Benzodiazepines - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References 059784352X, 9780597843525, 9781417512713

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BENZODIAZEPINES A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R EFERENCES

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 ©2004 by ICON Group International, Inc. Copyright ©2004 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., 1960Benzodiazepines: 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: 0-597-84352-X 1. Benzodiazepines-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 benzodiazepines. 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 BENZODIAZEPINES .................................................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Benzodiazepines .......................................................................... 14 E-Journals: PubMed Central ....................................................................................................... 48 The National Library of Medicine: PubMed ................................................................................ 51 CHAPTER 2. NUTRITION AND BENZODIAZEPINES .......................................................................... 69 Overview...................................................................................................................................... 69 Finding Nutrition Studies on Benzodiazepines ........................................................................... 69 Federal Resources on Nutrition ................................................................................................... 73 Additional Web Resources ........................................................................................................... 74 CHAPTER 3. ALTERNATIVE MEDICINE AND BENZODIAZEPINES.................................................... 75 Overview...................................................................................................................................... 75 National Center for Complementary and Alternative Medicine.................................................. 75 Additional Web Resources ........................................................................................................... 82 General References ....................................................................................................................... 86 CHAPTER 4. DISSERTATIONS ON BENZODIAZEPINES ..................................................................... 87 Overview...................................................................................................................................... 87 Dissertations on Benzodiazepines ................................................................................................ 87 Keeping Current .......................................................................................................................... 88 CHAPTER 5. PATENTS ON BENZODIAZEPINES ................................................................................ 89 Overview...................................................................................................................................... 89 Patents on Benzodiazepines ......................................................................................................... 89 Patent Applications on Benzodiazepines ................................................................................... 104 Keeping Current ........................................................................................................................ 121 CHAPTER 6. BOOKS ON BENZODIAZEPINES .................................................................................. 123 Overview.................................................................................................................................... 123 Book Summaries: Online Booksellers......................................................................................... 123 Chapters on Benzodiazepines ..................................................................................................... 127 CHAPTER 7. MULTIMEDIA ON BENZODIAZEPINES ....................................................................... 133 Overview.................................................................................................................................... 133 Video Recordings ....................................................................................................................... 133 Audio Recordings....................................................................................................................... 134 CHAPTER 8. PERIODICALS AND NEWS ON BENZODIAZEPINES .................................................... 137 Overview.................................................................................................................................... 137 News Services and Press Releases.............................................................................................. 137 Newsletter Articles .................................................................................................................... 140 Academic Periodicals covering Benzodiazepines........................................................................ 142 CHAPTER 9. RESEARCHING MEDICATIONS .................................................................................. 143 Overview.................................................................................................................................... 143 U.S. Pharmacopeia..................................................................................................................... 143 Commercial Databases ............................................................................................................... 144 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 147 Overview.................................................................................................................................... 147 NIH Guidelines.......................................................................................................................... 147 NIH Databases........................................................................................................................... 149 Other Commercial Databases..................................................................................................... 151 The Genome Project and Benzodiazepines ................................................................................. 151 APPENDIX B. PATIENT RESOURCES ............................................................................................... 155 Overview.................................................................................................................................... 155

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Patient Guideline Sources.......................................................................................................... 155 Finding Associations.................................................................................................................. 159 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 161 Overview.................................................................................................................................... 161 Preparation................................................................................................................................. 161 Finding a Local Medical Library................................................................................................ 161 Medical Libraries in the U.S. and Canada ................................................................................. 161 ONLINE GLOSSARIES................................................................................................................ 167 Online Dictionary Directories ................................................................................................... 169 BENZODIAZEPINES DICTIONARY........................................................................................ 171 INDEX .............................................................................................................................................. 255

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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 benzodiazepines 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 benzodiazepines, 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 benzodiazepines, 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 benzodiazepines. 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 benzodiazepines, 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 benzodiazepines. 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 BENZODIAZEPINES Overview In this chapter, we will show you how to locate peer-reviewed references and studies on benzodiazepines.

The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and benzodiazepines, 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 “benzodiazepines” (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: •

Identifying a Neurobiological Basis for Drug Therapy in TMDs Source: JADA. Journal of American Dental Association. 127(5): 581-593. May 1996. Summary: Emerging results from clinical and basic research indicate that persistent pain results in changes in the central nervous system. This article reviews data that support the use of tricyclic antidepressants for neurogenic or atypical pain, and benzodiazepines for musculoskeletal pain. Other topics covered include the pathophysiology of persistent pain and the pharmacological management of temporomandibular disorders (TMDs) with antidepressants, benzodiazepines, muscle relaxants, non-opioid analgesics, corticosteroids, and opioids. The authors stress that dentists must weigh the benefits of the chronic administration of a drug for the management of TMDs against the equivocal scientific support for the use of many drug

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classes and the potential for serious toxicity with prolonged administration. 3 figures. 80 references. (AA-M). •

Flexible Sigmoidoscopy Source: American Family Physician. 63(7): 1375-1380. April 1, 2001. Contact: Available from American Academy of Family Physicians. 11400 Tomahawk Creek Parkway, Leawood, KS 66211-2672. (800) 274-2237. Website: www.aafp.org. Summary: Flexible sigmoidoscopy remains a common tool used for the periodic screening of colorectal cancer. This article reminds family care physicians of the recommendations for the use of flexible sigmoidoscopy. Most organizations recommend screening at three to five year intervals beginning at age 50 for persons with average risk. Extensive training in endoscopic maneuvering, colorectal anatomy, and pathologic recognition is required. Most physicians report comfort performing the procedure unsupervised after 10 to 25 supervised sessions. The procedure itself involves the insertion of the sigmoidoscope through the anus and distal rectum and advancement of the scope tip to an average depth of 48 to 55 centimeters in the sigmoid colon. Once the sigmoidoscope has been appropriately advanced, the scope is slowly withdrawn, allowing for the inspection of colon mucosa during withdrawal. Polyps less than 5 millimeters in diameter should be biopsied. Polyps 5 to 10 millimeters or greater can be assumed to be adenomatous, and follow up colonoscopy for complete polypectomy is required. Diverticulosis, hemorrhoids, nonspecific colitis and pseudomembranes may also be encountered during inspection. Use of preprocedural benzodiazepines can be helpful in reducing patient discomfort. 2 figures. 10 references.

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Sleep Disorders: A Common Problem Among Kidney Patients? Source: For Patients Only. 8(1): 8-10, 24. January-February 1995. Contact: Available from Contemporary Dialysis, Inc. 6300 Variel Avenue, Suite I, Woodland Hills, CA 91367. Summary: In this article, the author provides readers with information about an oftenencountered, but little-discussed complication of dialysis, insomnia. Topics include the adequacy of dialysis and its impact on the sleep habits of patients; restless leg syndrome (RLS) and the role of peripheral neuropathy in its development; the use of Sinemet to treat RLS; using conventional sleep aids, including Ambien; the use of muscle relaxants, or benzodiazepines, for milder forms of RLS; psychological sleep disturbances; and adjunctive therapies, including Qigong, biofeedback, and meditation. The author encourages readers to become more self-aware and to participate as an active member of their own health care team. The article includes a short list of references and organizations that may provide additional information about sleep disorders and their therapy.

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Pathogenesis and Treatment of Portal-Systemic Encephalopathy: An Update Source: Digestive Diseases and Sciences. 37(3): 321-327. March 1992. Summary: Portal-systemic encephalopathy (PSE) remains a serious complication of chronic liver disease. Impairment of intellectual function, deterioration of personality, altered levels of consciousness, and neuromuscular incoordinations dominate the clinical presentation of PSE. This review covers the pathogenesis and treatment of PSE. The author makes reference, where appropriate, to studies in human material as well as to work in experimental animal models of PSE and to clinical studies with new

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therapeutic agents. Topics include the ammonia hypothesis; the GABA theory; endogenous benzodiazepines; and other neurotransmitter systems. 2 figures. 2 tables. 55 references. •

Restless Legs Syndrome: Detection and Management in Primary Care Source: American Family Physician. 62(1): 108-114. July 1, 2000. Contact: Available from American Academy of Family Physicians. 11400 Tomahawk Creek Parkway, Leawood, KS 66211-2672. (800) 274-2237. Website: www.aafp.org. Summary: Restless legs syndrome (RLS) is a neurologic movement disorder that is often associated with a sleep complaint. This article explores the role of the primary care physician in the diagnosis and management of RLS. Patients with RLS have an irresistible urge to move their legs, usually due to disagreeable sensations that are worse during periods of inactivity and often interfere with sleep. The authors estimate that between 2 and 15 percent of the population may experience symptoms of RLS. Primary RLS likely has a genetic origin. Secondary causes of RLS include iron deficiency, neurologic lesions, pregnancy, and uremia (urea in the blood). RLS also may occur secondarily to certain medications. The diagnosis of RLS is based primarily on the patient's history. A list of questions to assess the likelihood of RLS is included in the article. Drug therapy includes dopaminergic agents, opioids, benzodiazepines, and anticonvulsants. The primary care physician can incorporate sleep and RLS related questions into the general review of systems as a useful step in diagnosing RLS. Most patients with RLS can obtain symptomatic relief with commonly prescribed medications and support. 5 tables. 30 references.

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Considerations for the Use of Oral Sedation in the Institutionalized Geriatric Patient During Dental Interventions: A Review of the Literature Source: SCD. Special Care in Dentistry. 19(2): 56-63. March-April 1999. Contact: Available from Special Care Dentistry. 211 East Chicago Avenue, Chicago, IL 60611. (312) 440-2660. Fax (312) 440-2824. Summary: Some institutionalized elderly persons need a sedative prior to a dental examination or treatment because they have a disturbance due to physical illnesses, degenerative changes in the brain, or psychiatric disorders, associated with advanced aging. Oral administration is one of the safest methods of delivery of a sedative drug. It is almost universally acceptable, easy to administer, costs little, has a low incidence and severity of adverse reactions, and requires no additional formal specialized training for the dentist. However, theoretical and practical knowledge of sedation is essential. This article reviews the literature on oral sedation for the geriatric patient. Benzodiazepines are most often used for oral sedation of geriatric patients. The properties of these drugs are reviewed, and recommendations are made with respect to the drugs of choice and their dosage. Generally, fast acting benzodiazepines of short duration, with rapid rate of elimination and no active metabolites, are recommended. The authors note that the drug of choice, and the dosage, will vary according to the medical history and physical condition of the patient. 6 tables. 48 references.

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Behavioral Problems in Nursing Home Residents: Safe Ways To Manage Dementia Source: Postgraduate Medicine. 97(5): 189-191, 195-196. May 1995. Summary: This article addresses behavioral problems in nursing home residents and the use of patient assessment and treatment options, both pharmacological and non-

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pharmacological, that can help control these behaviors. Non-pharmacological treatment options include environmental changes, bright-light treatment, and restraints and behavior modification. Pharmacological options involve the use of neuroleptics, benzodiazepines, and other agents such as beta-blocker therapy, carbamazepine, lithium, trazodone hydrochloride, and buspirone hydrochloride. According to the authors, patients should be assessed to differentiate delirium from dementia, and possible precipitants of disturbed behavior should be investigated. The authors suggest that ultimately, long-term success with patients with dementia may depend in part on realistic expectations. 21 references. •

Causes and Treatment of Behavioral Changes Source: Consultant. 28(1): 43-45, 48. January 1988. Summary: This article describes Alzheimer's disease as an increasingly common management concern for primary care physicians. Although little can be done for the primary symptoms of the dementing process, the secondary behavioral complications of this illness may be amenable to behavioral or pharmacologic manipulation. Agitation may be responsive to environmental or psychosocial intervention. Treatment with low doses of antidepressants can improve depressive symptoms. Mild anxiety is best treated with emotional support from the family and caregiver. Benzodiazepines can be used with caution. Insomnia can be reduced by encouraging a routine that prevents daytime napping and keeping the patient busy during the day. Pharmacotherapy for disturbed sleep often causes more harm than good and should be avoided if possible. 3 references. (AA-M).

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Burning Mouth Syndrome Source: American Family Physician. 65(4): 615-620. February 15, 2002. Contact: Available from American Academy of Family Physicians. Publications Division, 11400 Tomahawk Creek Parkway, Leawood, KS 66211-2672. (800) 944-0000. Website: www.aafp.org/afp. Summary: This article discusses burning mouth syndrome (BMS), a condition that is characterized by a burning sensation in the tongue or other oral sites, usually in the absence of clinical and laboratory findings. Affected patients often present with multiple oral complaints, including burning, dryness, and taste alterations. Burning mouth complaints are reported more often in women, especially after menopause. Typically, patients awaken without pain but note increasing symptoms through the day and into the evening. Conditions that have been reported in association with BMS include chronic anxiety or depression, various nutritional deficiencies, type 2 diabetes, and changes in salivary function. However, these conditions have not been consistently linked with the syndrome, and their treatment has had little impact on BMS symptoms. Recent studies have pointed to dysfunction of several cranial nerves associated with taste sensation as a possible cause of BMS. Given in low dosages, benzodiazepines, tricyclic antidepressants, or anticonvulsants may be effective in patients with BMS. Topical capsaicin has also been used in some patients. 1 table. 31 references.

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Pharmacologic Treatments for Temporomandibular Disorders Source: Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics. 83(1, Supplement): 134-142. January 1997.

