207, 237 Dendrites, 18, 207, 231 Dendritic, 31, 57, 207, 248

Density, 32, 200, 207, 232, 247 Dental Care, 79, 207 Dental Caries, 207, 215 Dental Waste, 197, 207 Dentate Gyrus, 207, 219 Depersonalization, 207, 234, 244 Depolarization, 207, 246 Deprivation, 38, 208 Derealization, 207, 208, 234 Desensitization, 22, 58, 138, 208 Detoxification, 41, 59, 147, 208 Deuterium, 208, 220 Developed Countries, 130, 208 Developing Countries, 130, 208 Dexmedetomidine, 208, 226 Dextroamphetamine, 37, 191, 208, 227 Diabetes Mellitus, 141, 150, 208, 217 Diagnostic procedure, 121, 167, 208 Dialyzer, 208, 218 Diaphoresis, 130, 208 Diarrhea, 127, 143, 147, 208, 223 Diastolic, 208, 220 Diencephalon, 200, 208, 220, 238, 250, 251 Digestion, 190, 196, 198, 208, 216, 223, 225, 248 Digestive system, 208, 216 Digestive tract, 195, 208, 246 Dilatation, 192, 208, 239, 253 Dimethyl, 143, 209, 223 Direct, iii, 10, 16, 42, 46, 201, 209, 234, 243, 250 Discrimination, 15, 27, 127, 201, 209, 246 Disease Progression, 162, 209, 254 Disinfectant, 209, 213 Disorientation, 204, 207, 209 Disparity, 94, 209 Disposition, 11, 52, 56, 209 Dissociation, 190, 209 Distal, 57, 195, 209, 211, 239, 240 Disulfiram, 40, 126, 133, 152, 209 Diuresis, 151, 209 Dizziness, 209, 234 Domestic Violence, 57, 209, 238 Dopamine Agonists, 106, 137, 209 Dorsal, 125, 210, 237 Dorsum, 210 Dosage Forms, 48, 210 Dose-dependent, 210, 255 Drive, ii, vi, 4, 58, 109, 210 Drug Delivery Systems, 48, 210 Drug Design, 54, 210 Drug Interactions, 210

Index 261

Drug Resistance, 210 Drug Tolerance, 45, 128, 210, 251 Duct, 191, 210, 244 Duodenum, 196, 210, 212, 216, 248 Dynorphins, 210, 232 Dyskinesia, 141, 150, 193, 210 Dyspnea, 210, 234 Dystonia, 85, 193, 210 E Eating Disorders, 60, 126, 139, 141, 150, 156, 210 Ectopic, 125, 211 Edema, 127, 143, 211, 224 Effector, 33, 189, 203, 211, 231 Effector cell, 211, 231 Efficacy, 8, 12, 15, 22, 26, 31, 32, 58, 59, 62, 65, 122, 137, 210, 211, 252 Elasticity, 211, 238 Elective, 211 Electrode, 25, 211 Electroencephalography, 131, 211, 226 Electrolyte, 205, 207, 211, 215, 228, 232, 238, 247 Electrons, 196, 211, 223, 233, 241, 242 Electrophoresis, 7, 211 Electrophysiological, 20, 25, 48, 57, 135, 136, 139, 211 Electroporation, 47, 211 Embryo, 197, 199, 211, 221, 227, 229, 232 Empirical, 32, 56, 211 Emulsion, 195, 211, 215 Encapsulated, 122, 212 Endocarditis, 84, 85, 88, 212 Endocardium, 212 Endocrine System, 212, 230 Endopeptidases, 212, 240 Endorphin, 35, 196, 212 Endoscope, 212 Endoscopic, 18, 212 Endothelial cell, 197, 212, 251 Endotoxins, 203, 212 End-stage renal, 4, 212 Enhancers, 147, 212 Enkephalin, 31, 84, 196, 212, 239 Entorhinal Cortex, 30, 212, 219 Environmental Health, 172, 174, 212 Enzymatic, 198, 203, 207, 212, 219, 237, 243 Enzyme, 190, 202, 210, 211, 212, 227, 228, 237, 240, 246, 249, 251, 254, 255 Enzyme Inhibitors, 212, 237 Epidemic, 60, 144, 156, 212, 248 Epidemiological, 84, 96, 213

