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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. Alcoholismdrug therapy. WI HA51L v. 1141995 I QV 84 P5361995] QP905.H3 vol. 114 [QP801.A3] 615'.1 s - dc20 [615' .7828] 94-28586
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© Springer-Verlag Berlin Heidelberg 1995
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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 pharmacology of alcohol, particularly as it relates to alcohol abuse. The overriding 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 implications 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), Department 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, Treatment 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 Comparative 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 Institute on Alcohol Abuse and Alcoholism, 6000 Executive Blvd., Rockville, 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 University 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 Pharmacology, 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 GABAA Receptor ......................... 30
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 GABAA Receptor ......................... 40 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
Contents XV
B. Ethanol and Excitatory Amino Acid Receptors. . . . . . . . . . . . . . . . 76 I. Characteristics of Glutamate Receptors . . . . . . . . . . . . . . 76
II. Ethanol and NMDA Receptor Function: Acute Effects. 79 1. Mechanism of Action of Ethanol . . . . . . . . . . . . . . . . . 81 2. Effects of Anesthetics and Sedative Hypnotics. . . . . . 81 3. Ethanol and the NMDA Receptor In Vivo. . . . . . . . . 83 4. Ethanol and the NMDA Receptor
in Development. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85 III. Ethanol andNMDA Receptor Function:
Chronic Effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86 1. Role of NMDA Receptors in Ethanol
Withdrawal (Physical Dependence) . . . . . . . . . . . . . . . 88 2. Role of NMDA Receptors in Ethanol Tolerance. . . . 91 3. Role of NMDA Receptors
in Opiate Tolerance and Dependence . . . . . . . . . . . . . 94 C. Summary: Ethanol and the NMDA Receptor. . . . . . . . . . . . . . . . . . 95 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
CHAPTER 5
Effects of Alcohol on GABA-Mediated Neurotransmission M.K. TICKU and A.K. MEHTA ................................. .
A. Introduction ............................................. . B. Behavioral Studies ........................................ . C. Binding Studies .......................................... . D. Functional Studies ........................................ .
I. Electrophysiological Studies ....................... . II. Chloride Flux ................................... .
E. Ro15-4513: Ethanol Antagonist ............................ . F. Molecular Biological Studies ............................... . G. Chronic Ethanol Treatment
and GABA Receptor Gene Expression ...................... . H. Conclusions ........................................... .
References .................................................. .
CHAPTER 6
Involvement of CNS Catecholamines in Alcohol Self-Administration, Tolerance, and Dependence: Preclinical Studies
103
103 104 105 106 106 107 108 110
112 112 113
H.A. SAMSON and P.L. HOFFMAN. . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . 121
A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121 B. Acute Effects of Investigator-Administered Ethanol:
Potential for Catecholamine Involvement in Ethanol Reinforcement .................................. 121
XVI Contents
I. Norepinephrine................................... 121 II. Dopamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
C. Oral Ethanol Self-Administration in Nonoperant Situations ..... 124 I. Limited Access Ethanol Drinking Situations . . . . . . . . . . 124
1. Norepinephrine................................ 124 2. Dopamine..................................... 124
II. Continuous Access Ethanol Drinking Situations. . . . . . . 125 1. Norepinephrine................................ 125 2. Dopamine..................................... 125
III. Operant Paradigms of Oral Ethanol Self-Administration. . . . . . . . . . . . . . . . . 126 1. Norepinephrine................................ 126 2. Dopamine..................................... 126
D. Chronic Effects of Ethanol on Noradrenergic and Dopaminergic Activity ................................. 127
I. Norepinephrine................................... 127 II. Dopamine ....................................... 129
E. Role of Catecholamines in Ethanol Tolerance and Physical Dependence. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
I. Tolerance........................................ 130 II. Physical Dependence. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
F. Summary................................................. 132 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
CHAPTER 7