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Summary: This article on pharmacologic treatments for temporomandibular disorders is from a special supplement issue on the NIH Technology Assessment Conference on the management of temporomandibular disorders (TMDs), held in April 1996. The author notes that drugs are widely used in the management of acute and chronic orofacial pain. Whereas the use of analgesics for acute orofacial pain is well documented, the use of a broad spectrum of drugs for chronic pain is based on few studies. In the absence of data supporting a therapeutic benefit for a drug used chronically for pain, toxicity associated with the drug can still occur. It is critical, therefore, to assess the balance between therapeutic benefit and safety. The author reviews current evidence supporting the use of several drug classes for TMD and identifies therapeutic controversies in need of further research. Drug classes discussed include nonopioid analgesics, opioids, corticosteroids, antidepressants, benzodiazepines, and muscle relaxants. Assuming that a reliable differential diagnosis can be performed, pain with a neuropathic or atypical component would recommend a trial with a tricyclic antidepressant. Pain of musculoskeletal origin is probably best managed by physical medicine procedures, possibly supplemented with a short trial of a benzodiazepine or an NSAID. Patients with manifestations of psychosocial dysfunction may not benefit from drug therapy aimed at pain and should be considered as candidates for physical medicine modalities and behavioral methods. 3 figures. 1 table. 55 references. (AA-M). •

Pharmacologic Management of Myofascial Pain and Dysfunction Source: Oral and Maxillofacial Surgery Clinics of North America. 7(1): 87-97. February 1995. Summary: This article on the pharmacologic management of myofascial pain and dysfunction is from an issue of Oral and Maxillofacial Clinics on the medical management of temporomandibular disorders (TMD). The authors discuss the most frequently used classes of drugs, providing information about their mechanism of action, indications and contraindications, methods of use, and possible adverse side effects. Specific drugs discussed include anti-inflammatory medications, including nonsteroidal anti-inflammatory drugs, and corticosteroids; muscle relaxants (other than benzodiazepines); antianxiety medications; antidepressant medication; opiate narcotic analgesics; and local anesthetics. A final section covers the placebo effect. The author emphasizes the importance of understanding the patient in terms of compliance and tolerance of side effects in order to achieve successful management with pharmacologic therapy. 2 figures. 6 tables. 25 references. (AA-M).

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Practical Considerations in Managing Alzheimer's Disease Source: Geriatrics. 42(10): 55-61. October 1987. Summary: This article presents a panel discussion on the role of the physician in the treatment of Alzheimer's, including handling the patient's response to the diagnosis, managing behavioral aspects of the illness, treatment of depression and other emotional symptoms, treatment of other medical conditions, and helping patients live with cognitive impairment. The panelists also considered such drug therapy as THA, Hydergine neuroleptics for agitation, and benzodiazepines for sleep disorders.

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Current Perspectives on Drug Therapies for Anorexia Nervosa and Bulimia Nervosa Source: Drugs. 41(3): 367-377. March 1991. Contact: Available from ADIS International. Suite B-30, Oxford Court Business Center, 582 Middletown Boulevard, Langhorne, PA 19047. (215) 752-4500. ISSN: 0012-6667.

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Summary: This article presents current perspectives on drug therapies for anorexia nervosa and bulimia nervosa. Topics include diagnostic considerations, drug treatment for anorexia nervosa, and drug treatment for bulimia nervosa. The authors maintain that there is little if any role for pharmacotherapy in anorexia nervosa. Drugs used to promote food intake and weight gain in bulimia nervosa have provided disappointing results. Newer antidepressants, anticonvulsants, benzodiazepines, lithium, fenfluramine, and opiate antagonists may prove useful, although all require further research. 1 table. 85 references. •

Burning Mouth Syndrome: An Update Source: JADA. Journal of the American Dental Association. 126(7): 842-853. July 1995. Contact: Available from ADA (American Dental Association) Publishing Company. 211 East Chicago Avenue, Chicago, Ill 60611. (312) 440-2867. Summary: This article provides an overview of burning mouth syndrome (BMS), a chronic oral-facial pain condition that affects many U.S. adults. The authors provide an update on what is known about the epidemiology, etiology, and treatment of BMS. Specific topics include the clinical presentation of BMS; statistics on the incidence and prevalence of BMS; oral disorders that can result in BMS, such as denture allergy, salivary dysfunction, or taste disturbances; systemic conditions that can result in BMS, such as hematological disorders, nutritional disorders, anemias, central nervous system disorders, psychological disorders, diabetes mellitus, or Sjogren's syndrome; and treatment options, including the use of antidepressants and benzodiazepines. The authors conclude that the dental profession should formulate standardized symptom and diagnostic criteria so that multidisciplinary investigations can identify effective and reliable treatment strategies. 2 figures. 2 tables. 65 references. (AA-M).

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Tinnitus: Keeping Up to Date Source: Hearing Health. 12(6): 40-42. November-December 1996. Contact: Available from Voice International Publications, Inc. P.O. Drawer V, Ingleside, TX 78362-0500. Voice/TTY (361) 776-7240. Fax (361) 776-3278. Website: www.hearinghealthmag.com. Summary: This article reviews some recent research on tinnitus and its management. Topics include tinnitus in children, benefits or detriments of alcohol use in people with tinnitus, drug treatment and tinnitus, psychological factors, and future research, particularly that on children with tinnitus. Drugs discussed include carbamazepine, betahistine hydrochloride, benzodiazepines, propranol, pitzotifen, and antidepressants. The author notes that most children with tinnitus believe it is normal, a regular aspect of every day life. The author stresses that children must be educated about avoiding loud noise.

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Use of Psychotropic Medication in the Management of Problem Behaviors in the Patient With Alzheimer's Disease Source: Medical Clinics of North America. 78(4): 811-822. July 1994. Summary: This article reviews the literature on alternatives to neuroleptics in the treatment of the agitated patient with progressive dementia. Specific neuroleptics discussed are the following: serotoninergic agents (trazodone), azapirones (buspirone), benzodiazepines, beta-blockers, anticonvulsants, and lithium. The authors state that, although a variety of potential alternatives to the neuroleptics in the management of

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agitated behavior in Alzheimer's disease exist, more large, well-controlled studies are needed. At present, neuroleptics remain the standard treatment for this problem. 2 tables, 59 references. •

Management of the Psychotic Patient Source: Oral and Maxillofacial Clinics of North America. 10(3): 457-464. August 1998. Contact: Available from W.B. Saunders. Periodicals Fulfillment, 6277 Sea Harbor Drive, Orlando, FL 32887-4800. (800) 654-2452. Website: www.wbsaunders.com. Summary: This article reviews the pharmacologic management of the psychotic patient, to familiarize oral and maxillofacial surgeons with the care of these patients. The author notes that the trend to outpatient care extends to the psychiatric patient and more health care providers will be faced with the care of this patient population. The author reviews potential drug interactions and clinical considerations for patients already under maintenance therapy. The article covers antipsychotic agents, mood disorders, HCAs (including tricyclic drugs), MAOIs (derivatives of hydrazine or amphetamine), SSRIs (antidepressants), bipolar disorder, and antianxiety agents, specifically benzodiazepines, barbiturates, and buspirone. The emphasis in each section is on pharmacodynamics, drug interactions, and anesthetic concerns. 3 tables. 25 references.

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Pharmacologic Approach to Management of Agitation Associated With Dementia Source: Journal of Clinical Psychiatry. 55(Suppl):13-17. February 1994. Summary: This article reviews the phenomenology of agitation and its pharmacologic treatment in patients with dementia, including the use of benzodiazepines, neuroleptics, beta-adrenergic-blocking agents, serotonergic agents, carbamazepine, and lithium. Persistent and acute agitation may be treated through sedation with neuroleptics or benzodiazepines. However, care should be taken to not maintain patients on these medications for protracted period of time, i.e., beyond 4 to 6 weeks. For chronic agitation, the severe side effects and limited efficacy of neuroleptics and benzodiazepines diminish their usefulness. The authors recommend a trial of the serotonergic agents, including buspirone, trazodone, and serotonin selective reuptake inhibitor antidepressants, as first-line treatment for chronic agitation in patients with dementia. Second-line treatment includes beta-blockers, carbamazepine and lithium when agitation is associated with manic affects. The authors suggests the usage of neuroleptics when agitation is derived from psychotic ideation. The authors state that no gold standard exists for the treatment of chronic agitation in older patients with dementia. They recommend more placebo-controlled, double-blind studies to assess therapeutic efficacy, and these should utilize valid scales to define and rate agitation. 1 table, 58 references.

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Pharmacologic Treatment of Behavioral Symptoms of Alzheimer's Dementia - A Review and a Possible Strategy Source: Clinical Gerontologist. 16(1): 3-16. 1995. Summary: This article reviews the use of both neuroleptics and nonneuroleptics in the treatment of behavioral symptoms of Alzheimer's disease. The author suggests that using current knowledge about the possible neurobiological basis of behavioral symptoms in Alzheimer's disease and the actions of medications may make possible a pharmacologic strategy for the treatment of aggression and agitation in Alzheimer's disease. This strategy may need to consider the specific neural network dysfunction as

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determined by neuroradiologic, electroencephalographic, and neuropsychological testing. The author suggests that proposed strategy is an empirical one that has not been validated through appropriate scientific study, but has been used clinically. The treatment strategy for acute agitation usually depends on antipsychotics for psychotic behaviors and benzodiazepines for nonpsychotic behavior. For chronic psychotic agitation, the strategy suggests use of neuroleptics as a first step, with appropriate drugs added according to patient response. The strategy for chronic nonpsychotic agitation calls for the treatment of specific psychiatric syndromes and neural dysfunctions, with specific suggestions for drug types for use in neural dysfunction. Symptoms other than agitation that may be amenable to a pharmacologic approach are emotional lability, abulia, sleep disturbances, decreased food intake, and inappropriate sexual behavior. 52 references. •

Guidelines for Prescribing Psychoactive Drugs in the Elderly: Part 1 Source: Geriatrics. 46(9): 40-47. September 1991. Summary: This journal article describes guidelines for prescribing psychoactive drugs in the elderly. Primary care physicians are usually the first to see elderly patients with emotional problems secondary to dementia and other psychiatric disorders. Because these problems often can be treated effectively, physicians should have a working knowledge of the guidelines for optimal use of psychoactive medications. This article provides an up-to-date compendium of prescribing information on benzodiazepines and antidepressants for use by primary care physicians in treating elderly patients with cognitive or behavioral dysfunction. Included is practical information on the half-life of drugs, time to steady state, and other data geriatricians need for effective prescribing and dosing.

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Effect of a Program of Diverse Activities on Disturbed Behavior in Three Severely Demented Patients Source: International Psychogeriatrics. 9(4): 423-430. December 1997. Summary: This journal article describes the effects of a daily program of diverse activities on the disturbed behavior of three patients with severe dementia, aged 76, 81, and 82 years. The patients were on a Dutch psychogeriatric ward and had severe disturbed behavior that had not responded to benzodiazepines or antipsychotic drugs. The Behavioral Rating Scale for Psychogeriatric Inpatients, Social Dysfunction and Aggression Scale, and Clinical Global Impression/Improvement Scale were used to assess behavior during baseline, intervention, and followup periods of 4 weeks each. During the intervention period, the patients participated in a twice-daily program of various group, musical, physical, and social activities off the ward. During baseline and followup, they followed the regular ward activities. The patients had different responses to the intervention. One patient worsened during intervention but improved during followup. The second patient improved on global functioning during intervention, and then worsened during followup. The third patient exhibited aggressive behavior which worsened during intervention; during followup, the aggressive behavior improved but global functioning declined. The authors explore possible implications for practice and further research. 3 figures, 2 tables, 25 references.

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Donepezil Improves Symptoms of Delirium in Dementia: Implications for Future Research Source: Journal of Geriatric Psychiatry and Neurology. 11: 159-161. Fall 1998.

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Summary: This journal article discusses a case study of delirium, complicated by preexisting dementia, that was resolved rapidly following initiation of the cholinesterase inhibitor donepezil. The authors suggest that cholinergic dysfunction may have played a role in the etiology of the patient's delirium. Delirium is a common complication of dementia that may produce agitation, which may be refractory to conventional medications such as antipsychotics and benzodiazepines. Delirium may also produce considerable morbidity. Delirium is not always reversible and there is no specific treatment for persistent delirium; the main treatment approach is to treat the underlying medical problem. The authors state that future research needs to be directed at the issue of cholinergic activity in delirium through monitoring serum anticholinergic activity and its response to procholinergic therapy. 17 references. (AA-M). •

Depression, Anxiety, and Sleep Disturbances Source: International Psychogeriatrics. 8(Supplement 3): 415-418. 1996. Summary: This journal article discusses issues in the treatment of depression, anxiety, and sleep disturbances in patients with dementia. The author reviews evidence suggesting that both pharmacologic and nonpharmacologic therapies are effective for the treatment of depression, and that treatment for depression in dementia should focus not only on symptomatic relief but also on functional improvement. He notes that little attention has been given to the treatment of anxiety in patients with dementia, and advises that benzodiazepines should be used with caution in such patients because of the risk of worsening their cognitive function. He also discusses considerations in the effective management of sleep disturbance in patients with dementia, including the use of nonpharmacologic approaches such as activity programs, environmental interventions, and educational interventions.