Epidermis, 125, 205, 213, 219, 241 Epinephrine, 189, 209, 213, 232, 242, 253 Erythrocytes, 192, 197, 213, 245 Escalation, 17, 34, 45, 52, 213 Esophagus, 208, 213, 216, 236, 248 Estradiol, 65, 213 Estrogen, 65, 213 Ethanol, 18, 126, 137, 213 Ethnic Groups, 47, 213 Eukaryotic Cells, 213, 253 Euphoria, 37, 131, 213 Evacuation, 204, 213, 216 Evoke, 213, 248 Excipients, 48, 213 Excitability, 17, 47, 213, 229 Excitation, 30, 49, 201, 213 Excitatory, 16, 28, 41, 195, 213, 217, 231 Excitatory Amino Acids, 213, 231 Exhaustion, 192, 214 Exogenous, 14, 197, 214, 216 Expiration, 214, 243 Extracellular, 14, 32, 57, 63, 194, 214, 228, 247 Extracellular Space, 14, 57, 214, 228 Extraction, 124, 214 Extrapyramidal, 137, 190, 191, 193, 209, 214 Extremity, 198, 214 Exudate, 214, 233 F Family Planning, 173, 214 Fat, 123, 197, 205, 214, 225, 243 Fatigue, 103, 214, 218 Fatty acids, 190, 214 Feces, 204, 214, 248 Fetus, 83, 110, 214, 236 Fibrinogen, 214, 237, 251 Fibrosis, 214, 244 Fissure, 207, 214, 238 Fixation, 214, 245 Fluid Therapy, 215, 232 Fluorescence, 18, 215 Fluorine, 123, 215 Flushing, 209, 215 Focus Groups, 12, 215 Fold, 39, 214, 215 Forearm, 197, 215 Forensic Medicine, 88, 215 Frontal Lobe, 200, 215, 238 Fructose, 215, 217, 223 Functional magnetic resonance imaging, 19, 37, 215

262 Drug Addiction

Fungemia, 197, 215 G Gallbladder, 189, 208, 215, 216 Gamma Rays, 215, 242 Gamma-hydroxybutyrate, 131, 132, 215 Ganglia, 189, 195, 215, 230, 231, 235, 249 Ganglionic Blockers, 215, 226 Gangliosides, 98, 215 Gap Junctions, 216, 250 Gas, 199, 215, 216, 220, 223, 232, 253, 254 Gas exchange, 216, 254 Gastric, 210, 216, 219 Gastric Emptying, 216 Gastrin, 216, 219 Gastroenterology, 159, 216 Gastrointestinal, 134, 135, 136, 139, 159, 198, 213, 216, 226, 245, 247, 249 Gastrointestinal tract, 159, 213, 216, 226, 245 Gastroparesis, 5, 216 Gene, 11, 12, 16, 18, 23, 32, 33, 34, 39, 45, 46, 63, 98, 142, 144, 151, 157, 166, 197, 216, 237, 245 Gene Expression, 11, 16, 18, 23, 33, 35, 45, 63, 98, 142, 216 Gene Targeting, 46, 216 Genetic Engineering, 196, 202, 216 Genetic Markers, 66, 216 Genetic testing, 216, 237 Genetics, 11, 22, 29, 33, 46, 53, 61, 216, 228, 235 Genital, 195, 216 Genotype, 56, 216, 236 Geriatric, 4, 216 Gestation, 216, 235, 236 Gland, 135, 136, 139, 189, 216, 220, 234, 236, 245, 248, 251 Globus Pallidus, 195, 217, 241 Glomerular, 5, 217, 223, 243 Glomerular Filtration Rate, 5, 217 Glomerulus, 217 Glucocorticoid, 145, 217, 219 Glucose, 197, 200, 208, 217, 220, 222, 244, 253 Glucose Intolerance, 208, 217 Glutamate, 17, 27, 30, 31, 35, 43, 49, 51, 52, 57, 73, 123, 217, 224, 227 Glycoprotein, 56, 214, 217, 251 Glycoside, 75, 217, 244 Gonadal, 217, 248 Governing Board, 217, 238 Grafting, 125, 217

Granulocytes, 217, 246, 255 Gravis, 126, 217 Growth, 23, 29, 131, 189, 192, 193, 199, 200, 208, 217, 222, 226, 230, 236, 244, 251, 253 Growth factors, 23, 217 H Habituation, 148, 217 Haematoma, 217, 218 Haemorrhage, 141, 217 Half-Life, 133, 152, 218 Hallucination, 132, 218 Haptens, 190, 218 Headache, 134, 136, 145, 218, 220 Headache Disorders, 218 Health Education, 155, 174, 218 Health Services, 24, 53, 163, 218 Health Status, 162, 218 Hearing Disorders, 202, 218 Heart attack, 199, 218 Heart failure, 218, 238 Hematocrit, 5, 197, 218 Hematoxylin, 14, 218 Heme, 196, 206, 218 Hemodialysis, 5, 208, 218, 224 Hemorrhage, 206, 218, 241, 248 Hemostasis, 218, 245 Hepatic, 126, 190, 207, 219, 229 Hepatitis, 4, 10, 11, 12, 24, 51, 159, 219, 254 Hepatocytes, 219 Hepatology, 4, 159, 219 Hereditary, 201, 219, 229, 230, 237 Heredity, 216, 219 Heterogeneity, 38, 190, 219 Hippocampus, 20, 48, 59, 207, 219, 225, 249 Histamine, 191, 193, 219 Homeless Persons, 38, 219 Homeostasis, 88, 219, 247 Homicide, 174, 219 Homogeneous, 204, 219, 235 Homologous, 46, 58, 206, 216, 219, 245, 250 Homosexuality, 68, 155, 157, 164, 219 Hormonal, 34, 65, 194, 205, 219 Horny layer, 213, 219 Host, 195, 219, 221, 254 Hybridomas, 211, 219 Hydrocortisone, 25, 219 Hydrogen, 123, 138, 196, 199, 207, 208, 220, 228, 231, 233, 235, 240 Hydromorphone, 129, 220 Hyperglycaemia, 141, 150, 220