5-HT Mediation of Alcohol Self-Administration, Tolerance, and Dependence: Pre-Clinical Studies G.A. HIGGINS, A.D. LE, and E.M. SELLERS. With 3 Figures... . . .. . 139
A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139 B. Overview of the 5-HT System: Morphology and Receptors. . . . . . 139 C. 5-HT and Alcohol Self-Administration. . . . . . . . . . . . . . . . . . . . . . . 141
I. Increasing 5-HT Function. . . . . . . . . . . . . . . . . . . . . . . . . . 141 1. Indirect 5-HT Agonists
and Alcohol Self-Administration ................. 141 2. 5-HT Receptor Agonists
and Alcohol Self-Administration. . . . . . . . . . . . . . . . . 143 3. Treatments that Enhance 5-HT Function
and Other Consummatory Behaviours. . . . . . . . . . . . . 145 4. Treatments that Enhance 5-HT Function
and Other Drug-Reinforced Behaviour. . . . . . . . . . . . 147 II. Reducing 5-HT Function. . . . . . . . . . . . . . . . . . . . . . . . . . . 147
1. 5-HT Receptor Antagonists and Alcohol Self-Administration ................. 147
2. 5-HT Lesions and Alcohol Self-Administration. . . . . 149
Contents XVII
3. Treatments that Reduce 5-HT Function and Other Consummatory Behaviours. . . . . . . . . . . . . 150
4. Treatments that Reduce 5-HT Function and Other Drug-Reinforced Behaviour. . . . . . . . . . . . 150
III. Biochemical Factors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151 IV. Summary........................................ 152
D. 5-HT, ~lcohol Tolerance, and Physical Dependence. . . . . . . . . . . 155 I. General Aspects of Alcohol Tolerance. . . . . . . . . . . . . . . 155
1. Definition and Classification . . . . . . . . . . . . . . . . . . . . . 155 2. Features of Ethanol Tolerance . . . . . . . . . . . . . . . . . . . 156
II. Role of 5-HT in Ethanol Tolerance/Dependence. . . . . . 156 III. Differences in 5-HT Regulation of Ethanol Drinking
and Ethanol Tolerance ............................ 157 IV. 5-HT and Ethanol Dependence. . .. . . . .. . . . . . . . . . . . . 158
E. Effects of Chronic Ethanol Administration on 5-HT Receptors .. 158 I. Intoxication...................................... 158
F. Interaction of 5-HT and Opioids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159 G. General Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
CHAPTER 8
Opioid Mediation of Alcohol Self-Administration: Pre-Clinical Studies l.R. VOLPICELLI, B.l. BERG, and N.T. WATSON. . . . . . . . . . . . . . . . . .. . 169
A.Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169 B. Alcohol Drinking Enhances Opioid System Activity. . . . . . . . . . . . 169
I. Opioid Peptides Are Produced in the Metabolism of Alcohol (TIO Alkaloid Hypothesis) . . . . . . . . . . . . . . . 169
II. Alcohol Drinking Leads to Changes in Opioid Receptor Sensitivity . . . . . . . . . . . . . . . . . . . . . . 170
III. Alcohol Drinking Leads to the Release of Endogenous Opioids . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
C. Genetic Susceptibility to Alcohol Abuse . . . . . . . . . . . . . . . . . . . . . . 171 D. Modulating Opiate Receptor Activity
Influences Alcohol Drinking ................................ 172 I. Low Doses of Opioids Increase Alcohol Drinking . . . . . 173
II. Moderate to High Doses of Opioids Suppress Alcohol Drinking. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174
III. Alcohol Drinking Increases During Opiate Withdrawal. 175 E. Uncontrollable Stress and Alcohol Abuse. . . . . . . . . . . . . . . . . . . . . 175
I. Post-Stress Alcohol Drinking. . . . . . . . . . . . . . . . . . . . . . . 176 F. Opiate Antagonists Attenuate Alcohol Drinking. . . . . . . . . . . . . . . 176
I. Why Do Organisms Abuse Alcohol? ................ 178 G. Summary................................................. 180 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
XVIII Contents
CHAPTER 9
Animal Models of the Alcohol Addiction Process K.A. GRANT ................................................. 185
A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185 B. Alcohol-Seeking Behavior. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186 C. Initiation................................................. 188
I. Models to Assess Environmental Effects in the Initiation of Alcohol-Seeking ................. 189
II. Models to Assess the Genetic Basis of Initiation of Alcohol-Seeking. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192
III. Models to Assess the Psychopharmacological Basis of Initiation of Alcohol-Seeking. . . . . . . . . . . . . . . . . . . . . 195
D. Transition to Abuse and Dependence (Maintenance) . . . .. . . .. . . 201 I. Role of Tolerance in the Maintenance
of Excessive Alcohol-Seeking. . . . . . . . . . . . . . . . . . . . . . . 202 II. Role of Sensitization in the Maintenance
of Excessive Alcohol-Seeking. . . . . . . . . . . . . . . . . . . . . . . 204 III. Role of Dependence in the Maintenance
of Excessive Alcohol-Seeking. . . . . . . . . . . . . . . . . . . . . . . 206 IV. Role of Environmental Interactions in the Maintenance
of Excessive Alcohol-Seeking Behavior . . . . . . . . . . . . . . 208 V. Role of Conditioned Effects in the Maintenance