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Pharmacologic Management of Alzheimer's Disease Source: Clinics in Geriatric Medicine. 14(1): 129-146. February 1998. Summary: This journal article discusses pharmacologic approaches to the management of Alzheimer's disease (AD) and some of its symptoms. The first section discusses treatment strategies using various types of cholinergic drugs, including acetylcholine (ACh) precursors, cholinesterase inhibitors, a combination of ACh precursors and cholinesterase inhibitors, cholinergic agonists, and indirect enhancement of cholinergic activity in the brain. The next three sections address the use of antiinflammatory agents, antiamyloidogenic and antioxidant therapy, and estrogen replacement therapy to prevent or delay the onset of AD. The fifth section examines the management of psychosis and agitation in AD with such medications as antipsychotics, benzodiazepines, trazodone, buspirone, anticonvulsants, beta-adrenergic blockers, lithium, and selective serotonin reuptake inhibitors. Finally, the article discusses the use of selected antidepressant medications for the management of depressive symptoms in dementia. 67 references.

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Cognitive Side Effects of Medications Source: Neurologic Clinics of North America. 16(1): 141-155. February 1998. Summary: This journal article discusses the cognitive side effects of medicines that are commonly used in clinical settings. Researchers provide an overview of the direct effects on the central nervous system from several major clinical drug groups. Their study covers neuropsychiatric drugs (e.g., psychotropic agents, antidepressants, neuroleptics, antiparkinsonian agents) and medicinal drugs (e.g., antihypertensives, cardiac drugs,

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anticholinergics, anti-inflammatory agents, antibiotics). Researchers found that cognitive side effects may be produced by a variety of medications from multiple drug classes. The most commonly implicated drugs are the anticholinergics, benzodiazepines, narcotics, neuroleptics, and sedative-hypnotics. The authors discuss the specific cognitive problems that these drugs may produce. 131 references. •

Clinical Presentation and Pharmacological Therapy in Corticobasal Degeneration Source: Archives of Neurology. 55: 957-961. July 1998. Summary: This journal article evaluates the clinical presentation and treatment outcome of patients clinically diagnosed with corticobasal ganglionic degeneration. Researchers performed a chart review of 147 patients who were seen in movement disorder clinics. Clinical presentation, medications used, response to medications, and adverse effects were recorded. Data showed that parkinsonian features were present in all patients, other movement disorders in 89 percent, and higher cortical dysfunction in 93 percent. Ninety-two patients received dopaminergic drugs; 24 percent received a beneficial effect. Forty-seven of the patients received benzodiazepines; there was myoclonus improvement in 23 percent of these patients and dystonia improvement in 9 percent. Frequent adverse effects included somnolence, gastrointestinal complaints, confusion, dizziness, hallucinations, and dry mouth. The authors conclude that pharmacological intervention was largely ineffective in managing corticobasal degeneration; new treatments are needed. 2 tables, 29 references.

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Treating Sleep Disorders in Patients With Fibromyalgia Source: Journal of Musculoskeletal Medicine. 14(6):25-28,33-34; June 1997. Summary: This journal article for health professionals reviews current knowledge about sleep disorders in patients with fibromyalgia and the treatment strategies currently used. Sleep disturbance may be central to the fibromyalgia syndrome. Many patients have difficulty in falling and staying asleep and awaken unrefreshed with intensified morning aching. Alpha-delta sleep, in which internally triggered arousal results in delta sleep deprivation, appears responsible. Moreover, such triggers may also lead to depressed and anxious mood, fatigue, morning stiffness, and musculoskeletal pain, which, in turn, contribute to the nonrestorative sleep cycle. Success in improving sleep is greatest when general approaches and specific sleep interventions are combined. Psychotherapy, behavioral therapy, and exercise may lead to better sleep habits and symptomatic relief. Tricyclic agents improve sleep and overall functioning. Benzodiazepines administered with nonsteroidal anti-inflammatory drugs may improve sleep and decrease tenderness. 29 references and 2 tables. (AA-M).

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Psychiatric Symptoms and Behavioral Disturbances in Dementia: A Review of Therapy Source: International Psychogeriatrics. 8(Supplement 2): 201-207. 1996. Summary: This journal article reviews selected drug treatments for psychiatric symptoms and behavioral disturbances in dementia. Several different classes of drugs have been used in the treatment of behavioral disorders in dementia: neuroleptics, anticonvulsants, antidepressants, beta-blockers, and benzodiazepines. Neuroleptics are the drugs of first choice for treating behavioral disorders, and they generally are considered to be moderately effective. These drugs are known to improve anxiety and mood; and reduce aggression, agitation, hostility, and uncooperativeness. Anticonvulsants such as carbamazepine and sodium valproate also may be effective in

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some patients with dementia. Antidepressants have been used not only for the treatment of depression but also to reduce agitation, aggression, and shouting in patients without a definable additional affective disorder. Beta-blockers generally have been found to be effective in younger patients with evidence of brain damage, and several reports have suggested that pindolol may be effective in dementia. Patients with dementia of the Lewy body type appear to be particularly sensitive to neuroleptics, and these drugs often result in a severe Parkinsonian-like reaction. Risperidone, a new atypical neuroleptic, may be effective in treating psychotic symptoms in this type of dementia. 1 table, 25 references. •

Criterion Validity: Do the Symptoms Respond to Treatment - Pharmacologic or Nonpharmacologic? Antipsychotic Treatment in Outpatients With Dementia Source: International Psychogeriatrics. 8(Supplement 3): 355-361. 1996. Summary: This journal article reviews the literature on antipsychotic treatment in patients with behavioral disturbances of dementia. First, it reviews results from the four randomized, double-blind, placebo-controlled trials of neuroleptics in dementia which were published in the past 20 years. Then it summarizes findings concerning the efficacy and safety of clozapine, risperidone, and benzodiazepines. Next, the article discusses the optimal dose of haloperidol, the optimal duration of antipsychotic treatment, and antipsychotic side effects. In 1 study of the course of psychopathology, conducted by the author and colleagues, 235 patients with early, probable Alzheimer's disease (AD) were followed at 6-month intervals for up to 5 years. Agitation was found to be the most persistent symptom, which suggests that prolonged treatment may be needed. Finally, the article suggests an approach to initiating and monitoring antipsychotic treatment in older patients with dementia. In the author's opinion, the available data, while limited, suggest that antipsychotic drugs may be effective in treating psychotic symptoms and behavioral problems in some patients with dementia. However, the relative efficacy of antipsychotics in different subtypes of dementia, such as AD and multiinfarct dementia, has not been adequately studied. 35 references.

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Treatment Strategies for Agitation and Psychosis in Dementia Source: Journal of Clinical Psychiatry. 57(Supplement 14): 21-29. 1996. Summary: This journal article reviews treatment strategies for agitation and psychosis in patients with dementia, specifically Alzheimer's disease. It describes types of behavioral disturbances that are associated with dementia and a systematic approach used in evaluating and managing these behavioral complications. It discusses the treatment of psychosis in dementia using traditional antipsychotic agents (haloperidol and thioridazine), newer antipsychotic agents (clozapine and risperidone), and other drugs. It also discusses the benefits and side effects of treatment of agitation in dementia using antipsychotic agents; anticonvulsant agents (carbamazepine and valproic acid); anxiolytic agents (benzodiazepines and buspirone); antidepressants (trazodone and selegiline); serotonin selective reuptake inhibitors (alaproclate, citalopram, fluvoxamine, fluoxetine, and sertraline); cholinergic therapy; and other therapies such as electroconvulsive therapy, hormonal therapy, and phototherapy. 4 tables, 97 references.

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Pharmacotherapy for Long-Term Care Residents With Dementia-Associated Behavioral Disturbance Source: Journal of Psychosocial Nursing. 36(2): 27-31. 1998.

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Summary: This journal article summarizes Federal guidelines for benzodiazepine and antipsychotic drug use in long-term care residents with dementia. The Nursing Home Reform Amendments of the Omnibus Budget Reconciliation Act of 1987 (OBRA 87) have resulted in close supervision of the use of unnecessary drugs for residents in Medicare and Medicaid certified nursing homes. They require documenting the behavioral indication for psychotropic drugs, monitoring their safety and efficacy, drug holidays, behavioral management instead of drugs when possible, and systematic dose reductions unless clinically contraindicated. Long-acting benzodiazepines generally are not recommended for use in older patients. Short-acting benzodiazepines may be used for anxiety, insomnia, and dementia-associated agitated states that represent a danger to the patient or others. Antipsychotics may be used for dementia with psychotic features, continuous crying or screaming that impairs functional status, and dangerous behavior. 3 tables, 14 references.

Federally Funded Research on Benzodiazepines The U.S. Government supports a variety of research studies relating to benzodiazepines. 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 benzodiazepines. 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 benzodiazepines. The following is typical of the type of information found when searching the CRISP database for benzodiazepines: •

Project Title: ABUSE LIABILITY OF BENZODIAZEPINES AND CAFFEINE Principal Investigator & Institution: Griffiths, Roland R.; Professor; Psychiatry and Behavioral Scis; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 01-FEB-1975; Project End 28-FEB-2004 Summary: (Applicant's Abstract) Research in baboons is proposed to characterize the intravenous reinforcing and physical dependence-producing effects of benzodiazepines and also to examine caffeine reinforcement interactions with cocaine and nicotine. Two self-injection studies will determine whether physical dependence enhances the reinforcing effects of a benzodiazepine. A series of three studies will address concerns that the abuse liability of benzodiazepines is enhanced by interactions with opioids by determining whether chronic opioid exposure increases benzodiazepine self-injection and whether the discriminative stimulus effects of benzodiazepines and opioids mutually potentiate each other. One study will determine whether the abuse liability of sedative drugs can be reduced by slowing the rate of drug onset. A final self-injection

2 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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study will explore the concern that flunitrazepam has a particularly high abuse liability. A second series of studies will examine benzodiazepine physical dependence. Studies will examine precipitated withdrawal effects produced by a series of novel partial/selective benzodiazepine receptor agonists in benzodiazepine-dependent baboons. Another study will use drug discrimination methods to examine the effects of these same compounds in benzodiazepine-dependent baboons that have been trained to discriminate the benzodiazepine antagonist flumazenil. A third study will explore using an antagonist to decrease the severity and/or shorten the time course of the spontaneous withdrawal syndrome. Finally, two studies will explore recent findings suggesting that caffeine potentiates the reinforcing effects of cocaine and nicotine by characterizing the effects of caffeine on the self-injection of cocaine and nicotine, and the effects of cocaine and nicotine on caffeine self-injection. Benzodiazepines are among the most widely prescribed of all psychotropic medications and caffeine is the most widely used psychotropic drug in the world. There are health risk concerns about benzodiazepine abuse and physical dependence among polydrug abusers and patients, and also about excessive caffeine use in a significant portion of the population. This research will advance our understanding of factors which contribute to the overuse, abuse and dependence on these widely self-administered drugs, provide valuable insights into possible interactions of these drugs with other widely abused drugs, and will ultimately contribute to the development of improved prevention, control and treatment procedures for various forms of drug abuse. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ACUTE DRUG WITHDRAWAL IN A GENERAL MEDICAL SETTING Principal Investigator & Institution: Weaver, Michael F.; Internal Medicine; Virginia Commonwealth University Richmond, Va 232980568 Timing: Fiscal Year 2002; Project Start 01-JUL-1998; Project End 30-JUN-2004 Summary: This is a proposal for a Mentored Clinical Scientist Development Award to provide supervised experience in clinical research, didactic education, and some clinical activities. This will provide a foundation for a career in academic medicine with opportunities for research, teaching, and some clinical practice. This award will allow the candidate to begin research in substance abuse treatment and Health Services Research (HSR) in a supervised setting. The effects of symptom-triggered therapy versus scheduled dosing for acute withdrawal from alcohol will be studied in a general medical population. The first two years of the award period will be spent taking graduate courses in biostatistics, pharmacology, research design and methodology, attending seminars on HSR topics, and refining the final study protocol by doing a pilot study. Practical clinical experience will be gained in outpatient clinics including rotation through community programs such as a local methadone maintenance clinic, a residential center for pregnant and newly delivered women and their young children, and inpatient substance abuse services in a large urban teaching hospital. Symptomtriggered therapy with benzodiazepines is the treatment of choice for alcohol withdrawal. It has not been studied in a general medical population. Patients admitted to two general medical wards will be assigned as randomly as possible to symptomtriggered or scheduled therapy for acute alcohol withdrawal. They will be regularly assessed by a clinical assessment tool to evaluate its applicability in this population. Data will be collected on concurrent medical problems, total dose of medication for withdrawal, duration of treatment, complications, length of stay, and recidivism. The medication protocols will be evaluated in terms of acceptance by nurses and physicians, especially housestaff. The data will be evaluated from a HSR standpoint to help

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determine the most cost-effective regimen for acute drug withdrawal in a general medical population. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ALPHA1 PATHOPHYSIOLOGY