Index 263

Hyperlipidaemia, 141, 220 Hypersensitivity, 54, 136, 190, 208, 220, 244, 245 Hypertension, 131, 134, 147, 150, 199, 218, 220, 223, 226, 236, 238, 239 Hyperthyroidism, 220, 239 Hypertrophy, 205, 220, 238, 252 Hypnotic, 195, 220 Hypoglycaemia, 207, 220 Hypoglycemia, 134, 136, 157, 220 Hypotension, 151, 193, 205, 209, 215, 220 Hypothalamic, 11, 15, 220 Hypothalamus, 194, 205, 208, 212, 220, 225, 236, 239 Hypoxia, 198, 200, 207, 220 I Iatrogenic, 75, 220 Ibogaine, 166, 220 Id, 48, 111, 114, 179, 184, 186, 220 Imaging procedures, 32, 220 Immune function, 124, 220 Immune response, 15, 193, 205, 218, 220, 221, 245, 249, 254 Immune Sera, 221 Immune system, 135, 136, 139, 145, 162, 196, 211, 220, 221, 226, 229, 253, 255 Immunization, 62, 144, 221, 245 Immunodeficiency, 6, 86, 134, 135, 136, 153, 154, 155, 161, 162, 164, 174, 178, 221 Immunodeficiency syndrome, 153, 154, 155, 161, 162, 164, 174, 178, 221 Immunoglobulins, 221, 237 Immunologic, 87, 201, 221, 242, 255 Immunology, 87, 190, 221 Immunosuppressive, 217, 221 Immunotherapy, 196, 208, 221 Impairment, 123, 200, 207, 210, 221, 227, 240 Impulsive Behavior, 44, 221 In vitro, 14, 17, 20, 32, 48, 49, 54, 124, 221, 237 In vivo, 14, 17, 18, 20, 22, 33, 48, 54, 63, 131, 144, 221, 228 Incontinence, 54, 127, 147, 221 Incubated, 28, 221 Incubation, 39, 221 Indicative, 46, 63, 155, 221, 234, 253 Induction, 33, 50, 131, 132, 138, 192, 193, 215, 221, 242 Infarction, 198, 200, 221 Infertility, 134, 136, 222

Inflammation, 190, 193, 202, 214, 219, 222, 233, 241, 243, 253 Inflammatory bowel disease, 54, 222 Infusion, 18, 128, 222, 252 Ingestion, 130, 222, 228, 237 Inhalation, 147, 222, 237 Initiation, 39, 61, 62, 222, 252 Innervation, 30, 198, 222 Inositol, 222, 227, 245 Inotropic, 209, 222 Insight, 22, 25, 30, 35, 99, 222 Insomnia, 149, 222, 225 Insulin, 5, 141, 150, 222 Insulin-dependent diabetes mellitus, 222 Interferon, 159, 222 Interferon-alpha, 222 Intermittent, 16, 31, 51, 215, 223 Internal Medicine, 34, 37, 86, 104, 216, 223 International Cooperation, 154, 223 Intestinal, 127, 143, 223 Intestine, 198, 223, 224 Intoxication, 94, 207, 223, 255 Intracellular, 17, 25, 30, 41, 58, 61, 222, 223, 227, 238, 242, 244, 246 Intracellular Membranes, 223, 227 Intracranial Embolism, 200, 223 Intracranial Embolism and Thrombosis, 200, 223 Intramuscular, 129, 223, 234 Intraocular, 147, 223 Intraocular pressure, 147, 223 Intravenous, 4, 14, 74, 88, 97, 104, 129, 132, 147, 155, 159, 215, 222, 223, 234 Intrinsic, 190, 223 Inulin, 217, 223 Involuntary, 48, 195, 197, 201, 223, 229 Ion Channels, 35, 58, 194, 223, 231, 250 Ionizing, 190, 223, 242 Ions, 195, 198, 209, 211, 220, 223, 238 Irritable Bowel Syndrome, 54, 134, 135, 136, 223 Ischemia, 123, 131, 192, 194, 198, 215, 223, 231 Isradipine, 43, 223 J Joint, 157, 224 K Kainate, 30, 35, 224 Kb, 172, 224 Kidney Failure, 212, 224 Kinetic, 22, 223, 224

