EXS71 Toward a Molecular Basis of Alcohol Use and Abuse Edited by B. Jansson H.JomvaIl U. Rydberg L. Terenius B.L. Vallee Birkhauser Verlag Basel . Boston . Berlin Editors Prof. B. Jansson Prof. H. Jornvall Department of Psychiatry Department of Medical Biochemistry Karolinska Institutet and Biophysics Huddinge University Hospital Karolinska Institutet S-14186 Huddinge S-171 77 Stockholm Sweden Sweden Prof. U. Rydberg Prof. B.L. Vallee Prof. L. Terenius Center for Biochemical and Department of Clinical Neuroscience Biophysical Sciences and Medicine Karolinska Institutet Harvard Medical School 5-171 76 Stockholm Seeley G. Mudd Building Sweden 250 Longwood Avenue Boston, MA 02115 USA Library of Congress Cataloging-in-Publication Data Deutsche Bibliothek Cataloging-in-Publication Data Toward a molecular basic of alcohol use and abuse / ed. by B. Jansson ... - Basel; Boston; Berlin: Birkhauser, 1994 (Experientia: Supplementum ; 71) ISBN-13: 978-3-0348-7332-1 NE: Jansson, Bengt [Hrsg.] The publisher and editor can give no guarantee for the information on drug dosage and adminis tration contained in this publication. The respective user must check its accuracy by consulting other sources of reference in each individual case. The use of registered names, trademarks etc. in this publication, even if not identified as such, does not imply that they are exempt from the relevant protective laws and regulations or free for general use. 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, re-use of illustrations, recitation, broadcasting, reproduction on microfilms or in other ways, and storage in data banks. For any kind of use permission of the copyright owner must be obtained. © 1994 Birkhauser Verlag, PO Box 133, CH-4010 Basel, Switzerland Softcover reprint of the hardcover 1st edition 1994 Camera-ready copy prepared by the authors Printed on acid-free paper produced from chlorine-free pulp ISBN-13: 978-3-0348-7332-1 e-ISBN-13: 978-3-0348-7330-7 001: 10.1007/978-3-0348-7330-7 987654321 Contents Preface ............................................... IX Perspectives B.L. Vallee Alcohol in human history 1 Section 1: Neurophannacological aspects L. Terenius Reward and its control by dynorphin peptides 9 C. Alling, L. Gustavsson, C. Larsson, C. Lundqvist, D. Rodriguez and P. Simonsson Adaptation of signal transduction in brain . . . . . . . . . . . . . . . . . . . . . . . .. 19 R. Roivainen, B. Hundle and R.O. Messing Protein kinase C and adaptation to ethanol . . . . . . . . . . . . . . . . . . . . . . .. 29 S. Biffo, G. Dechant, H. Okazawa and y'-A. Barde Molecular control of neuronal survival in the chick embryo . . . . . . . . . . . . .. 39 N. Wilke, M. Sganga, S. Barhite and M.E Miles Effects of alcohol on gene expression in neural cells .................. 49 P.L. Hoffman and B. Tabakoff The role of the NMDA receptor in ethanol withdrawal . . . . . . . . . . . . . . . .. 61 S. Nakanishi, M. Masu, Y. Bessho, Y. Nakajima, Y. Hayashi and R. Shigemoto Molecular diversity of glutamate receptors and their physiological functions 71 f.-C. Schwartz, f. Diaz, N. Griffon, D. Levesque, M.-P' Martres and P. Sokoloff Multiple dopamine receptors: The D3 receptor and actions of substances of abuse. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 81 P.R. Hartig Molecular pharmacology of serotonin receptors .. . . . . . . . . . . . . . . . . . .. 93 G.E Koob, S. Rassnick, S. Heinrichs and E Weiss Alcohol, the reward system and dependence ...... . . . . . . . . . . . . . . . .. 103 VI Section 2: Biological markers and special clinical features U. Rydberg Clinical aspects on molecular probes, markers and metabolism 115 J. Knop Familial alcoholism: Family, twin adoption and high risk studies 121 G.R. Uhl Association strategies in substance abuse . 133 L. Farde, S. Pauli, J.-E. Litton, C. Halldin, J. Neiman and G. Sedvall PET-determination of benzodiazepine receptor binding in studies on alcohol- ism ............................................. 143 M. Linnoila, M. Virkkunen, T. George, M. Eckardt, J.D. Higley, D. Nielsen and D. Goldman Serotonin, violent behavior and alcohol ....... . . .. 155 J.M. van Ree, M. Kornet and C. Goosen Neuropeptides and alcohol addiction in monkeys .................... 165 l. Diamond andA.S. Gordon The role of adenosine in mediating cellular and molecular responses to ethanol 175 M. Salaspuro Helicobacter pylori alcohol dehydrogenase. . . . . . . . . . . . . . . . . . . . . . . .. 