ADRENOCEPTOR

SUBTYPES

AND

ROLE

IN

Principal Investigator & Institution: Perez, Dianne M.; Associate Staff; Cleveland Clinic Foundation 9500 Euclid Ave Cleveland, Oh 44195 Timing: Fiscal Year 2002; Project Start 15-JUL-1999; Project End 30-JUN-2003 Summary: Our major objective is to elucidate the molecular and biochemical mechanisms both in vitro and in vivo involved in binding and activation of alpha1adrenergic receptors (ARs) and its subsequent action on the autonomic nervous system. Alpha1-adrenergic receptors are members of the G-protein-coupled receptor family of proteins that mediate the effects of the sympathetic nervous system by binding the endogenous neurotransmitters, epinephrine and norepinephrine. Signal transduction by alpha1-ARs is involved in a variety of responses such as neurotransmission, smooth muscle contraction, cardiac and other organ system homeostasis. These receptors are a therapeutic target in the current management of hypertension, benign prostatic hypertrophy and impotence. Alterations in the signaling pathways and/or receptors themselves may contribute to the pathogenesis of neurological and cardiovascular diseases. Thus, a detailed understanding of the structure-function of these receptors and their signal transduction mechanisms will be crucial to our understanding of the pathology and treatment of these diseases. Our laboratory has made considerable strides into the structure-function of alpha1-ARs subtypes (alpha1a, alpha1b, alpha1d) by characterizing determinants in the binding pocket that contribute to agonist binding and subtype selectivity. We have also through the use of constitutively active mutations provided insights into the activation mechanism. Based on these results, we now propose to address the following specific aims on structure-function analysis in vitro by concentrating on how antagonists and benzodiazepines bind and modulate alpha1-AR function and the mechanism of the poor efficacy of the alpha1d-subtype. This will enhance our understanding of the binding pocket, the signaling differences between alpha1-subtypes and may enhance new drug design. We will also explore possible pathologies from alpha1-subtype overactivity in vivo and to more clearly define the role of the alpha1a-subtype in cardiovascular function. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: AMPHETAMINE, GABA TRANSMISSION, AND BEHAVIOR Principal Investigator & Institution: Gruen, Rand J.; Psychiatry; New York University School of Medicine 550 1St Ave New York, Ny 10016 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 31-MAR-2004 Summary: (Adapted from the Investigator's Abstract) A large percentage of individuals who are dependent on amphetamine (amph), abuse other drugs. The most frequent pattern of polydrug abuse involves the conjoint use of amph and drugs with anxiolytic and/or sedative properties-i.e., benzodiazepines (BZs) and alcohol. Polydrug abusers are more difficult to treat due to complications which arise during detoxification involving multiple substances, and they are more likely to experience trauma, accidents, and disruptions in their family, work, and social environment. The broad, long-term objectives of this research then, are to identify biological factors which underlie this pattern of polydrug abuse. The role of GABA in amph use has not been studied

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extensively. In addition to its rewarding properties, amph intoxication is associated with a sense of anxiety and tension. Ligands that bind to the GABA-A/BZ receptor complex play a central role in anxiety. Drugs like alcohol and BZs, which exert some of their effects through the GABA-A/BZ receptor complex, appear to reduce the anxiogenic effects of amph-this may provide an incentive for their use. The specific aims of this research are to: (1) Study the effects of acute amph on behavior and GABA-A receptor binding. We will: a) examine the time-course of the effects of acute amph; and b) determine whether the effects of acute amph on behavior and GABA-A receptor binding are mediated through the GABA-A/BZ receptor complex; (2) Study the effects of repeated intermittent exposure to amph on behavior and GABA-A receptor binding. We will: a) determine whether repeated exposure leads to the development of tolerance with respect to the behavioral and receptor changes seen following acute challenge; b) determine whether reinstatement of the anxiogenic behavioral response following a dose escalation in preexposed animals is mediated through the GABA-A/BZ receptor complex; c) examine the duration of the effects of preexposure to amph; and (3) Examine the effects of amph on BZ receptor binding. We will: a) examine the time-course of the effects of acute amph; b) determine whether repeated exposure leads to the development of tolerance with respect to the receptor changes seen following acute challenge. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANESTHETIC EFFECTS ON GLYCINE AND GABA-A RECEPTORS Principal Investigator & Institution: Mihic, S John.; Associate Professor; Neurobiology; University of Texas Austin 101 E. 27Th/Po Box 7726 Austin, Tx 78712 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 30-JUN-2005 Summary: (provided by applicant): The overall objective of the proposed work in this developmental grant application is to further understanding of the mechanisms of ligand-gated ion channel activation, desensitization and allosteric modulator action. To this end we propose the electrophysiological characterization of newly-discovered mutants of glycine alpha1 and GABA-A alpha1 and beta2 receptor subunits. Single amino acid mutations of these subunits have been identified that result in channels that open spontaneously and desensitize in the absence of agonist. Tonic opening is revealed by a reversible strychnine- or bicuculline-induced outward current. Tonically-opening glycine and GABA-A receptors will be transiently expressed in mammalian HEK 293 cells and characterized using a fast drug application system. The use of a fast drug exchange system will allow for an accurate assessment of rates of channel opening, closing and desensitization after applying GABA-A and glycine receptor agonists or antagonists to receptors composed of wild-type or mutated subunits. Single channel outside-out patch recordings of our tonically-open channels are hypothesized to display bursts of channel opening events separated by quiescent, desensitized periods. We will then take advantage of the tonic opening and desensitization that occur spontaneously in these mutated receptors to clarify the molecular mechanisms underlying the actions of allosteric modulators. GABA and glycine receptor function is allosterically modulated by numerous classes of agents such as the barbiturates, benzodiazepines and steroidal and volatile anesthetics. Using the receptor mutants we have already created, and new mutants we propose to make, we will test the hypothesis that modulatory concentrations of these agents affect the functioning of tonically-open GABA-A and glycine receptors in the absence of agonist binding to the neurotransmitter receptor binding site, allowing us to dissociate modulator-induced stabilization of open channel states and effects on desensitization from their effects on increasing the affinity of

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neurotransmitter for its receptor. The work proposed will increase understanding not only of basic receptor/channel processes, but also shed insight into the molecular mechanisms of receptor modulation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANXIOLYTIC EFFECTS AND ABUSE OF BZ RECEPTOR LIGANDS Principal Investigator & Institution: Rowlett, James K.; Assistant Professor; Psychiatry; Harvard University (Medical School) Medical School Campus Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 15-JUN-1998; Project End 31-MAY-2004 Summary: (Applicant's Abstract) Benzodiazepines (BZs) are widely prescribed for the management of anxiety and sleep disorders, but their clinical usefulness is constrained by a significant potential for abuse and dependence. Considerable research is now focused on elucidating the mechanisms of action underlying the behavioral effects of BZs and related drugs, with the goal of increasing clinical utility and reducing abuse liability. Our proposed research will specifically evaluate the role of BZ receptor selectivity and intrinsic efficacy as determinants of the therapeutic vs. abuse -related effects of this important class of drugs. BZ ligands differing in receptor selectivity and/or agonist efficacy will be used as probes to characterize mechanisms of action in nonhuman primate models predictive of anxiolytic activity, subjective effects, and abuse liability. Anxiolytic activity will be evaluated in rhesus monkeys using conflict procedures in which food-maintained behavior is concurrently suppressed by response produced presentations of an aversive stimulus. Subjective effects will be evaluated in monkeys trained to discriminate the conventional BZ agonist triazolam or the BZ 1selective agonist zolpidem from vehicle. Abuse potential will be evaluated using fixedand progressive-ratio schedules of i.v. drug self-administration. Quantitative pharmacological tools including isobolographic analysis and in vivo apparent pA2 analysis will be used in conjunction with drug interaction studies to dissociate effects due to receptor selectivity and agonist efficacy. Identification of compounds that are effective anxiolytics lacking abuse potential in our studies will provide needed information for developing safer and more broadly effective anti-anxiety medications, as well as compounds that may be beneficial in the pharmacological management of BZ dependence. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BABAA RECEPTORS IN AGING & ALZHEIMER'S DISEASE Principal Investigator & Institution: Gandy, Samuel E.; Director; Lankenau Institute for Medical Research Wynnewood, Pa 19096 Timing: Fiscal Year 2002; Project Start 30-SEP-1999; Project End 31-JUL-2004 Summary: (Applicant's abstract) Gamma-amino butyric acid (GABA), the major inhibitory neurotransmitter in the mammalian CNS, hyperpolarizes neuronal membranes by opening a C1 channel intrinsic to the GABA A receptor. The proposed studies investigate the anatomical features and expression of selected GABA A receptor subunits (i.e., alpha1, alpha2, alpha3, alpha4, alpha5, beta1-3, gama2) in human hippocampus of non-pathologic mature and aged individuals (30-90 years of age) and those with Alzheimer's disease (AD) pathology. Underlying these studies are investigations of the P.I. and co-investigators demonstrating (I) subunit specific alteration (i.e., alpha1) in the CA1 field and dentate gyrus of aged rats; (ii) GABA A receptor subunit protein and mRNA alterations (i.e., alpha1, beta2, beta3) in the hippocampal formation of aged brains with AD pathology; (iii) time-dependent

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alterations of GABA A beta2/3 immunoreactivity in the dentate gyrus following perforant pathway lesions. In addition, pharmacological studies have demonstrated altered drug sensitivities, for example, to benzodiazepines, in the elderly. To date, it is not known the extent to which altered drug responses in the elderly may be attributed to emotional or physical disease, over- or undernutrition, use or abuse of other medications, or alterations in the molecular composition of the GABA A receptor. Throughout these studies we will employ immunohistochemical, in situ hybridization, in situ autoradiogaphic, and biochemical techniques in order to study the regional and laminar pattern of GABA A receptor subunit protein and mRNA expression in the hippocampal formation of aging individuals (SPECIFIC AIM 1) and those with varying extent of AD pathology (SPECIFIC AIM 2). It is our hypothesis that selected GABA A receptor subunits will display differential levels of expression and binding within the various regions of the hippocampus. Moreover, brain tissue obtained from elderly patients will not only show altered levels of expression of specific GABA A subunits, but will have a different subunit composition of the GABA A receptor complex compared to controls. In AD, we hypothesize that these receptor subunits will also display altered levels of expression and binding within selected subregions of the hippocampus. In addition, many of these changes will occur during the early phases of the disease (i.e., plastic/compensatory phase) and be unique from those observed during the end stages of the disease (i.e., neurodegenerative phase). A unique aspect of this study is the study of both aging and AD subjects. Notably, a comparison of these two populations of subjects will provide us with the opportunity of differentiating whether alterations in the anatomy of specific GABA A receptor subunits are associated with normal aging or represent a neuropathologic process. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: KINETICS

BENZODIAZEPINE MODULATION

OF GABAA RECEPTOR

Principal Investigator & Institution: Czajkowski, Cynthia M.; Associate Professor; Physiology; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2002; Project Start 15-SEP-2002; Project End 30-JUN-2007 Summary: (provided by applicant): Benzodiazepines (BDZs) exert anxiolytic and antiepileptic effects in the central nervous system (CNS) by allosteric modulation of the GABAA receptor Cl- current (IGABA). Because of the widespread clinical utility of these drugs, understanding the mechanism(s) by which BDZs alter ion channel function is an important pharmacological inquiry. To identify the structural determinants underlying BDZ modulation of kinetic transitions of channel activation, one must first determine the effects of BDZs on identified, wild-type GABAA receptors. This will be approached using rapid drug application techniques and single-channel recordings to test which of the microscopic kinetic rate constants are altered by modulatory BDZs in a1 B2g2 receptors. We will make use of mutations in the GABA binding site, the pore region, and the extracellular loop to tease apart the contributions of BDZs to binding/unbinding and gating/desensitization of IGABA. We will also make use of tethered tandem subunits to functionally separate the contributions of each of the two GABA binding sites to these processes. The studies outlined in this application will help to establish the functional mechanisms of action for clinically relevant drugs on a major CNS variant of the GABAA receptor, and aid in establishing testable hypotheses regarding structurefunction relationships in this and other ligand-gated ion channels. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BENZODIAZEPINE-INDUCED GABAA RECEPTOR PLASTICITY Principal Investigator & Institution: Olsen, Richard W.; Professor; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002 Summary: The GABA inhibitory synaptic system plays a major role in the central nervous system and is implicated in human neurological and psychiatric disorders such as epilepsy, stress, anxiety and panic disorders, sleep disorders, and drug dependence, especially to benzodiazepines and ethanol. The major postsynaptic GABA receptors involved in rapid inhibitory neurotransmission are the GABA/A receptors (GABA). GABAR proteins are subject to regulation at the level of transcription, translation, assembly, cell targeting, and the functional level. Endogenous regulation includes modulation by phosphorylation, zinc ions, and neuroactive steroids. GABAR are the known target of numerous clinically relevant drugs, including anti-epileptic antianxiety, and sedative/hypnotic/aesthetic agents. These include the widely used benzodiazepines, barbiturates, and possibly alcohol. GABAR are widely accepted as the major candidate molecular target of general anesthetic action. Their predominant role in the brain makes GABA likely players in the normal plasticity mechanisms that accompany ordinary and extraordinary experiences. By subjecting rats, or in some cases, cells, to somewhat extraordinary experiences that are considered to involve GABAR, we will investigate whether plastic changes in GABAR occur and the molecular and cellular mechanisms of the long-term modifications. In particular, chronic exposure of rats to benzodiazepines, but probably an elevation of GABAR function, leads to tolerance, especially to the anti-epileptic actions of these drugs. Tolerance is accompanied by a reduced GABAR function, reduced enhancement of GABAR function by benzodiazepines, and uncoupling of GABA- benzodiazepine binding measured in vitro. Tolerance to benzodiazepines can be mimicked in cells expressing recombinant GABAR that lack normal transcriptional control, and can be reversed rapidly by exposure in rats and in cells by exposure to the benzodiazepine antagonist flumazenil. This strongly suggests that the tolerance and reversal result from a physicochemical modification of the GABAR protein itself. This project will attempt to unearth this molecular mechanisms of plasticity. Ultimately therapeutic strategies could be based on our studies, aimed rationally at preventing the unwanted or pathological alterations in GABA/A receptors characteristic of several neurological and psychiatric disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BIOACTIVE CYCLOADDUCTS