264 Drug Addiction

L Labile, 45, 203, 224 Language Disorders, 202, 224 Large Intestine, 208, 223, 224, 243, 246 Latent, 60, 224, 238 Lectin, 224, 227 Lens, 224, 238 Lesion, 123, 224, 225, 250, 253 Lethal, 130, 195, 224 Leucine, 196, 224 Leukopenia, 224, 255 Library Services, 184, 224 Lice, 17, 224 Lie detector, 130, 131, 224 Life Expectancy, 4, 130, 224 Ligaments, 205, 224 Ligands, 128, 134, 136, 140, 141, 142, 225, 242 Limbic, 24, 27, 29, 89, 137, 191, 225, 238 Limbic System, 191, 225, 238 Linkage, 118, 142, 200, 216, 225 Lipid, 70, 222, 225 Lipophilic, 126, 225 Lithium, 193, 225 Liver, 4, 89, 132, 159, 189, 190, 196, 208, 212, 214, 215, 216, 219, 225, 228 Lobe, 200, 225, 239 Lobeline, 133, 225 Localization, 14, 66, 135, 136, 139, 225, 226 Localized, 128, 198, 207, 212, 214, 217, 222, 225, 228, 233, 236, 253 Locomotion, 225, 236 Locomotor, 27, 36, 38, 43, 46, 225 Longitudinal Studies, 18, 225 Longitudinal study, 55, 225 Lymphatic, 222, 225, 237, 251 Lymphatic system, 225, 251 Lymphocyte, 193, 226, 227 Lymphoid, 192, 226 M Magnetic Resonance Imaging, 226 Magnetoencephalography, 131, 226 Malignant, 13, 193, 226, 230, 242 Malingering, 5, 226 Malnutrition, 5, 190, 194, 226 Manic, 193, 197, 225, 226, 240 Manic-depressive psychosis, 226, 240 Manifest, 195, 226 Marital Status, 226, 246 Marital Therapy, 9, 226 Masturbation, 68, 226 Maximum Tolerated Dose, 210, 226

Mecamylamine, 17, 127, 226 Medetomidine, 147, 208, 226 Medial, 15, 48, 217, 226 Mediate, 15, 17, 27, 30, 33, 41, 45, 54, 61, 62, 209, 226 Mediator, 145, 226, 245 MEDLINE, 173, 227 Medullary, 227, 241 Meiosis, 227, 250 Melanin, 227, 236, 253 Memantine, 26, 227 Membrane Glycoproteins, 227 Membrane Proteins, 7, 227 Memory, 15, 20, 27, 33, 35, 44, 46, 49, 89, 99, 135, 192, 207, 227 Meninges, 200, 206, 227 Menopause, 227, 238, 239 Mental Disorders, 227, 240 Mental Health, iv, 6, 13, 24, 52, 158, 162, 172, 175, 227, 241 Mental Processes, 209, 227, 240 Mental Retardation, 202, 227 Mentors, 25, 44, 227 Mesoderm, 125, 227, 253 Mesolimbic, 137, 146, 193, 227, 254 Metabolic disorder, 135, 227 Metabolite, 197, 209, 227, 239 Metabotropic, 17, 57, 123, 227 Methamphetamine, 25, 30, 43, 44, 227 Methanol, 122, 228 Methionine, 196, 209, 228, 239 MI, 13, 187, 228 Microbe, 228, 252 Microbiology, 189, 194, 228 Microdialysis, 17, 43, 63, 228 Microorganism, 202, 228, 234, 254 Microscopy, 14, 218, 228 Mineralization, 228, 233 Mineralocorticoids, 189, 205, 228 Modeling, 29, 77, 210, 228 Modification, 7, 32, 34, 58, 153, 216, 228, 241, 255 Molecular Probes, 211, 228 Molecule, 54, 122, 145, 193, 196, 203, 206, 209, 211, 213, 217, 224, 228, 233, 242, 246, 253 Monitor, 18, 20, 42, 131, 228, 232 Monoamine, 63, 140, 191, 208, 228 Monoamine Oxidase, 191, 208, 228 Morals, 163, 229 Morphine, 19, 31, 35, 38, 44, 47, 128, 130, 132, 146, 151, 198, 202, 220, 229, 230, 233

Index 265

Morphological, 18, 92, 211, 229 Morphology, 18, 61, 229 Morula, 197, 229 Mother-Child Relations, 97, 229 Motility, 123, 229, 245 Movement Disorders, 137, 191, 193, 229 Mutagenesis, 58, 229 Mutagens, 229 Myasthenia, 126, 229 Myocardial infarction, 3, 131, 205, 228, 229, 239 Myocardium, 192, 228, 229 N Naive, 19, 25, 66, 128, 229 Naloxone, 128, 196, 229 Naltrexone, 40, 57, 229 Naphazoline, 147, 229 Narcolepsy, 131, 132, 208, 229 Narcosis, 229 Narcotic, 157, 158, 189, 229 Nausea, 193, 209, 210, 216, 230, 234 Necrosis, 200, 221, 228, 229, 230 Needle Sharing, 155, 162, 230 Neonatal, 56, 92, 95, 230 Neoplasm, 130, 230 Neoplastic, 219, 230 Neostriatum, 199, 230, 241 Nerve Fibers, 198, 230 Nerve Growth Factor, 23, 230, 231 Networks, 20, 125, 230 Neural, 17, 18, 20, 22, 33, 41, 48, 52, 56, 58, 60, 62, 92, 105, 125, 146, 190, 215, 229, 230 Neurodegenerative Diseases, 140, 195, 230 Neuroendocrine, 11, 150, 230 Neuroleptic, 190, 193, 230 Neuromuscular, 189, 230, 231, 243 Neuromuscular Junction, 189, 230, 231, 243 Neuronal, 17, 18, 20, 23, 27, 30, 31, 33, 47, 50, 58, 61, 124, 125, 137, 141, 229, 230, 242 Neuronal Plasticity, 23, 27, 230 Neuropathy, 195, 231 Neuropeptide, 43, 128, 145, 205, 231 Neuroprotective Agents, 141, 231 Neurosis, 131, 149, 231 Neurotic, 132, 149, 231 Neurotic Disorders, 149, 231 Neurotoxicity, 96, 231 Neurotoxin, 30, 231 Neurotransmitters, 46, 213, 231, 239, 247

