Handbook of Experimental Pharmacology Volume 114 Editorial Board G.V.R. Born, London P. Cuatrecasas, Ann Arbor, MI D. Ganten, Berlin H. Herken, Berlin K.L. Melmon, Stanford, CA The Pharmacology of Alcohol Abuse Contributors RF. Anton, H.C. Becker, B.J. Berg, M.J. Bohn, K.E. Bremner D.A. Ciraulo, RK. Fuller, J. Gelernter, K.A. Grant, D. Hersh G.A. Higgins, P.L. Hoffman, C.M. Knapp, H.R Kranzler A. Dzung Le, S.W. Leslie, RZ. Litten, J. Littleton, P. Manu A.T. McLellan, A.K. Mehta, J. Moring, C. Miiller, C.A. Naranjo M.K. Romach, H. Rommelspacher, H.H. Samson, B.F. Sands E.M. Sellers, W.J. Shoemaker, M.K. Ticku, D.M. Tomkins J.R. Volpicelli, N.T. Watson, T.M. Worner Editor Henry R. Kranzler Springer-Verlag Berlin Heidelberg New York London Paris Tokyo Hong Kong Barcelona Budapest HENRY R. KRANZLER, M.D. Associate Professor and Director Division of Addictive Disorders Department of Psychiatry, MC2lO3 University of Connecticut School of Medicine 263 Farmington Avenue Farmington, CT 06030 USA With 7 Figures and 8 Tables ISBN-13: 978-3-642-78437-8 e-ISBN-13: 978-3-642-78435-4 DOl: 10.1007/978-3-642-78435-4 Library of Congress Cataloging-in-Publication Data. The pharmacology of alcohol abuse I contributors, R.F. Anton ... [et al.]; editor, Henry R. Kranzler. p. cm. - (Handbook of experimental pharmacology, v. 114) Includes bibliographical references and index. ISBN 0-387-57125-6 1. Alcohol-Physiological effect. 2. Alcoholism-Physiological aspects. I. Anton, Raymond F. II. Kranzler, Henry R., 1950- . III. Series. [DNLM: 1. Alcohol, Ethyl-pharmacology. 2. Alcoholism-metabolism. 3. Alcoholism drug therapy. WI HA51L v. 1141995 I QV 84 P5361995] QP905.H3 vol. 114 [QP801.A3] 615'.1 s - dc20 [615' .7828] 94-28586 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other ways, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer-Verlag. Violations are liable for prosecution under the German Copyright Law. © Springer-Verlag Berlin Heidelberg 1995 Softcover reprint of the hardcover 1st edition 1995 The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product liability: The publisher cannot guarantee the accuracy of any information about dosage and applica tion contained in this book. In every individual case the user must check such information by consulting the relevant literature. Typesetting: Best-set Typesetter Ltd., Hong Kong SPIN: 10077716 27/3130/SPS - 5 43210 - Printed on acid-free paper Dedicated to my wife Leah, and our children Elissa, Seth, and Evan with love Preface In recent years alcohol abuse has received increased international attention. Such attention is justified by the enormous negative impact that this disorder has on health, as well as on economic and social well-being. Governmental and other sources of research support have promoted substantial investigation into the negative consequences of alcohol, examining both animal models and human subjects. Consequently, there has been a virtual explosion of preclinical and clinical data, much of it focused on alcohol's pharmacologic effects. However, there have been few efforts to integrate this wealth of new information into a single, manageable volume. This volume provides an up-to-date, in-depth treatment of the phar macology of alcohol, particularly as it relates to alcohol abuse. The over riding theme of the book is the interplay between the preclinical and clinical domains. Increasingly, these areas of investigation have served to inform one another, a trend that can be expected to grow with time. The topics covered include the effects of alcohol on biological systems and the impact of medications on those effects. In addition, recent insights obtained from molecular biological investigations are discussed in terms of their relevance for understanding the effects of alcohol at the cellular level and the implica tions of these for the development of medications. Consideration is also given to important methodological issues that influence the evaluation of medications in the context of clinical trials. This integration of basic and clinical science is intended to be useful to both investigators and clinicians alike. Scientific and administrative efforts to streamline the transition from the bench to the clinic can be expected to speed development and to reward those who have broad familiarity with the process. The focus of this volume is on the integration and utility of research findings obtained using diverse approaches and how these findings may influence both clinical practice and subsequent investigation. Farmington, CT, USA HENRY R. KRANZLER Acknowledgement. This work was supported in part by grants K20-AA00143 (to Dr. Kranzler) and P50-AA0351O from the National Institute on Alcohol Abuse and Alcoholism, Rockville, MD, USA. List of Contributors ANTON, RoFo, Center for Drug and Alcohol Programs (CDAP), Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, 