COMPOUNDS

FROM

ACYLNITROSO

Principal Investigator & Institution: Miller, Marvin J.; George & Winifred Clark Chair Professor; Chemistry and Biochemistry; University of Notre Dame 511 Main Bldg Notre Dame, in 46556 Timing: Fiscal Year 2003; Project Start 15-MAY-2003; Project End 30-APR-2007 Summary: (provided by applicant): The general hypothesis of this proposal is that cycloadducts from Diels-Alder reactions of dienes with transient acyl nitroso moieties, generated by oxidation of hydroxamic acids, can serve as versatile building blocks for syntheses of a number of important and often novel bioactive molecules. The specific aims include (1) methodology development and enhancement, and (2) applications to the syntheses and study of focused targets. Methodology enhancement will include hydroxamate, 1, and diene, 3, variation, alternative asymmetric methods, and determination of the scope and limitations of a new pi-allyl polarity reversal process

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that will significantly increase synthetic versatility. Applications will include both nucleophilic and electrophilic C-O bond cleavage of 4 with N-O bond retention, in both intermolecular and intramolecular processes; N-O bond cleavage to give substituted carbocycles 5; and C=C bond reactions to give 6 and other intermediates. Products from these reactions will be used to prepare focused sets of targets, including: novel 5lipoxygenase inhibitors, neuraminidase inhibitors, benzodiazepines, diazepines, carbocyclic nucleosides and analogs (aristeromycin, carbavir, abacavir, stavudine, carbocyclic oxanosine, and their nor analogs, carbocyclic forms of polyoxins, sinefungin, nucleoside Q, puromycin and analogs), novel phosphodiesterase inhibitors, streptazolin, novel oxazolidinone antibiotics, diketopiperazines (tryprostatin analogs), novel amino acids and peptides related to bacterial diaminopimelic acids (DAP) as well as new amino acids and peptides that represent the first of a novel class of antibiotics. That this tremendous variety of targets can be accessed from the same set of precursors attests to the tremendous potential of readily available acylnitroso cycloaddition products for the design, synthesis and study of bioactive compounds, many of which will be novel. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHRONIC NEUROCHEMISTRY

BENZODIAZEPINES:

BEHAVIOR

AND

Principal Investigator & Institution: Greenblatt, David J.; Professor and Chair; Pharmacol & Exper Therapeutics; Tufts University Boston Boston, Ma 02111 Timing: Fiscal Year 2002; Project Start 30-SEP-1987; Project End 31-JAN-2006 Summary: Benzodiazepine agonists continue to be the principal pharmacologic option available for the treatment of anxiety, panic disorders, and insomnia. Despite an overall record of efficacy and safety that is generally favorable, concerns regarding tolerance, dependence, withdrawal syndromes, and abuse of benzodiazepines remain issues of medical and public health importance. Also of concern is the usage of these agents by the elderly, who may have increased susceptibility to adverse CNS depressant effects. There is continuing need for basic mechanistic data on the causes and consequences of tolerance and withdrawal; such data can form the basis for strategies to identify patients at highest risk, or to develop other pharmacologic interventions to minimize the risk of tolerance and dependence. We propose to continue and broaden our ongoing research program having this overall objective. The core of the model involves male CD-1 mice that receive continuous infusions of benzodiazepine agonists, or vehicle control, for up to 14 days via implanted osmotic pumps. During the period of infusion, and in the 7-day post-infusion withdrawal period, the following outcomes are determined: computerized ambulatory activity; pentylenetetrazole seizure threshold; in vivo benzodiazepine receptor occupancy; in vitro receptor binding; GABA(A) receptor function; receptor autoradiography; receptor subunit mRNA expression; and plasma and brain concentrations of infused substances. The principal research questions to be addressed include the following: a. Do benzodiazepine agonists with relative selectivity for the BZ1 receptor subtype have reduced liability to produce tolerance, dependence and withdrawal? b. Does the protein kinase C second messenger pathway have a modulatory role in benzodiazepine-associated tolerance? c. Does the excitatory amino acid (EAA) receptor system co-modulate the development of tolerance and withdrawal associated with benzodiazepine agonists, and does pharmacologic antagonism of specific EAA receptor systems modify these phenomena? d. Do aging organisms have differential patterns of benzodiazepine tolerance and withdrawal? Are such differences explained by protein kinase C or EAA regulatory systems? These studies should continue to provide mechanistic data relevant to the clinical management and

22

Benzodiazepines

prevention of tolerance and dependence problems associated with therapeutic use of benzodiazepine agonists. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SENSITIVITY

CLINICAL-GENETIC

VARIATION

IN

GABA

/ALCOHOL

Principal Investigator & Institution: Roache, John D.; Associate Professor of Psychiatry and Ph; Psychiatry; University of Texas Hlth Sci Ctr San Ant 7703 Floyd Curl Dr San Antonio, Tx 78229 Timing: Fiscal Year 2002; Project Start 05-SEP-2002; Project End 31-AUG-2005 Summary: (provided by applicant): NIAAA is dedicated to understanding the genetic factors that increase vulnerabilIty to alcoholism. Previous research has suggested that children of alcoholic fathers are at increased risk, perhaps because of a reduced or altered sensitivity to the effects of alcohol. A functional polymorphism of the GABA-A receptor a6 gene has been identified as a plausible cause for reduced sensitivity to motor impairment by alcohol or benzodiazepines. The polymorphism is a Proline to Serine amino acid substitution at position #385 (i.e., Pro385Ser). This is a revised R21 application that, in response to previous review critiques, has narrowed the focus of this exploratory study to more certainly address the role of the Pro385Ser a6 polvmorphism in conferring an altered drug response to positive modulators of the GABA-A complex in the children of alcoholic fathers who have not yet exhibited alcohol abuse or dependence. The proposal applies a human pharmacogenetic approach to experimentally test the hypothesis that within the population of male and female social drinkers aged 21-25 years who are presumed at risk for alcoholism because of a Family History of paternal alcoholism, there remain differences in sensitivity to motor impairment from alcohol and benzodiazepines that can be accounted for by the presence of the Pro385Ser polymorphism. Furthermore, we will explore whether this reduced impairment also may be associated with reduced self-reports of intoxication or enhanced euphoric or reinforcing effects. Participants who are social drinkers without a DSM- IV, Axis-I diagnosis, will be selected into two groups based upon whether they are homozygous (Pro/Pro) or heterozygous (Pro/Ser) for the serine-substituted allele (Pro385Ser) of the a6 subunit. In a 2x5 factorial mixed-model ANOVA design, participants from each of these groups will be tested in a crossover study administering challenge doses of placebo, ethanol, and triazolam in a laboratory environment where subjective, motor, and behavioral responses can be repeatedly assessed using standard techniques with which the investigators have a great deal of experience. This study will substantially extend our knowledge of functional differences in the pharmacodynamic effects of GABA-A positive modulators that may be attributable to the a6 polymorphism or other associated genes co-occurring within the same chromosomal cluster. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DIRECT INTERACTION BETWEEN GABA-A AND GABA-B RECEPTORS Principal Investigator & Institution: Hall, Randy A.; Pharmacology; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2008 Summary: (provided by applicant): Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the mammalian brain. GABA exerts its physiological actions in the brain via the activation of two distinct types of receptor: GABA-A

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receptors, which are ligand-gated ion channels, and GABA-B receptors, which are G proteincoupled receptors. GABA-A and GABA-B receptors are known to exhibit forms of cross-talk and mutual regulation for which no mechanism has been defined. This project aims to study the importance of a novel and direct interaction found between the GABA-BR1 receptor and the gamma2 subunit of the GABA-A receptor. This physical association may provide a mechanism to allow for direct cross-talk between GABA-A and GABA-B receptors. The structural determinants and physiological significance of this interaction, however, are completely unknown at the present time. The specific regions of GABA-BR1 and the gamma2 subunit of the GABA-A receptor involved in mediating their interaction will be elucidated using a mutagenesis approach in combination with both co-immunoprecipitation and fusion protein pull-down studies. The effects of GABA-A receptor association on GABA-B receptor pharmacology will be studied in ligand binding assays, and GABA-A receptor modulation of GABA-B receptor signaling and internalization will also be analyzed. Furthermore, GABA-B receptor regulation of GABA-A receptor pharmacology, channel activity and phosphorylation will be examined, with an emphasis on determining the functional importance of the direct interaction between GABA-BR1 and the GABA-A receptor gamma2 subunit. These studies will shed new light on the regulation of cellular responses to GABA and the molecular basis for cross-talk between GABA-A and GABAB receptors. Such information is critical for a comprehensive understanding of pharmaceuticals acting on GABA receptors. GABA-A receptors are the targets for such commonly prescribed therapeutic drugs as benzodiazepines and barbiturates, while the more recently-identified GABA-B receptors represent excellent potential targets for novel therapeutic drugs aimed at treating disorders such as schizophrenia, epilepsy, anxiety, chronic pain and depression. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DISCRIMINATIVE EFFECTS OF BENZODIAZEPINE WITHDRAWAL 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 2002; Project Start 15-MAR-1995; Project End 31-JAN-2007 Summary: Benzodiazepines and related gamma-amino butyric acid (GABA)A modulators are used widely for their anxiolytic, hypnotic and anti- convulsant effects. These same compounds are also abused, both alone and in combination with other classes of drugs (e.g., opioids), and long- term use of benzodiazepines can lead to clinically significant physical dependence. The GABAA receptor complex is the site of action of other drugs of abuse (e.g., ethanol) and GABAergic systems, in general, are thought to indirectly modulate the effects of still other drugs of abuse (e.g., cocaine). Much has been learned over the past 10 years from molecular studies on GABA receptors, yet little of this knowledge has been applied to studies in behaving organisms, particularly with regard to GABA neurobiology and substance abuse. Procedures have been developed under this grant for studying discriminative stimulus effects of GABAA modulators in rhesus monkeys and studies proposed in this application will use those procedures to investigate the neurobiology of drugs that vary in their actions on GABAergic systems. Studies under Aim 1ill will compare GABAergic and other drugs for their ability to prevent and reverse benzodiazepine withdrawal and also to mimic the subjective (discriminative) effects of benzodiazepine in normal subjects. A parallel study (Aim II) will establish a discrimination with flumazenil in monkeys treated daily with the a1-s3lective positive modulator zolpidem to test whether this widely-prescribed sedative/hypnotic produces dependence that can be

24

Benzodiazepines

differentiated from that produced by diazepam.Neuroactive steroids will be studied under Aim III to see whether th eye modify the behavioral effects of other compounds that act at the GABAA receptor complex. This study is founded on positive preliminary data with pregnanolone and a literature showing that neuroactive steroids uncouple benzodiazepine receptors from the GABAA receptor complex in vitro. Blind evaluation of compounds will continue the auspices of the Drug Evaluation Committee of the College on Drug Dependence under Aim IV. Collectively, these studies will provide important quantitative information on the nature of drug/receptor and drug/drug interactions for GABAA modulators and related drugs. These data will promote an understanding of GABAergic neurotransmission and abuse liability for a variety of clinically relevant compounds. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DRUGS OF ABUSE: NEURONAL SURVIVAL AND SIGNALING Principal Investigator & Institution: Moulder, Krista L.; Psychiatry; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 01-FEB-2003; Project End 31-JAN-2005 Summary: (provided by applicant): The broadest objective of the proposed research is to characterize the changes in synaptic signaling that accompany increases and decrease in electrical activity. Chronic exposure to drugs of abuse such as ethanol, barbiturates, and benzodiazepines causes a downregulation in electrical activity, which ultimately leads to neuronal death. The goal of Aim 1 is to determine whether this decrease in neuronal activity results in reduced neurotransmitter release because of drug effects on Ca2+ currents, or in enhanced neurotransmitter release through initiation of homeostatic mechanisms. Such changes in synaptic signaling could either lessen or intensify the effects of drugs of abuse on neuronal survival. The goal of Aim 2 is to determine the effects on synaptic signaling caused by mimicking increased electrical activity with K+ depolarization. Preliminary data indicate that depolarization curtails development of glutamatergic synapses, while leaving inhibitory currents intact. Experiments will be conducted to distinguish whether a presynaptic and a postsynaptic mechanism accounts for this effect of K+ on excitatory currents. Both Aim 1 and Aim 2 will utilize whole-cell, patch-clamp techniques in a hippocampal microculture paradigm, which will facilitate examination of synaptic electrophysiology. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: EMOTIONAL CONTROL OF SEDATIVE SELF-MEDICATION IN PTSD Principal Investigator & Institution: Casada, John H.; Psychiatry; University of Texas Hlth Sci Ctr San Ant 7703 Floyd Curl Dr San Antonio, Tx 78229 Timing: Fiscal Year 2002; Project Start 01-MAR-2001; Project End 29-FEB-2004 Summary: (Applicant's Abstract) Candidate: John Casada, M.D., Ph.D. is an Assistant Professor engaged in research and clinical care focusing on posttraumatic stress disorder (PTSD). His primary career goal is to become an independent investigator conducting clinical research on the interaction of PTSD and sedative drug abuse. Though he has completed training in basic neuroscience and has conducted psychophysiology research in PTSD, he has no training in substance abuse research. Therefore, he plans to pursue training in grant preparation, human laboratory research methods, data interpretation, manuscript preparation, and operant behavioral theories essential to substance abuse research. Environment: Dr. Casada has received departmental support for his PTSD