Neurotrophins, 23, 231 Neutrons, 190, 231, 241 Niacin, 123, 231, 253 Nicotine, 10, 11, 12, 17, 26, 64, 107, 110, 127, 137, 225, 231, 242 Nicotinic Antagonists, 18, 231 Nitrogen, 150, 190, 192, 214, 232, 253 Nonverbal Communication, 202, 232, 240 Norepinephrine, 22, 190, 209, 232, 242 Notochord, 125, 232 Nuclear, 74, 100, 189, 195, 211, 213, 215, 225, 230, 232, 241, 251 Nuclei, 57, 190, 191, 211, 216, 225, 226, 231, 232, 237, 240 Nucleic acid, 229, 232, 244, 255 Nutritional Support, 5, 232 O Obsession, 203, 232 Ocular, 147, 232 Odour, 194, 232 Ointments, 210, 232 Opacity, 207, 232 Opioid Peptides, 128, 210, 232 Opium, 148, 229, 233, 234 Opportunistic Infections, 162, 233 Oral Health, 3, 233 Orbit, 233 Orbital, 19, 233 Orderly, 23, 233 Orthostatic, 193, 233 Osmotic, 190, 233 Osteomalacia, 3, 233 Osteomyelitis, 74, 233 Osteoporosis, 3, 233 Outpatient, 9, 50, 59, 64, 147, 233 Ovariectomy, 65, 233 Ovaries, 233, 245 Ovary, 213, 233 Overdose, 127, 143, 233 Oxidation, 197, 206, 233 Oxygen Consumption, 233, 243 Oxygenation, 59, 234 P Palliative, 234, 251 Palsy, 102, 134, 135, 136, 137, 139, 234, 247 Pancreas, 189, 208, 216, 222, 234 Panic, 134, 138, 141, 150, 163, 234 Panic Disorder, 138, 234 Papaverine, 233, 234 Paralysis, 132, 234, 247 Parasitic, 224, 234 Parenteral, 102, 129, 130, 149, 234

266 Drug Addiction

Paresthesias, 234 Parkinsonism, 193, 234 Particle, 234, 247, 252 Patch, 17, 25, 49, 51, 57, 234, 252 Pathogen, 6, 221, 234 Pathologic, 196, 205, 220, 234, 253 Pathophysiology, 137, 139, 234 Patient Education, 13, 161, 178, 182, 184, 187, 234 Penicillin, 192, 234 Penis, 204, 235 Peptide, 24, 35, 43, 128, 135, 136, 139, 196, 212, 233, 235, 239, 240 Perception, 16, 207, 218, 235, 244 Perfusion, 130, 220, 235 Perinatal, 83, 93, 95, 235 Peripheral Nervous System, 230, 234, 235, 239, 249 Personality Disorders, 142, 235 Perspiration, 130, 208, 235 Petechiae, 217, 235 PH, 75, 76, 92, 143, 235 Pharmaceutical Preparations, 200, 213, 235 Pharmaceutical Solutions, 210, 235 Pharmacist, 105, 235 Pharmacodynamic, 25, 235 Pharmacogenetics, 53, 235 Pharmacokinetic, 22, 25, 56, 235 Pharmacologic, 11, 13, 19, 30, 62, 94, 192, 218, 235, 252, 253 Pharmacotherapy, 21, 22, 40, 42, 50, 73, 235 Pharynx, 198, 236 Phenotype, 46, 56, 236 Phenoxybenzamine, 147, 236 Phenyl, 138, 150, 236 Phenylalanine, 236, 253 Phobias, 141, 150, 236 Phospholipases, 236, 246 Phospholipids, 214, 222, 236 Phosphorus, 198, 236 Phosphorylate, 28, 236 Phosphorylated, 28, 58, 236 Phosphorylation, 28, 58, 236 Physiologic, 11, 30, 190, 196, 218, 223, 236, 242 Physiology, 7, 23, 30, 44, 62, 66, 158, 211, 216, 236 Pilot Projects, 40, 236 Pilot study, 12, 13, 32, 40, 52, 64, 236