171 Ashley Avenue, Charleston, SC 29425-0742, USA BECKER, HoC., Center for Drug and Alcohol Programs (CDAP), Depart ment of Psychiatry and Behavioral Sciences, Medical University of South Carolina, 171 Ashley Avenue, Charleston, SC 29425-0742, USA BERG, BoJo, Department of Psychiatry, University of Pennsylvania, Treat ment Research Center, 3900 Chestnut Street, Philadelphia, PA 19104, USA BOHN, Mojo, Department of Psychiatry, B6/210 Clinical Science Center, University of Wisconsin-Madison Medical School, 600 Highland Avenue, Madison, WI 53792-2475, USA BREMNER, K.Eo, Addiction Research Foundation, University of Toronto, 33 Russell Street, Toronto, Ontario, M5S 2S1, Canada CIRAULO, DoA., Department of Veteran's Affairs Outpatient Clinic, Tufts University School of Medicine, 251 Causeway Street, Boston, MA 02114, USA FULLER, RoKo, Division of Clinical and Prevention Research, National Institute on Alcohol Abuse and Alcoholism, Room 14C-1O, Parklawn Building, 5600 Fishers Lane, Rockville, MD 20857, USA GELERNTER, Jo, Psychiatry 116A2, West Haven, Department of Veteran's Affairs, Medical Center, 950 Campbell Avenue, West Haven, CT 06516, USA GRANT, K.Ao, Department of Physiology and Pharmacology and Com parative Medicine, Wake Forest University, Bowman Gray School of Medicine, Medical Center Boulevard, Winston-Salem NC 27157, USA HERSH, Do, Alcohol Research Center, Department of Psychiatry, MC2103, University of Connecticut School of Medicine, Farmington, CT 06030, USA x List of Contributors HIGGINS, G.A., Glaxo Unit of Behavioural Psychopharmacology, Division of Biosciences, University of Hertfordshire, Hatfield, Herts., ALlO 4AB, Great Britain HOFFMAN, P.L., Department of Pharmacology, University of Colorado Health Sciences Center, Campus Box C 236, 4200 East Ninth Avenue, Denver, CO 80262 USA KNAPP, C.M., Department of Veteran's Affairs Outpatient Clinic, Tufts University School of Medicine, 251 Causeway Street, Boston, MA 02114, USA KRANZLER, H.R., Alcohol Research Center, Department of Psychiatry, MC2103, University of Connecticut School of Medicine, 263 Farmington Avenue, Farmington, CT 06030-2103, USA LB, A. DZUNG, Pre-Clinical Treatment Research Unit, Clinical Research and Treatment Institute, Addiction Research Foundation, 33 Russell Street, Toronto, Ontario, M5S 2S1, Canada LESLIE, S.W., Division of Pharmacology, College of Pharmacy and Institute of Neurosciences, University of Texas at Austin, Austin, TX 78712, USA LIlTEN, R.Z., Division of Clinical and Prevention Research, National Insti tute on Alcohol Abuse and Alcoholism, 6000 Executive Blvd., Rock ville, MD 20892, USA LIlTLETON, J., Division of Biomedical Science, Kings College, Manresa Road, Chelsea, London, SW3 6LX, Great Britain Present address: Tobacco and Health Research Institute, University of Kentucky, Cooper and University Drives, Lexington, KY 40546-0236, USA MANU, P., Medical Services, Long Island Medical Center, The Long Island Campus for the Albert Einstein College of Medicine, Hillside Hospital, Glen Oaks, NY 11004, USA McLELLAN, A.T., Department of Psychiatry, Philadelphia VAMC and University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA MEHTA, A.K., Department of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78284-7764, USA MORING, J., Alcohol Research Center, Department of Psychiatry, MC-141O, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA MULLER, c., Institute of Clinical Chemistry and Biochemistry, Free Univer sity of Berlin, Augustenburger Platz 1, D-13353 Berlin, Germany List of Contributors XI NARANJO, c.A., Psychopharmacology Research Program, Sunnybrook Health Science Centre (Room E249), Departments of Pharmacology, Psychiatry and Medicine, University of Toronto, 2075 Bayview Avenue, Toronto, Ontario, M4N 3M5, Canada ROMACH, M.K., Clinical Research and Treatment Institute, Addiction Research Foundation and Department of Psychiatry, University of Toronto, 33 Russell Street, Toronto, Ontario, M5S 2S1, Canada ROMMELSPACHER, H., Department of Neuropsychopharmacology, Psychiatric Hospital, Free University of Berlin, Ulmenallee 30, D-14050 Berlin, Germany SAMSON, H.H., Department of Physiology and Pharmacology, Bowman Gray School of Medicine, Medical Center Boulevard, Winston-Salem NC 27157-1083, USA SANDS, B.F., Substance Abuse Treatment Programs, Department of Veteran's Affairs Outpatient Clinic, 251 Causeway Street, Boston, MA 02114, USA SELLERS, E.M., Clinical Research and Treatment Institute, Addiction Research Foundation and Departments of Pharmacology, Medicine and Psychiatry, University of Toronto, 33 Russell Street, Toronto, Ontario, M5S 2S1, Canada SHOEMAKER, W.J., Alcohol Research Center, Department of Psychiatry, MC-141O, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA TICKU, M.K., Department of Pharmacology, Division of Molecular Phar