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studies and the support of his chairman, Charles Bowden, M.D., in establishing the Emotional Trauma Program, which serves to coordinate PTSD research activities at the University Hospital System and Veterans Administration Hospital. This Mentored Career Development Award will allow Dr. Casada to formalize a mentoring relationship with John Roache, Ph.D. and provide protected time to develop research expertise and career development opportunities in collaboration with the NIDA-funded researchers in the Division of Alcohol and Drug Addiction Research. The proposed research will use human laboratory techniques to assess the role of highly arousing, negative valence emotional states, such as anxiety and anger, to promote self-medication with benzodiazepines and alcohol in PTSD patients. To accomplish this, four tasks (Guided Muscle Relaxation, Stroop Color-Word Task, Script-Driven Imagery, and the Point Subtraction Aggression Paradigm) will be used to experimentally vary levels of arousal and negative valence in 18 PTSD patients and 18 subjects who have experienced trauma but never developed PTSD. Motivation and preference for alprazolam and alcohol will be assessed by the Multiple Choice Questionnaire (MCQ) under double blind, double dummy conditions. Emotional responses will be assessed using skin conductance and heart rate as measures of arousal, corrugator electromyogram as an indicator of negative valence, and anxiety and anger ratings as self-report measures of subjective mood. This experiment will be the first to assess sedative drug self-administration in PTSD patients under controlled conditions in the human laboratory. These data will determine the role of anxiety and anger types of emotional reactions as a motive for self-medication in PTSD patients. More importantly, the data also will provide practical information for the clinical treatment of PTSD patients and others with anxiety who may be at risk for abusing prescription anxiolytics or alcohol. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GABA A RECEPTOR MODULATORS IN THE DEVELOPING RAT FOREBRA Principal Investigator & Institution: Henderson, Leslie P.; Professor; Physiology; Dartmouth College 11 Rope Ferry Rd. #6210 Hanover, Nh 03755 Timing: Fiscal Year 2002; Project Start 28-SEP-2000; Project End 30-JUN-2004 Summary: (Adapted from the applicant's Description) Anabolic androgenic steroids (AAS) are synthetic derivatives of testosterone that in recent years have become significant drugs of abuse among preteen and teenage children. AAS are known to elicit detrimental effects on neuroendocrine function, as well as increase psychiatric symptoms, including anxiety, paranoia, hostility, and aggression in adults. However, little is known as to the mechanism of action of these compounds in the central nervous system, and even less is known about how these compounds may act in the developing brain. Neural transmission mediated by GABAA receptor is the primary molecular target for a wide range of both therapeutic and abused drugs, including neurosteroids, benzodiazepines, and ethanol. The investigators have shown recently that AAS induce rapid, reversible, and region-specific modulation of GABAergic currents in the forebrain of prepubertal rats, and thus can be added to the list of substances that act as allosteric modulators of this channel. Both the ontogeny of GABAA receptor subunit gene expression and developmental changes in receptor pharmacology have been well described in the hippocampus and cerebellum during the first two weeks of postnatal development. In contrast, there is a dearth of information delineating developmental changes in receptor pharmacology for other forebrain regions or in the hypothalamus, and few studies have assessed changes in GABAA receptor expression associated with puberty. In particular, no experiments have been performed to determine if sensitivity

26

Benzodiazepines

to AAS is significantly different during the progression from puberty to adulthood. In this application, the investigators will use molecular biological and electrophysiological approaches to determine if, concomitant with puberty, there are significant changes in GABAA receptor subunit expression, as well as the ability of AAS to modulate GABAergic synaptic currents. In addition, the investigators will use electrophysiological and behavioral approaches to determine if chronic AAS exposure in peripubertal versus adult rats induces significant changes in the ability of benzodiazepines or neurosteroids, as well as the AAS, to modulate GABAA receptor currents and to elicit anxiolytic or sedative effects. Together, these studies will demonstrate if puberty is associated with significant changes in the acute or chronic actions of AAS at the GABAA receptor, and thus provide important new information to indicate if adolescents are at increased risk for abuse of AAS or other psychoactive drugs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GABAA RECEPTOR CHANNEL ALTERATION BY PROLONGED SEIZURES Principal Investigator & Institution: Macdonald, Robert L.; Professor; Neurology; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 20-JAN-2000; Project End 30-NOV-2003 Summary: (Verbatim from the Applicant's Abstract) While most partial and generalized seizures are relatively brief in duration, during some seizures, early termination fails and a prolonged epileptic state occurs that has been termed status epilepticus. Status epilepticus is relatively common, has a high morbidity and mortality and is a medical emergency requiring immediate treatment. Spontaneous seizure termination may involve activation of gamma-aminobutyric acid (GABA) receptor (GABAR)-mediated inhibition. If the GABAergic inhibition fails to terminate the seizure, a progressive reduction of GABAR-mediated inhibition develops that, when severe enough, results in a prolonged seizure. Status epilepticus in humans is treated acutely with benzodiazepines as well as barbiturates, which enhance GABAR-mediated inhibition. However, benzodiazepines are often efficacious early but not late in status epilepticus. We have shown that properties of dentate granule cell GABAR are altered during prolonged seizures in rats, with a reduction in benzodiazepine and zinc sensitivity without a change in GABA or pentobarbital sensitivity. These observations suggest that GABAR function changes during prolonged seizures, extending seizure duration and producing refractoriness to benzodiazepine treatment. Development of an understanding of this seizure-induced receptor plasticity would enhance understanding of spontaneous seizure termination and permit development of new treatment strategies for status epilepticus. The hypothesis to be tested is that during prolonged seizures, hippocampal dentate granule cell GABAR pharmacological and biophysical properties change due either to a change in receptor subtype composition or to receptor phosphorylation. The specific aims are to determine the : 1) dependence on seizure duration of development of insensitivity to benzodiazepines, 2) time course of development of decreased sensitivity of granule cell GABAR currents to diazepam and zinc, 3) sensitivity of granule cell GABAR currents GABAR modulators following prolonged seizures, 4) transient and steady state kinetic properties of granule cell GABAR single channel currents following prolonged seizures, 5) rate of recovery of regulation by diazepam and zinc of granule cell GABAR current following prolonged seizures, 6) rate of recovery of regulation by allosteric regulators of granule cell GABAR current following prolonged seizures, 7) dependence on PKA of recovery of granule cell GABAR current following prolonged seizures, 8) dependence on other kinases of

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recovery of granule cell GABAR current following prolonged seizures and 9) regulation of benzodiazepine, zinc and other allosteric regulator sensitivity of GABARs by phosphorylation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GABAPENTIN DETOXIFICATION

AND

LORAZEPAM

IN

OUTPATIENT

Principal Investigator & Institution: Malcolm, Robert J.; Professor; Medical University of South Carolina 171 Ashley Ave Charleston, Sc 29425 Timing: Fiscal Year 2002 Summary: The alcohol withdrawal syndrome (AWS) has been treated for nearly forty years with the remarkably safe and effective benzodiazepines (BZs). In the outpatient treatment of AWS, interactions with alcohol and the abuse liability of BZs invite comparisons with agents that do not share these susceptibilities. In our original Alcohol Research Center component comparing Lorazepam (LZ) to Carbamazepine (CBZ), the latter was significantly more effective in suppressing the acoustic startle response, and anxiety and depressive symptoms during treatment. In the immediate seven-day post treatment, LZ subjects showed higher levels of multiple dimensions of AWS symptoms, including higher withdrawal scores, poor sleep, and greater subjective discomfort than CBZ. CBZ, useful in research has limited clinical applications because of its widespread interactions and uncommon but serious toxicities. In the present application, we propose a double-blind controlled trial of gabapentin (GBP, 80) vs. LZ (N=80) in treatment seeking outpatients experiencing AWS. Multiple domains of AWS will be evaluated during a five-day outpatient treatment interval and a seven-day post treatment phase. Serial measures include electrophysiologic tests of eye blink acoustic startle response, aggregate withdrawal symptoms as evaluated by the CIWA-Ar, subjective assessments of sleep, global discomfort, anxiety, depression, and need for additional medications. Side effects and safety will be compared. GMP, a unique anticonvulsant, is not a controlled substance, soon will be generic, has benign side effects, has no interactions with other drugs, and has limited interactions with alcohol. Side effects and safety will be compared. GBP, a unique anticonvulsant, is not a controlled substance, soon will be generic, has benign side effects, has no interactions with other drugs, and has limited interactions with alcohol. Should GBP be superior to LZ for the treatment of AWS, it could revise the way AWS is managed in outpatients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC AND OTHER DETERMINANTS OF IN VIVO CYP3A ACTIVITY Principal Investigator & Institution: Wilkinson, Grant R.; Professor of Pharmacology; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 01-DEC-1982; Project End 30-JUN-2007 Summary: (provided by applicant): CYP3A is the most abundant of the human cytochrome P450 enzymes in both the intestine and liver. As a result, it is involved in the metabolism of over 50 percent of drugs and is an important determinant of first-pass metabolism following oral drug administration. Despite being metabolized by CYP3A, however, different substrates appear to interact with the enzyme in different ways, so that the metabolic clearance of one does not correlate with that of another. One hypothesis to account for this lack of correlation is that it reflects, in part, the different relative contributions of intestinal and hepatic CYP3A, and, thus, the route of drug

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Benzodiazepines

administration. Drugs with different metabolic characteristics and routes of administration (midazolam, triazolam and alprazolam) will be used to test this hypothesis. A second possibility that will be investigated is that the CYP3A substrateactive site interaction is substrate-dependent, accordingly, drugs may be characterized into different "groups." Correlation within "groups" will, therefore, be present to a far greater extent than between "groups." In addition to the noted benzodiazepines, this hypothesis will be tested with other CYP3A substrates, such as cyclosporine-A, erythromycin and nifedipine, which are postulated to belong to other "groups." An important characteristic of CYP3A is marked interindividual variability in activity (10to more than 40-fold), which significantly contributes to differences in drug responsiveness between subjects. A genetic determinant(s) is considered to be important in this regard but has never been formally defined and may, in fact, be different according to the tissue localization of CYP3A. Accordingly, the inheritability of CYP3A activity will be determined in monozygotic and dizygotic twins to test the hypothesis that a genetic factor is more important in regulating basal CYP3A-mediated metabolism in the liver than that in the intestine, and also in the enzyme?s inducibility at these two sites. Studies are also proposed which will establish the in vivo functional consequences of the allelic variants CYP3A4*1B and CYP3A5*3, and other known single nucleotide polymorphisms (SNPs). Finally, investigations in European-, African-American, and Japanese populations will be undertaken in order to identify SNPs associated with the interindividual variability in CYP3A activity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC VULNERABILITY TO DRUGS OF ABUSE Principal Investigator & Institution: Buck, Kari J.; Associate Professor; Behavioral Neuroscience; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2003; Project Start 01-AUG-1989; Project End 31-MAR-2005 Summary: Quantitative trait loci (QTLs) are chromosomal regions containing genes that influence a complex trait such as drug withdrawal severity. We have established that there is a great deal of common genetic influence on withdrawal from barbiturates, benzodiazepines, nitrous oxide, and alcohol. During the current period, we have mapped several QTLs that jointly have a major influence on the severity of pentobarbital (PB) withdrawal. The three largest QTLs are on mouse chrs 1, 4 and 11. QTLs in each of these regions have also been provisionally mapped for diazepam withdrawal, and definitively mapped for ethanol withdrawal: the chr 1 QTL was also provisionally mapped for nitrous oxide withdrawal. Using congenic strains to isolate each of the three QTLs against a uniform (inbred) genetic background, we propose to continue toward the eventual identification of the genes that underlie each PB withdrawal QTL. We propose to: (1) Test congenics for the strongest PB QTLs for their pleiotropic effects on withdrawal from other drugs of abuse; (2) Produce polycongenics in different combinations to determine whether gene-gene (epistatic) interactions are additive, potentiating in some combinations, or epistatic in some other way; (3) Narrow each QTL interval from our present approximately 20 cM to approximately 1 cM using interval specific congenic strains (ISCS); (4) Scan promising candidate genes for cDNA differences between B6 and D2 genotypes by SSCP; (5) Produce polycongenics from specific donor segment (SDS) congenics produced from appropriate interval specific congenic strains, and test for epistatic interactions among QTLs, as well as QTL pleiotropisms for withdrawal from other drugs, and for other drug-related responses known to be genetically correlated with PB withdrawal severity; and (6) Start with an F2