Pituitary Gland, 135, 136, 139, 145, 205, 206, 236, 239 Placenta, 213, 236, 239 Plants, 190, 196, 199, 202, 217, 223, 224, 229, 232, 236, 244, 252 Plasma, 7, 17, 31, 56, 145, 147, 190, 192, 200, 214, 217, 218, 220, 224, 228, 237, 254 Plasma cells, 192, 237 Plasma protein, 56, 190, 237 Plasmids, 211, 237 Plasticity, 20, 22, 23, 33, 75, 237 Platelet Activation, 237, 246 Pleomorphic, 232, 237 Plexus, 198, 237 Poisoning, 207, 223, 230, 237, 245 Polygraph, 130, 131, 237 Polymerase, 159, 237 Polymerase Chain Reaction, 159, 237 Polymers, 48, 131, 237, 240 Polymorphism, 12, 47, 237 Polysaccharide, 193, 200, 237 Posterior, 125, 191, 200, 210, 234, 237 Postherpetic Neuralgia, 191, 238 Postmenopausal, 233, 238 Postnatal, 23, 27, 238 Postsynaptic, 17, 137, 238, 246, 250 Post-synaptic, 61, 238 Post-translational, 7, 58, 238 Post-traumatic, 134, 135, 136, 139, 145, 218, 229, 238 Post-traumatic stress disorder, 134, 135, 136, 139, 145, 238 Postural, 124, 238 Potassium, 17, 58, 228, 238 Potassium Channels, 17, 238 Potentiate, 238, 239 Potentiation, 238, 246 Practicability, 238, 252 Practice Guidelines, 175, 238 Prazosin, 147, 238 Precursor, 35, 209, 211, 212, 232, 236, 238, 239, 253 Predisposition, 47, 144, 238 Prefrontal Cortex, 17, 49, 238 Presbyopia, 147, 238 Prescription drug abuse, 13, 239 Presynaptic, 138, 195, 239, 250 Presynaptic Terminals, 195, 239, 250 Prevalence, 4, 51, 73, 144, 162, 174, 239 Preventive Health Services, 203, 239 Probe, 19, 43, 228, 239 Problem Solving, 21, 239

Index 267

Prodrug, 122, 239 Progesterone, 239, 248 Progression, 18, 63, 159, 192, 239 Progressive, 7, 34, 36, 43, 48, 49, 65, 137, 139, 199, 207, 210, 213, 217, 230, 237, 239, 243 Projection, 16, 30, 31, 232, 238, 239, 243, 254 Prone, 14, 49, 239 Pro-Opiomelanocortin, 35, 233, 239 Prophase, 239, 250 Prophylaxis, 141, 239 Propranolol, 21, 40, 239 Prospective study, 55, 225, 239 Prosthesis, 3, 240 Prostitution, 162, 163, 240 Protease, 58, 202, 240 Protease Inhibitors, 58, 240 Protein C, 7, 190, 191, 195, 240 Protein S, 45, 157, 197, 240, 250 Proteins, 7, 14, 18, 30, 33, 35, 41, 58, 61, 66, 123, 125, 147, 191, 193, 199, 200, 202, 203, 211, 216, 227, 228, 232, 235, 237, 240, 242, 245, 252 Proteolytic, 190, 203, 214, 240 Protocol, 9, 42, 240 Protons, 190, 220, 223, 240, 241 Proximal, 209, 239, 240, 245 Psychic, 93, 97, 148, 231, 240, 245 Psychology, 8, 12, 21, 39, 44, 48, 52, 57, 60, 91, 101, 203, 209, 240 Psychomotor, 43, 48, 50, 136, 207, 230, 240 Psychopathology, 9, 29, 55, 118, 240 Psychosis, 23, 36, 87, 193, 240, 241 Psychotherapy, 97, 226, 240, 242 Psychotomimetic, 191, 208, 241 Psychotropic, 151, 158, 241 Public Health, 6, 12, 24, 26, 36, 67, 74, 79, 82, 86, 92, 146, 157, 175, 241 Public Opinion, 106, 241 Public Policy, 144, 155, 157, 173, 241 Publishing, 67, 159, 241 Pulmonary, 88, 97, 197, 204, 205, 224, 241, 254 Pulmonary Artery, 197, 241, 254 Pulmonary Embolism, 88, 241 Pulmonary hypertension, 205, 241 Pulse, 58, 224, 228, 237, 241 Purpura, 217, 241 Purulent, 189, 241 Putamen, 31, 43, 195, 230, 241 Pyogenic, 97, 233, 241

Pyramidal Tracts, 214, 241 Q Quality of Life, 13, 162, 241 R Race, 56, 201, 208, 241 Radiation, 131, 189, 192, 195, 215, 223, 241, 242, 255 Radioactive, 189, 195, 218, 220, 228, 232, 241, 242 Radioactivity, 189, 241 Radioimmunotherapy, 242 Radiolabeled, 140, 242 Radiotherapy, 3, 242, 248 Randomized, 8, 13, 33, 41, 57, 59, 64, 211, 242 Randomized clinical trial, 33, 57, 242 Rape, 238, 242 Reality Testing, 240, 242 Reassurance, 163, 242 Receptors, Adrenergic, 208, 226, 242 Receptors, Nicotinic, 231, 242 Receptors, Serotonin, 242, 245 Recombinant, 36, 242, 253 Recombination, 23, 46, 216, 242 Rectal, 129, 243 Rectum, 194, 208, 216, 221, 222, 224, 243 Recurrence, 197, 226, 243 Red Nucleus, 243, 254 Refer, 1, 142, 203, 209, 214, 225, 229, 230, 231, 240, 242, 243, 245 Refraction, 243, 248 Regimen, 50, 211, 235, 243 Rehabilitative, 72, 243 Relapse, 7, 8, 14, 18, 20, 26, 27, 32, 34, 39, 41, 50, 55, 58, 62, 64, 65, 81, 92, 94, 98, 147, 243 Reliability, 131, 243 Remission, 197, 226, 243 Renal failure, 207, 243 Respiration, 132, 199, 201, 224, 228, 237, 243 Respiratory Paralysis, 189, 243 Respiratory Physiology, 243, 254 Retinal, 209, 243 Rheumatism, 243, 244 Rheumatoid, 147, 202, 244 Rheumatoid arthritis, 147, 202, 244 Ribavirin, 159, 244 Rigidity, 234, 236, 244 Risk factor, 4, 5, 64, 93, 101, 163, 164, 239, 244 Risk-Taking, 174, 244