macology, The University of Texas, Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78284-7764, USA TOMKINS, D.M., Clinical Research and Treatment Institute, Addiction Research Foundation, University of Toronto, 33 Russell Street, Toronto, Ontario, M5S 2S1, Canada VOLPICELLI, J.R., Department of Psychiatry, Treatment Research Center, University of Pennsylvania School of Medicine, 3900 Chestnut Street/ 6178, Philadelphia, PA 19104, USA WATSON, N.T., Department of Psychiatry, University of Pennsylvania, Treatment Research Center, 3900 Chestnut Street, Philadelphia, P A 19104, USA WORNER, T.M., State University of New York, Health Science Center, 322 East 50th Street, Brooklyn, NY 10022, USA Contents CHAPTER 1 The Pharmacology of Alcohol Abuse: An Introduction H.R. KRANZLER. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 CHAPTER 2 Alcohol-Induced Changes in Neuronal Membranes J. MORING and W.J. SHOEMAKER. With 1 Figure. . . .. . . . ... . . .. . . .. 11 A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 B. Historical Overview. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 I. The Meyer-Overton Hypothesis. . . . . . . . . . . . . . . . . . . . . 11 II. Membrane Disorder. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 C. Membrane Lipid Effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 I. Disordering of Membranes by Acute Ethanol. . . . . . . . . 15 II. Partitioning of Ethanol into Membranes. . . . . . . . . . . . . . 17 III. Pressure Reversal of Acute Effects of Ethanol ........ 19 IV. Membrane Lipid Composition Changes Due to Chronic Ethanol Exposure .................. 20 1. Phospholipids.................................. 20 2. Cholesterol.................................... 21 3. Acyl Chain Composition. . . . . . . . . . . . . . . . . . . . . . . . 22 4. Do Lipid Composition Changes Cause Tolerance or Change Membrane Function? ................. 23 V. Effects of Ethanol on Membrane Lipid Domains . . . . . . 24 1. Lipid Classes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 2. Transbilayer Lipid Distribution .................. 25 3. Annular Lipids ................................ 26 4. Lateral Membrane Domains . . . . . . . . . . . . . . . . . . . . . 27 VI. Ethanol-Induced Hypothermia. . . . . . . . . . . . . . . . . . . . . . 27 VII. Lipid Effects on Proteins. . . . . . . . . . . . . . . . . . . . . . . . . . . 28 D. Membrane Protein Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 I. Direct Effects of Acute Ethanol on Proteins . . . . . . . . . . 29 XIV Contents 1. Firefly Luciferase .............................. 29 2. The GABA Receptor ......................... 30 A II. Protein Model of the Anesthetic Cutoff Effect. . . . . . . . 31 III. Effects of Ethanol on Calcium Channels ............. 32 IV. Effects of Ethanol on Intracellular Calcium. . . . . . . . . . . 34 V. Effects of Ethanol on G-Protein-Related Systems ..... 35 1. Acute Effects on Protein Kinase C . . . . . . . . . . . . . . . . 36 2. The Adenylyl Cyclase System . . . . . . . . . . . . . . . . . . . . 37 3. Chronic Effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 VI. Effects of Chronic Ethanol on Receptor Subunit Expression . . . . . . . . . . . . . . . . . . . . 39 1. The GABA Receptor ......................... 40 A 2. Origin of mRNA Effects. . . . . . . . . . . . . . . . . . . . . . . . 41 E. Conclusions .............................................. 41 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 CHAPTER 3 Effects of Ethanol on Voltage-Dependent Calcium Channel Function S.W. LESLIE.................................................. 55 A. Voltage-Dependent Calcium Channels ....................... 55 I. Introduction ..................................... 55 II. L Type Channels ................................. 55 III. N, P, and T Type Channels. . . . . . . ... . . . . .. . . . . ... . . 58 1. Conclusions ................................... 60 B. Effects of Ethanol and Other Sedative-Hypnotic Drugs on Voltage-Dependent Calcium Channels. . . . . . . . . . . . . . . . . . . . . 60 I. Ethanol Effects on Ion Channels. . . . . . . . . . . . . . . . . . . . 60 II. Ethanol Effects on Different Types of Calcium Channel. 62 III. Brain Regional Differences in the Effects of Ethanol. . . 64 IV. Chronic Ethanol Effects on Calcium Channels . . . . . . . . 65 V. Calcium Channel Blockers and Ethanol Preference. . . . 66 VI. Conclusions...................................... 67 C. Effects of Barbiturates and Benzodiazepines on Calcium Channels ...................................... 67 I. Conclusions...................................... 69 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 CHAPTER 4 Effects of Alcohol on Excitatory Amino Acid Receptor Function P .L. HOFFMAN. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 I. Site of Action of Ethanol: Protein Versus Lipid. . . . . . . 75