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population, screen for additional QTLs not previously ascertained and produce additional congenics to facilitate eventual cloning of the genes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETICALLY ENCODED PHOTOTRIGGERS OF NEURONAL ACTIVITY Principal Investigator & Institution: Miesenbock, Gero; Sloan-Kettering Institute for Cancer Res New York, Ny 10021 Timing: Fiscal Year 2003; Project Start 23-SEP-2003; Project End 31-JUL-2007 Summary: (provided by applicant): Heterologous proteins capable of transducing optical stimuli into electrical signals can be used to control the function of excitable cells in intact tissues or organisms. Restricted genetically to circumscribed populations of cellular targets, these selectively addressable sources of depolarizing current can be used to supply distributed inputs to neural circuits, elucidate functional synaptic connections, probe the response characteristics of circuits and systems, and unveil behaviorally relevant information carried in distributed neural representations. To achieve genetically localized photostimulation, we express ligand-gated ion channels in neurons that normally lack them, and render the agonists that gate the conductances of these channels biologically inert by chemical modification with photoremovable blocking groups ('cages'). A key-and-lock mechanism thus ensures temporal control and cell-type specificity of photostimulation: the initiation of an action potential requires a light pulse that liberates free agonist (the 'key'), and a target neuron that has been genetically programmed to express the cognate ligand-gated ion channel (the 'lock'). The Objective of this project is to advance the development of highly selective phototriggers with fast kinetics (Specific Aims 1 and 2), create modular mammalian expression systems (Specific Aims 3 and 4), and initiate optical analyses of functional neural circuits in the mammalian brain, with an emphasis on networks of inhibitory (GABAergic) interneurons in the cortex and hippocampus (Specific Aim 5). GABAergic circuits are of basic importance to the processing, storage, and retrieval of information, as illustrated by the effects of agents such as ethanol and benzodiazepines, and by the involvement of interneurons in diseases such as schizophrenia and Alzheimer's disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GHB TOLERANCE AND DEPENDENCE Principal Investigator & Institution: Kuhn, Cynthia M.; Professor; Pharmacology and Cancer Biology; Duke University Durham, Nc 27706 Timing: Fiscal Year 2003; Project Start 20-SEP-2003; Project End 31-MAY-2007 Summary: (provided by applicant): The purpose of this proposal is to investigate mechanisms of Gamma hydroxy butyrate (GHB) tolerance and dependence after chronic administration of low and high doses of GHB to rats. GHB is a novel sedative-hypnotic that is an emerging drug of abuse. GHB activates GHB, GABA-B and possibly GABA-A receptors, with a unique dose response relationship for each. When recreational users escalate use, tolerance develops and a withdrawal syndrome can occur that is characterized by insomnia, anxiety, and hallucinations. Tolerance and dependence to GHB are poorly characterized in animal models. We hypothesize that tolerance is related to dose and duration of exposure. We also hypothesize that the different receptor populations adapt at varying rates. We postulate that chronic treatment with lower doses or shorter regimens will cause tolerance at GHB and perhaps GABA-B receptors, while higher doses and longer treatments will lead to marked tolerance to

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Benzodiazepines

GHB, GABA-A and GABA-B receptors. We will assess tolerance to GHB effects on sleep time, tilt plane and plus maze performance after chronic treatment with low or high doses for 7, 14 or 21 days. We will assess spontaneous and GHB (NCS-382) and GABA-B (CGP46381) antagonist-precipitated withdrawal by measuring sleep-wake cycle, locomotion as well as blood pressure and heart rate. Cross-tolerance to GABA-B (baclofen) and GABA-A (pentobarbital, diazepam) agonists will be assessed with the same behavioral measures. We will characterize inhibitory GHB mechanisms using electrophysiologic techniques in frontal cortex. GHB effects on spontaneous, evoked and mini GABA-A IPSCs and on postsynaptic potassium conductance will be determined. The effects of low and high GHB concentrations will be contrasted, and blockade by NCS-382 and CGP46381 on all parameters will be determined. Tolerance to specific GHB and GABA-B mechanisms will be studied by evaluating the same parameters in frontal cortex slices from animals treated chronically with low or high dose GHB. Finally, we will assess GHB effects on GABA-A receptors in naive and tolerant animals by measuring effects on GABA-mediated C1 uptake into synaptoneurosomes and its modulation by benzodiazepines, barbiturates and neurosteroids. These experiments should ultimately lead to the development of more effective pharmacotherapies for GHB dependence, which is an emerging drug abuse problem. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GLUTAMATE HIPPOCAMPUS

RECEPTORS

IN

FLURAZEPAM-TOLERANT

Principal Investigator & Institution: Van Sickle, Bradley J.; Pharmacology and Therapeutics; Medical College of Ohio at Toledo Research & Grants Admin. Toledo, Oh 436145804 Timing: Fiscal Year 2002; Project Start 01-JUN-2002 Summary: Benzodiazepines (BZs) are useful clinically, however tolerance to many of their actions occurs with prolonged administration. Investigations of GABA-A receptors (GABARs) in rats chronically treated with flurazepam have shown significant decreases of inhibitory function in hippocampus and have uncovered changes in excitatory amino acid receptor (EAAR)-mediated activity. Preliminary studies of NMDA and AMPA receptors detected changes in subunit mRNA and protein, consistent with the hypothesis that impaired GABAR-mediated inhibition leads to compensatory changes in EAARs. Electrophysiological studies suggest that functional EAAR-mediated transmission may be altered affecting synaptic plasticity as well. From these findings, three hypotheses were developed and will be tested by 3 Specific Aims: 1) is to characterize changes in NMDA and AMPA receptor protein and receptor number using i) quantitative immunohistochemistry, ii) Western analysis and iii) autoradiographic binding studies; 2) is to examine changes in functional EAAR-mediated transmission using whole cell recordings from CA1 pyramidal cells to measure i) characteristics of mEPSCs, ii) properties of stimulus- and agonist-evoked EPSCs and iii) shifts in doseresponse curves of evoked events by the NR2B-selective antagonist ifenprodil; 3) is to assess changes in synaptic plasticity by examining i) expression of Thr286phosphorylated CaMKII by Western analysis, ii) kinase activity of CaMKII and iii) the frequency-response function of LTP in BZ tolerant hippocampus. Tolerance occurs with many drugs of abuse, so a better understanding of EAAR regulation after chronic BZ may have broader implications in the area of drug abuse research. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HIPPOCAMPAL BENZODIAZEPINE TOLERANCE Principal Investigator & Institution: Tietz, Elizabeth I.; Professor; Pharmacology and Therapeutics; Medical College of Ohio at Toledo Research & Grants Admin. Toledo, Oh 436145804 Timing: Fiscal Year 2002; Project Start 01-JUL-1986; Project End 31-MAR-2005 Summary: Benzodiazepines (BZs) which act through the GABA/A receptor (GABAR), are potent anti-convulsant for a variety of epilepsies. Their clinical usefulness is limited by the appearance of functional tolerance, commonly-held to be mediated by changes at the post-synaptic on CA1 pyramidal cells in the in vitro hippocampus. In addition to changes in post-synaptic GABAR structure (alpha1 and beta3 subunit mRNA and protein down-regulation), measured in situ, and function (decreased mIPSC amplitude and C1-channel conductance), changes in GABAergic interneuron activity are proposed to contribute to BZ tolerance. Rapid BZ antagonist-induced restoration of GABAR subunit protein levels and mIPSC amplitude suggested that both translational and posttranslational mechanisms may interdependently contribute to BZ tolerance. Preliminary studies of PKA-mediated modulation of GABAR currents and the ability of a cAMP analogue to partially restore mIPSC amplitude in BZ-treated rats suggests that a modulation of PKA-mediated events, in part, contribute to GABAR system dysfunction. Additional studies have identified changes in excitatory amino acid part, contribute to GABAR system dysfunction. Additional studies have identified changes in excitatory amino acid receptor (EAAR) subunit mRNAs and protein suggesting that excitatory systems are also regulated by chronic BZ treatment in response to reduced GABA inhibition. Three central hypotheses were generated from these findings in in vitro and in situ hippocampus which will be addressed by 3 SPECIFIC AIMS: SPECIFIC AIM 1: to examine the role of intrinsic and extrinsic interneuron function in reducing GABA tone by sampling subpopulations of visualized CA1 interneurons using intracellular and whole-cell patch techniques. Specific Aim 2: is to explore the role of both 2A) translational, i.e., GABAR alpha1 subunit protein redistribution following chronic agonist and acute antagonist administration, using fluorescent co-localization and quantitative EM immunogold techniques and 2B) post-translational mechanisms, i.e., the effect of exogenous and endogenous stimulators of PKA-mediated protein phosphorylation to modulate mIPSC amplitude in CA1 pyramidal cells. SPECIFIC AIM 3: is to examine the compensatory changes which occur in excitatory amino acid receptor (EAAR) structure and function in CA1 pyramidal cells: 3A) Structural measures include: quantitative immunohistochemical techniques and Western blot analysis of microdissected hippocampus and changes in EAAR receptor binding using autoradiographic techniques. 3B) Whole-cell slice patch techniques will e used to measure EAAR receptor-mediated, evoked and miniature EPSC amplitude and decay kinetics. EAAR function will also be assessed using microfluorometric measurements of Ca2+ uptake into acutely dissociated CA1 pyramidal cells. Understanding the nature of the changes at inhibitory and excitatory synapses may allow the design of drugs and approaches to circumvent tolerance and allow us to gain a better understanding of basic mechanisms involved in the dysfunction of these receptor systems during anticonvulsant drug treatment of epileptic patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SYNDROME

HYPOCRETIN,

HISTAMINE

AND

THE

RESTLESS

LEGS

Principal Investigator & Institution: Allen, Richard P.; Assistant Professor; Neurology; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218

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Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2005 Summary: (provided by applicant): Restless Legs Syndrome (RLS) is a common sensorymotor disorders whose symptoms predominant at night and often lead to significant sleep loss and changes in one's quality of life. Rest and transiting between sleep and wake exacerbates RLS symptoms. Accordingly, alerting activities reduce while soporific ones exacerbate the symptoms. Sedating medications such as benzodiazepines, however, do not appear to exacerbate the disorder. RLS when even moderately severe profoundly disturbs sleep, reducing sleep times to 5-6 hours or less. Patients report some daytime problems with alertness and cognitive clarity but despite this reduction in sleep times untreated patients do not describe profound episodes of sleepiness that occur for normal subjects maintained on such restricted sleep schedules. There is apparently some alerting mechanism partially compensating for the sleep loss. Our recent work has found that nocturnal CSF values of hypocretin/orexin (Hcrt) are elevated in RLS patients not currently on treatment. Hcrt is almost absent in narcoleptics and serves to maintain wakefulness operating at least in part through the stimulating aspects of the histamine system. Several RLS patients on treatment with dopamine agents report some problems with sleepiness they had not previously experienced and several also report marked exacerbation of RLS symptoms by sedating anti-histamines. We have proposed that the Hcrt and histamine system activation reduces RLS symptoms for some RLS patients. DA treatment may reduce the activating benefit from this system leaving the patient vulnerable to sleepiness but also to further exacerbation of the symptoms by further reduction in this system by an anti-histamine medication. Thus, in this model, nocturnal Hcrt levels will be less for DA treated patients and antihistamine challenge provides a test discriminating those patients who have this aspect of RLS, identified in our prior work as those with the familial early-onset form of RLS. The anti-histamine challenge may therefore provide a new technique for discriminating types of RLS, possibly aiding in the diagnosis of RLS and opening up a new area of RLS research. The approach may also be extended to other DA related conditions involving sleepiness with DA treatment. This project seeks to determine if the nocturnal CSF hypocretin of RLS patients is lower when on DA treatment and to explore the development and evaluation of anti-histamine challenge for testing RLS patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MAPPING THE NEURAL SUBSTRATE OF ANXIETY Principal Investigator & Institution: Luscher, Bernhard; Biology; Pennsylvania State University-Univ Park 201 Old Main University Park, Pa 16802 Timing: Fiscal Year 2002; Project Start 01-MAY-2001; Project End 30-APR-2004 Summary: (provided by applicant) The objective of this proposal is to identify the neural substrates underlying trait anxiety. We have found that heterozygosity of the GABAA receptor y2 subunit gene leads to a subtle impairment of postsynaptic GABAA receptor function and trait anxiety in mice. The selective behavioral and cognitive deficits of y20/~ mice, together with established knowledge on the neural circuitry of conditioned fear and the regional distribution of the GABAA receptor deficit in =y2 0/+ mice, allow predictions as to which brain regions mediate trait anxiety. We hypothesize that GABAA receptor deficits in the cerebral cortex and/or hippocampus of y2 0/ mice lead to trait anxiety and that a GABAA receptor deficit that is confmed to these brain regions will result in trait anxiety-like behavior similar to the phenotype of =y2 0/+ mice. In order to map the brain regions that mediate trait anxiety, we have generated a mouse line that allows spatiotemporally restricted inactivation of the y2 subunit gene by means of the Cre/loxP system. Upon Cre induced inactivation of the y2 subunit gene, GABAA