268 Drug Addiction

Rod, 156, 201, 232, 244 Role-play, 13, 244 S Saline, 14, 18, 25, 49, 244 Saliva, 207, 244 Salivary, 48, 208, 244 Saponins, 244, 248 Schizoid, 244, 255 Schizophrenia, 49, 57, 122, 123, 124, 126, 131, 132, 137, 141, 150, 244, 254, 255 Schizophrenia, Catatonic, 131, 244 Schizotypal Personality Disorder, 207, 244, 255 Sclerosis, 134, 136, 137, 139, 202, 244 Screening, 3, 22, 23, 36, 41, 47, 48, 99, 146, 159, 201, 244 Second Messenger Systems, 231, 244 Secretion, 124, 135, 136, 139, 145, 205, 219, 222, 228, 235, 244, 245 Secretory, 245, 250 Sedative, 147, 149, 195, 202, 208, 226, 245 Segregation, 242, 245 Seizures, 131, 141, 207, 245 Self-Help Groups, 55, 245 Sella, 210, 236, 245 Senile, 150, 233, 245 Sensitization, 14, 16, 18, 24, 31, 33, 34, 38, 43, 44, 46, 49, 51, 54, 60, 245 Septal, 25, 225, 245 Septicemia, 88, 245 Septum, 24, 245 Septum Pellucidum, 245 Sequencing, 237, 245 Serotonin, 22, 122, 138, 140, 193, 229, 235, 242, 245, 253 Serum, 5, 159, 190, 191, 193, 203, 221, 228, 245 Sex Characteristics, 189, 192, 245 Sexual Abstinence, 162, 246 Sexual Harassment, 154, 246 Sexual Partners, 155, 246 Sexually Transmitted Diseases, 154, 246 Shame, 197, 246 Shock, 219, 246, 252 Side effect, 137, 138, 148, 190, 193, 196, 246, 252 Signal Transduction, 58, 61, 222, 246 Signs and Symptoms, 36, 132, 243, 246 Skeletal, 125, 192, 201, 231, 246 Skeleton, 224, 246 Skull, 206, 233, 246, 250 Sleep Deprivation, 38, 246

Small intestine, 210, 219, 223, 246 Smooth muscle, 131, 191, 219, 223, 229, 234, 247, 249 Social Environment, 241, 247 Social Problems, 48, 91, 247 Social Support, 50, 64, 247 Social Work, 85, 161, 163, 247 Sodium, 133, 152, 228, 247, 249 Solitary Nucleus, 194, 247 Solvent, 196, 213, 228, 233, 235, 247 Somatic, 189, 225, 227, 235, 238, 247 Sound wave, 204, 247 Spastic, 223, 247 Spasticity, 147, 150, 195, 247 Specialist, 179, 247 Species, 15, 127, 143, 213, 227, 234, 237, 241, 247, 249, 252, 253, 254, 255 Specificity, 16, 45, 87, 140, 190, 212, 247 Spectrum, 135, 136, 139, 248 Spike, 49, 248 Spinous, 213, 248 Sporadic, 230, 248 Stabilization, 41, 248 Standard therapy, 159, 248 Steel, 201, 248 Stereotactic, 76, 87, 101, 248 Sterile, 5, 6, 248 Sterility, 222, 248 Steroid, 25, 206, 244, 248 Stimulant, 22, 25, 29, 48, 49, 51, 126, 191, 208, 219, 227, 248 Stimulus, 26, 39, 49, 204, 210, 211, 213, 218, 221, 222, 223, 234, 236, 248, 251 Stomach, 189, 208, 213, 216, 219, 230, 236, 246, 248 Stool, 221, 223, 224, 248 Strand, 237, 248 Striatum, 14, 48, 50, 61, 75, 217, 230, 232, 248 Stroke, 35, 134, 136, 141, 172, 199, 231, 248 Structure-Activity Relationship, 54, 248 Stupor, 229, 244, 249 Subacute, 222, 249 Subarachnoid, 218, 249 Subclinical, 222, 245, 249 Subcutaneous, 129, 149, 211, 234, 249 Subiculum, 219, 249 Sublingual, 48, 129, 249 Subspecies, 247, 249 Substance P, 124, 227, 245, 249 Substrate, 21, 41, 43, 212, 249 Support group, 162, 249