185 M. lngelman-Sundberg, l. Johansson, l. Persson, M. Oscarson, Y. Hu, L. Bertilsson, M.-L. Dahl and F. Sjoqvist Genetic polymorphism of cytochrome P450. Functional consequences and possible relationship to disease and alcohol toxicity . . . . . . . . . . . . . . . . .. 197 C.A. Naranjo and K.E. Bremner Serotonin-altering medications and desire, consumption and effects of alcohol treatment implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 209 Section 3: Enzymatic aspects H. Jornvall The alcohol dehydrogenase system ............................. 221 D. W. Nebert Drug metabolism and signal transduction: Possible role of Ah receptor and arachidonic acid cascade in protection from ethanol toxicity ............ 231 J. Piatigorsky, M. Kantorow, R. Gopal-Srivastava and S.l. Tomarev Recruitment of enzymes and stress proteins as lens crystallins . . . . . . . .. 241 M. Ghosh, A. Avezoux, C. Anthony, K. Harlos and C. C. F. Blake X-ray structure of PQQ-dependent methanol dehydrogenase . . . . . . . . . . . .. 251 VII K. Wuthrich NMR, alcohols, protein solvation and protein denaturation 261 H. Eklund, S. Ramaswamy, B. V. Plapp, M. El-Ahmad, O. Danielsson, J. -0. Haag and H. Jarnvall Crystallographic investigations of alcohol dehydrogenases . . . . . . . . . . . . . .. 269 C. Duester Retinoids and the alcohol dehydrogenase gene family ................. 279 D./.N. Sherman, R.J. Ward, A. Yoshida and T.J. Peters Alcohol and acetaldehyde dehydrogenase gene polymorphism and alcoholism .. 291 J.-O. Haag, M. Estonius and o. Danielsson Site-directed mutagenesis and enzyme properties of mammalian alcohol de- hydrogenases correlated with their tissue distribution ................ 301 B. V. Plapp Control of alcohol metabolism ................................ 311 J. F. Riordan Angiotensin converting enzyme inhibitors and alcohol abuse . . . . . . . . . . . .. 323 Section 4: Clinical aspects and pharmacological approaches B. Jansson Treatment of alcoholism .................................... 333 M.A. Schuckit Alcohol sensitivity and dependence . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 341 C. P. O'Brien Treatment of alcoholism as a chronic disorder . . . . . . . . . . . . . . . . . . . . . .. 349 P.A.J. Janssen Addiction and the potential for therapeutic drug development .. . . . . . . . . .. 361 W.-M. Keung and B.L. Vallee Therapeutic lessons from traditional Oriental medicine to contemporary Occi- dental pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 371 R.O. Brady Potential gene therapy for alcoholism . . . . . . . . . . . . . . . . . . . . . . . . . . .. 383 E. Cordis Outlook: Prospects for alcoholism treatment ....................... 395 Subject index ........................................... 405 Preface Since the dawn of Western civilization, ethanol consumption has profoundly affected human affairs. In the course of history, the consequences of ethanol use and abuse have focused attention variously on its nutritional, psychological, medical, sociological, toxicological, philosophical, legal and religious implications. In this century, public attention has been directed progressively to the chronic medical consequences including morbidity and mortality, and the resultant economic burdens. There have often been hopes of decisive preventive or therapeutic action. However, these hopes have been thwarted by the meager knowledge of the biology and pathology including their underlying mechanisms of chronic ethanol abuse. This frustration has been intensified by the increasing realization that ethanol abuse now constitutes one of the major lethal human afflictions but not enough is known about the mechanisms involved. Ethanol related problems are multifactorial in character and this poses both investigative and intellectual challenges. Interdisciplinary barriers of language and knowledge have to be removed or overcome and dialogue established. The best approach, perhaps, is to develop, share and integrate pertinent information from the fields of molecular and cell biology. Advances in these areas have been quite remarkable in recent years and yet they still await translation into pharmacological progress. All the evidence suggests that we are on the verge of uncovering rewarding possiblities. Such considerations led us to convene a meeting of scientists working at the frontiers of