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receptor function will be impaired in selective brain regions defined by the Cre expression pattern of tissue-specific Cre-transgenes or by stereotaxically applied Creencoding virus. Subsequently, stereotaxic injection of Cre-recombinant virus will be used to further characterize trait anxiety. These experiments will include determination of the critical stage during development during which GABAergic deficits lead to trait anxiety. In addition, we will determine whether the cognitive deficits associated with trait anxiety reflect alteration of the acquisition or expression of conditioned fear. The neural circuits that are implicated in the anxiolytic action of the benzodiazepines have considerable anatomical overlap with the proposed neural circuits of trait anxiety and are of therapeutic interest. To test this hypothesis, Cre-induced inactivation of the y2 subunit gene, which is essential for benzodizepine action, will be used to map the brain regions mediating the anxiolytic effect of benzodiazepines. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISM OF ACTION OF BENZODIAZEPINES ON GABA RECEPTORS Principal Investigator & Institution: Weiss, David S.; Professor; Neurobiology; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2003; Project Start 01-APR-1997; Project End 28-FEB-2007 Summary: (provided by applicant): Gamma aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian brain. The binding of GABA to postsynaptic GABA receptors opens a chloride-selective ion pore that is an integral component of the multimeric receptor complex. The resulting chloride flux across the cell membrane inhibits the postsynaptic neuron. Dysfunctions in GABA-mediated inhibition have been implicated in the etiology of a variety of neurological and psychological disorders. Furthermore, GABA receptors are a primary target for several neuroactive drugs including barbiturates, steroids, general anesthetics, and benzodiazepines (BZ); the latter of which is the subject of this proposal. Although it has been known for quite some time that BZs modulate GABA receptors, the molecular mechanism is still unresolved. This proposal will use a combination of molecular biology, electrophysiology, single oocyte radioactive ligand binding, and site directed fluorescent labeling to gain structural and functional insights into the actions of BZs on GABA receptors. Some of these techniques are new to the BZ field and it is hoped they will bring some fresh perspectives to the problem. The design of more efficacious BZs that can target the many different GABA receptor subtypes that have been identified in the brain will ultimately depend on understanding the structural requirements and precise mechanism of action of this important class of neuroactive compounds. The results from these proposed studies are expected to contribute to that effort. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MECHANISMS IN RISK TAKING: DISINHIBITORY DRUGS OF ABUSE Principal Investigator & Institution: Lane, Scott D.; Psychiatry and Behavioral Scis; University of Texas Hlth Sci Ctr Houston Box 20036 Houston, Tx 77225 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2007 Summary: (provided by applicant): This application seeks to achieve two broad objectives: (i) to study the effects of disinhibitory drugs of abuse on (maladaptive) human risk-taking using laboratory behavior-based procedures; (ii) to identify basic behavioral mechanisms operating in individuals (specifically young adults) who show

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Benzodiazepines

heightened susceptibility to risk taking following use of disinhibitory drugs. Disinhibitory drugs can engender increases in the (otherwise low) frequency of certain behaviors. Use of disinhibitory drugs is associated with a number of risk-taking behaviors leading to harmful outcomes -- including automobile accidents, vandalism, violent crimes, sexual assault, and risky sexual behavior. Importantly, use of disinhibitory drugs and the risky behavior that often follows is prevalent among younger adults. The social and behavioral consequences of drug-mediated risk taking in young adults are thus a considerable public health concern and a vital scientific endeavor. Studying the relationship between disinhibitory drugs and risk-taking behavior under controlled laboratory conditions will provide important scientific information. The experiments in this application propose to investigate changes in risktaking following acute administration of four drugs abused by young adults: alcohol, marijuana, and the benzodiazepines alprazolam (Xanax) and flunitrazepam (Rohypnol). While many young adults use these drugs, not all abuse them, and not all engage in excessive risk-taking while under the influence. Thus, identification of basic behavioral processes and characteristics involved in risk-taking may help predict those whose behavior is most likely to be unduly influenced by drug use. Each of the four proposed experiments will employ a laboratory-based task to measure risk-taking. This task has been systematically developed over several years, and has been shown to be sensitive to (i) individual differences in risk-taking (in both adolescent and adult populations), and (ii) acute drug effects. Each participant will work on the risk-taking task following acute administration of one of the above-mentioned disinhibitory drugs. Using a within-subject design, a range of doses will administered in order to determine dose-effect relationships. Quantitative analyses of behavior patterns will be used to identify factors that may mediate this relationship. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISTIC STUDIES OF PRO-APOPTOTIC BENZODIAZEPINES Principal Investigator & Institution: Glick, Gary D.; Professor; Chemistry; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002; Project Start 01-MAY-2000; Project End 30-APR-2004 Summary: (Principal Investigator's Abstract) Systemic lupus erythematosus (SLE) is a multisystemic autoimmunune disorder of unknown etiology. Many patients afflicted with SLE develop a severe nephritis mediated by the localization of immune complexes within glomeruli. Current treatments of this nephritis and other symptoms of the disease center on the use of steroids or cytotoxic immunosuppressive agents. While effective in some patients, these agents are non-specific and can cause serious side effects that often force discontinuation of treatment. We have identified a benzodiazepine (1) that does not bind to the central benzodiazepine receptor, which shows significant efficacy in treating the glomerulonephritis and other symptoms of disease in both (NZB x NZW)F1 and MRL/MpJ-lpr/lpr mice, the two most clinically relevant animal modes of human SLE. Both in vitro and in vivo experiments demonstrate that this benzodiazepine selectively induces apoptosis in lymphocytes directly responsible for autoimmune (B and T cell) mediated inflammation. At therapeutic doses, treatment suppresses the autoimmune response without altering normal immune function or evidence of side effects. Further development of 1 into a clinically useful agent requires a better understanding of both how this molecule induces cell death, and by what means apoptosis of lymphocytes results in disease improvement. To address this need, we propose to characterize the effects 1 has on cellular immune function by determining the phenotype of lymphoid cells killed by 1 in

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vivo and in vitro. Phenotypic analysis will be based on plasma membrane determinants and cytokine expression. Next, to uncover the mechanism by which 1 functions, we will identify the sub-cellular systems (e.g. caspases, mitochondria and other components of death response) triggered to execute 1-mediated cell death. Lastly, we will isolate the receptor of 1 based on yeast three-hybrid screening. If 1 is lethal to yeast, we will pursue an alternative strategy of mutagenesis followed by classical yeast genetics and functional cloning to generate resistant strains and identify molecules necessary for 1induced death. The resistant strains developed will then serve as host strains for the three-hybrid system. These experiments will complement on-going efforts to identify the receptors(s) for 1 using more traditional affinity chromatography methods. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NEOPAIN MULTICENTER TRIAL: DATA COORDINATING CENTER Principal Investigator & Institution: Barton, Bruce A.; Senior Statistician and Vice President; Maryland Medical Research Institute, Inc 600 Wyndhurst Ave Baltimore, Md 21210 Timing: Fiscal Year 2001; Project Start 01-JUN-1999; Project End 31-MAY-2004 Summary: Frequent invasive procedures occur during neonatal intensive care causing pain and stress in preterm neonates during a critical period of increased brain plasticity. Repetitive painful experiences or prolonged exposure to analgesic drugs in preterm neonates may significantly alter their clinical and neurobehavioral outcomes. Analgesic practices recorded prospectively in 109 Neonatal Intensive Care Units (NICUs) showed that opioids and benzodiazepines were most commonly used, with large variations in clinical practice. No analgesia/sedation was given to 73.5 percent of neonates during NICU care or invasive procedures. A pilot randomized trial of morphine, midazolam, or placebo therapy in 69 preterm neonates showed reduced behavioral responses to pain and evidence of decreased incidence of death or neurologic injury in the morphine group. Trends for increased weight gain, earlier discharge, and other clinical outcomes support the need for and the feasibility of a definitive randomized trial. The NEOPAIN Multicenter Trial will randomize 940 ventilated neonates (24-32 weeks gestation) from 11 NICUs to receive continuous infusions of morphine or placebo. This design will provide 80 percent power for the detection of a 30 percent reduction in the composite outcome of neonatal death, Grade III or IV intraventricular hemorrhage, or periventricular leukomalacia. Data collection will include (maternal/infant) demographic, clinical and behavioral data. Other clinical outcomes include weight gain, severity of neonatal illness, and durations of NICU and hospital stay. Behavioral outcomes include neurobehavioral and psychometric testing at the time of hospital discharge. Trial coordination, data management and statistical analyses for the NOPAIN Trial are described in this application. The use of opioids (morphine and fentanyl) in preterm neonates is increasing without scientific evaluation and with scarce data on their clinical or adverse effects. The need for and clinical impact of prolonged analgesia in the NICU must be defined now before widespread use occurs. To provide data about the safety of opioid use, the effects of early pain/stress on the long-term neurobehavioral outcomes of prematurity in neonates without analgesia must be compared to the effects of analgesia use in neonates. This trial can provide those data. Thus, the results of this trial have the potential to significantly alter clinical practice in the NICU and reduce a major cause of severe morbidity and mortality in neonates. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NEURAL ACTIONS OF TOLUENE Principal Investigator & Institution: Woodward, John J.; Professor; Physiology and Neuroscience; Medical University of South Carolina 171 Ashley Ave Charleston, Sc 29425 Timing: Fiscal Year 2002; Project Start 15-APR-2002; Project End 28-FEB-2007 Summary: (provided by applicant): Volatile solvents such as toluene, benzene and trichloroethane are widely distributed in a variety of products encountered in both industrial and home settings. These include glues, thinners, rubber cements, aerosol sprays, nail polish removers, correction fluid and dry cleaning solvents. Although the occupational hazards of exposure to these solvents have been previously examined in a variety of toxicological studies, the cellular and molecular sites of action that account for their intoxicating effects are virtually unknown. Surveys of drug use show that a significant percentage of the population has used volatile solvents for their intoxicating properties and such use is especially prevalent among adolescents and teens who may have easy access to these products. Previous behavioral studies show that toluene and other abused volatile solvents display actions similar to that observed for CNS depressants such as ethanol, barbiturates, benzodiazepines, and anesthetics. Thus, we hypothesize that abused solvents, like other CNS depressants, may exert some of its neurobehavioral effects by altering the function of specific ion channels that are involved in mediating and modulating neuronal transmission. We have generated data to support this hypothesis and have demonstrated that toluene and other volatile solvents inhibit the function of recombinant and native NMDA and acetylcholine receptors expressed in oocytes and cultured neurons. This inhibition was dosedependent and was influenced by the subunit composition expressed. In contrast to ethanol, toluene had negligible effects on currents mediated by non-NMDA receptors or on G-protein coupled potassium channels. These results suggest that abused solvents may show greater selectivity than alcohol with respect to their ability to modulate the activity of neuronal ion channels. Studies outlined in this proposal will test this hypothesis by determining the sensitivity of recombinant and native ion channels to toluene and other volatile solvents that are subject to abuse. Two-electrode voltageclamp and patch-clamp electrophysiology will be used to analyze the solvent sensitivity of recombinant ionotropic receptors expressed in oocytes and HEK cells. The molecular sites of action for toluene will be explored by testing whether sites known to regulate the alcohol/anesthetic sensitivity of these channels also regulate solvent sensitivity. Finally, the relevance of the findings obtained in recombinant receptor systems will be assessed by measuring the effects of toluene and other abused solvents on ion channels expressed in cultured brain neurons using whole-cell patch clamp and calcium imaging. Results obtained from these studies outlined are expected to greatly expand our knowledge of the cellular and molecular targets of these important drugs of abuse. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NEUROIMAGING OF BENZODIAZEPINE-INDUCED AMNESIA Principal Investigator & Institution: Mintzer, Miriam Z.; Assistant Professor; Psychiatry and Behavioral Scis; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 30-SEP-2001; Project End 31-JUL-2004 Summary: (provided by applicant) There is concern about the abuse and long term use of benzodiazepine anxiolytic/hypnotic drugs by polydrug abusers and patients. One of the most insidious adverse effects of benzodiazepines is a profound impairment in the ability to form memories of personally experienced events (episodic memory encoding).

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This project will characterize the changes in brain activity reliably associated with benzodiazepine-induced impairment of episodic memory encoding by parametrically manipulating the level of impairment, and will examine the pharmacological and neurochemical mechanisms underlying these changes. Three double blind, placebocontrolled, within-subject outpatient studies in healthy volunteers are proposed, employing well-established methods in cognitive neuroscience. Following acute drug administration, brain activity associated with performance of a verbal episodic memory encoding task will be measured by regional cerebral blood flow (rCBF) using positron emission tomography (PET) with 15O-H20. Experiment 1 will manipulate the level of encoding impairment via administration of three dose levels of the benzodiazepine hypnotic triazolam. Experiment 2 will manipulate the level of encoding impairment via conjoint administration of triazolam and the benzodiazepine receptor specific antagonist flumazenil, which has been shown to reverse benzodiazepine-induced amnesia; this experiment will also provide information about the pharmacological mechanisms underlying benzodiazepine-induced changes in rCBF during encoding. Experiment 3 will provide information about the neurochemical specificity of benzodiazepine-induced changes in rCBF during encoding by comparing the pattern of rCBF changes produced by triazolam to that produced by scopolamine, a compound which induces comparable decrements in episodic memory encoding but which acts via different receptor site/neurochemical mechanisms. Results of this project will enhance the understanding of the brain mechanisms underlying a serious adverse effect of a widely prescribed and abused class of drugs. Ultimately, data from this research may contribute to the development of new classes of anxiolytic/hypnotic compounds with reduced memory impairing potential, as well as compounds which act to reverse the memory-impairing effects of benzodiazepines. Results of the proposed research also will enhance the understanding of the functional neuroanatomy of basic human memory processes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NEW RADIOTRACERS FOR NEUROLOGICAL PET Principal Investigator & Institution: Kilbourn, Michael R.; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002 Summary: The goals of this project are the design, synthesis and preliminary in vitro and in vivo evaluation of new radiolabeled ligands for the picrotoxin binding site of the GABAA receptor. In particular, we seek the identification and characterization of ligands that display sensitivity to the functional state of the GABAA receptor in vivo. The GABAA receptor is present at a very high proportion of synapses in the brain, and dysfunction of this receptor has been implicated in a wide variety of neurological, psychiatric and drug abuse conditions. The new radioligands to be prepared will be based on the recently reported dithiane and dithiane oxide structural class of high affinity picotoxin site ligands. Preliminary in vivo studies with 11C- and 18F- labeled dithiane oxides have demonstrated blood-brain-barrier permeability, metabolic stability in the blood, and some-dependent alterations of in vivo uptake in brain after administration of a GABA agonist. New compounds will be examined for in vitro binding affinities (inhibition of binding of [35S]TBPS to rodent cortical membranes. High affinity compounds (Ki