Index 269

Suppression, 49, 124, 134, 136, 149, 205, 249, 255 Supraspinal, 195, 249 Sweat, 220, 235, 249 Sympathetic Nervous System, 194, 249 Sympathomimetic, 191, 208, 209, 213, 227, 232, 249 Symptomatic, 148, 191, 249 Symptomatic treatment, 148, 191, 249 Symptomatology, 73, 249 Synapses, 138, 231, 232, 248, 250 Synapsis, 250 Synaptic, 7, 16, 20, 22, 23, 25, 28, 30, 31, 32, 33, 35, 49, 57, 61, 138, 231, 246, 250 Synaptic Transmission, 25, 35, 231, 250 Synaptic Vesicles, 250 Synergistic, 42, 250 Systemic, 14, 18, 49, 149, 194, 197, 198, 202, 207, 209, 213, 222, 245, 250, 252 Systolic, 220, 250 T Tardive, 141, 150, 193, 250 Telencephalon, 195, 250 Temporal, 37, 45, 191, 218, 219, 250 Temporal Lobe, 191, 250 Terminator, 250, 255 Testis, 213, 250 Tetracycline, 23, 250 Tetrahydrocannabinol, 31, 199, 251 Thalamus, 208, 225, 238, 251 Therapeutic Community, 76, 95, 251 Therapeutics, 15, 229, 251 Thermal, 209, 231, 237, 251 Thiamine, 98, 251 Thoracic, 85, 97, 198, 251 Threshold, 59, 213, 220, 251 Thrombin, 214, 240, 251 Thrombomodulin, 240, 251 Thrombosis, 223, 240, 248, 251 Thymus, 90, 221, 225, 251 Thyroid, 220, 251, 253 Thyroxine, 190, 236, 251 Token Economy, 69, 251 Tolerance, 16, 20, 22, 34, 58, 128, 146, 189, 198, 217, 220, 251 Tomography, 59, 62, 63, 86, 251 Tonicity, 210, 251 Tooth Preparation, 189, 251 Topical, 213, 251 Toxic, iv, 30, 141, 196, 213, 228, 231, 252, 255 Toxicity, 15, 75, 210, 226, 252

Toxicology, 24, 94, 103, 132, 174, 252 Toxins, 193, 212, 222, 242, 245, 252 Trace element, 215, 252 Traction, 201, 252 Transcription Factors, 33, 50, 252 Transdermal, 129, 132, 149, 252 Transduction, 58, 246, 252 Transfection, 196, 211, 252 Transfer Factor, 221, 252 Transfusion, 252 Translational, 34, 252 Transmitter, 24, 27, 29, 35, 189, 194, 195, 209, 213, 223, 227, 232, 250, 252 Transplantation, 4, 5, 125, 221, 252 Trauma, 35, 123, 132, 141, 207, 230, 231, 252 Treatment Outcome, 11, 28, 41, 50, 57, 252 Triad, 88, 252 Tricuspid Atresia, 205, 252 Tricuspid Valve, 84, 88, 252 Trigger zone, 193, 253 Trophoblast, 197, 253 Tryptophan, 202, 245, 253 Tubercle, 232, 253 Tuberculosis, 24, 153, 204, 253 Tyrosine, 61, 209, 253 U Ubiquitin, 58, 253 Ulcer, 253 Unconscious, 68, 192, 220, 253 Urethra, 235, 253 Urinary, 54, 127, 147, 221, 238, 253 Urinary Retention, 238, 253 Urine, 8, 40, 99, 197, 209, 221, 253 Urine Testing, 40, 253 V Vaccine, 62, 240, 253 Varicose, 30, 253 Vascular, 200, 218, 221, 222, 223, 225, 236, 253 Vasculitis, 200, 253 Vasoconstriction, 147, 213, 253 Vasodilation, 209, 234, 253 Vasodilator, 198, 209, 219, 234, 236, 253 VE, 154, 253 Vector, 252, 253 Vein, 192, 194, 223, 232, 253 Venlafaxine, 42, 254 Venous, 65, 87, 194, 197, 200, 223, 240, 252, 254 Ventilation, 15, 254

270 Drug Addiction

Ventral, 16, 17, 19, 37, 43, 56, 61, 125, 146, 220, 232, 254 Ventral Tegmental Area, 16, 17, 37, 43, 57, 146, 254 Ventricle, 128, 191, 194, 199, 205, 219, 220, 232, 241, 250, 251, 252, 254 Ventricular, 205, 252, 254 Vertebrae, 248, 254 Vertebral, 74, 232, 254 Veterinary Medicine, 173, 226, 254 Viral, 16, 51, 79, 159, 252, 254, 255 Viral Hepatitis, 79, 254 Viral Load, 159, 254 Viremia, 197, 254 Virulence, 194, 252, 254 Visceral, 54, 194, 195, 225, 254 Visceral Afferents, 194, 254

Vitro, 254 Vivo, 17, 18, 27, 63, 254 Volition, 223, 254 W Wakefulness, 207, 254 War, 72, 100, 238, 255 White blood cell, 192, 221, 224, 225, 226, 237, 255 X Xenograft, 192, 255 X-ray, 215, 232, 242, 248, 255 Y Yeasts, 236, 255 Z Zidovudine, 86, 255 Zymogen, 240, 255

Index 271

272 Drug Addiction

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