molecular and clinical sciences pertinent to the ethanol field. With the support of the Nobel Foundation, a symposium was held at the Nobel-Forum Conference Center of the Karolinska Institute in Stockholm in the fall of 1993. The participants were asked to emphasize conceptual features rather than experimental details of their work in order to stimulate future collaboration spanning conventional boundaries. Four such major sections now define the organization of the 39 chapters of this volume. Section 1 presents neuropharmacological aspects of ethanol consumption that include receptors, adaptive responses, signal transduction and the resultant reward systems. Section 2 deals with biological markers as well as with molecular genetics and clinical features in studies of families, twins, adoptions, and high risk groups. Section 3 cites x advances in the knowledge of alcohol metabolism, including the structure, function and polymorphism of relevant enzymes. The final section, devoted to clinical aspects and pharmacological approaches, features both generalized aspects of clinical treatments and inhibitors of unconventional approaches. The influences and interactions of cultural, social and other environmental factors with those of personality and behavior are not covered explicitly. It is hoped, nevertheless, that the present description of the actions of ethanol will be of interest to those concerned with the making of government policy and with the sociological aspects of ethanol use. We are grateful to the Nobel Foundation for its support in providing the impetus to discern corre lations between molecular events and clinical disease states. In our view, these pages provide both an introduction to current trends and an indication of more intensive studies yet to come on the molecular basis of the use and abuse of ethanol. Finally, we gratefully acknowledge the skilful secretarial assistance and preparation of the manuscripts by Ann-Margreth Gustavsson. Bengt Jansson, Hans Jornvall, Ulf Rydberg, Lars Terenius and Bert Vallee Karolinska Institutet and Harvard Medical School Stockholm and Boston, January 1994 bward aM olecular Basis of Alcohol Use and Abuse ed. by B. Jansson, H. JiirnvaI, U. Rydag, L Terenius &B . L Vallee © 1994 BirkMuserYertag Basel/Switzer1and Alcohol in human history Bert L. Vallee Center for Biochemical and Biophysical Sciences and Medicine, Harvard Medical School, 250 Longwood Avenue, Boston, Massachusetts 02115 USA Keynote: "Man's supposed love affair with alcohol turns out to have been less of a passionate infatuation than a marriage of convenience and necessity. " Summary The role of ethanol in the history of human development is here summarized under seven topics: I. Alcohol: the substitute for water as the major human beverage; II. Alcohol as a component of the diet and source of calories; III. Alcohol, concentration by distillation; IV. The Reformation, Temperance and Prohibition; V. Potable non alcoholic beverages: Boiled water (coffee, tea); VI. Purification and sanitation of water; VII. The present and future. I. Alcohol as the substitute for water as the major human beverage Until the 19th century human beings in Western society considered water unsuitable for consumption. The very earliest historic societies, whether Egyptian, Babylonian, Hebrew, Assyrian, Greek or Roman, unanimously rejected water as a beverage. Through the ages water was known to cause acute and chronic but deadly illnesses and to be poisonous and therefore was avoided, particularly when brackish. The Old and New Testaments are virtually devoid of references to water as a common beverage as is the Greek literature, excepting some positive statements regarding the quality of water from mountain springs (Marcuse, 1899; Glen W. Bowersock, personal communication). Bacteriological insight identifying waterborne infections would not occur until the 19th century. Water purification methods were unknown, and in the West - in contrast to the East - the benefits of boiling water (thereby destroying bacteria and other parasites) were neither appreciated nor attributed to that process. For nearly 10,000 years of known Western history, beer and wine, not water, were the major daily thirst quenchers, consumed by all ages. This simple statement does not make an impact commensurate with the consequences of this reality. Seafaring nations and explorers, e.g., knew