of Excessive Alcohol-Seeking Behavior . . . . . . . . . . . . . . 211 E. RemissionlTreatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212
I. Nonpharmacological Treatments to Reduce Alcohol Consumption. . . . . . . . . . . . . . . . . . . . 213
II. Pharmacological Treatments to Reduce Alcohol Consumption. . . . . . . . . . . . . . . . . . . . 213
F. Relapse.................................................. 215 I. Role of Conditioned Withdrawal
in the Relapse Process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215 II. Role of Conditioned Drug-Like Effects
in the Relapse Process. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216 G. Summary................................................. 218 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218
CHAPTER 10
Ethanol and Neurohormonal Regulation J. LmLEToN ................................................. 231
A. Effects of Ethanol on Neurohormones. . . . . . . . . . . . . . . . . . . . . . . . 231 I. Hypothalamic-Pituitary-Gonadal Axis. . . . . . . . . . . . . . . 233
1. Gonadotropin-Releasing Hormone Secretion. . . . . . . 234
Contents XIX
2. Gonadotropin Secretion. . . . . . . . . . . . . . . . . . . . . . . . . 234 3. Gonadal Endocrine Secretion. . . . . . . . . . . . . . . . . . . . 235 4. Gonadal Steroid Metabolism. . . . . . . . . . . . . . . . . . . . . 236 5. Consequences of Alterations in the HPG Axis. . . . . . 237 6. Hypothalamic-Pituitary-Gonadal Axis
and Fetal Development ......................... 237 7. Conclusions ................................... 239
II. Hypothalamic-Pituitary-Adrenal Axis. . . . . . . . . . . . . . . . 239 1. Corticotropin-Releasing Hormone Secretion. . . . . . . 240 2. Adrenocorticotropic Hormone Secretion .......... 240 3. Adrenal Steroids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241 4. Consequences of Alterations in the HP A Axis. . . . . . 242 5. Hypothalamic-Pituitary-Adrenal Axis
and Fetal Development . . . . . . . . . . . . . . . . . . . . . . . . . 243 6. Conclusions ................................... 244
III. Hypothalamic-Pituitary-Thyroid Axis. . . . . . . . . . . . . . . . 244 1. Thyrotropin-Releasing Hormone
and TSH Secretion ............................. 244 2. Thyroid Hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245 3. Consequences of Alterations in the HPT Axis. . . . . . 246 4. Conclusions ................................... 246
IV. Other Neurohormonal Systems. . . . . . . . . . . . . . . . . . . . . 246 1. Growth Hormone. . . . . . . . . .. . . . .. . . . . . . . . .. . . .. 247
B. Role of Neurohormonal Alterations in Ethanol Consumption. . . . 248 I. Opioid Peptides .................................. 249
II. Hypothalamic-Pituitary-Adrenal Axis. . . . . . . . . . . . . . . . 250 III. Appetitive Systems. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252
C. Overall Conclusions ....................................... 253 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254
CHAPTER 11
Clinical Application of Findings from Animal Research on Alcohol Self-Administration and Dependence M.K. ROMACH and D.M. TOMKINS .............................. 261
A. Overview................................................. 261 B. Alcohol Consumption. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
I. Clinical Aspects of Alcoholism. . . . . . . . . . . . . . . . . . . . . . 261 II. Animal Models of Alcoholism. . . . . . . . . . . . . . . . . . . . . . 265
1. Self-Administration............................. 266 2. Drug Discrimination. . . . . . . . . . . . . . . . . . . . . . . . . . . . 267 3. Genetic Strains ................................ 268
III. Preclinical Studies ................................ 268 1. Serotonin ..................................... 268
xx Contents
2. Opioids........................................ 270 3. Dopamine..................................... 271
IV. Clinical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272 1. Serotonin .............................. . . . . . . . 272 2. Opioids....................................... 275 3. Dopamine..................................... 277
C. Alcohol Withdrawal ..................................... 277 I. Preclinical Studies ................................ 277
II. Clinical Studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279 D. Comorbidity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281
I. Overview........................................ 281 II. Animal Models. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282
III. Clinical Studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283 1. Depression.................................... 283 2. Anxiety....................................... 284
E. Conclusions............................................... 285 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287
CHAPTER 12
Genetic Factors in Alcoholism: Evidence and Implications J. GELERNTER ................................................ 297
A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297 B. Clinical Studies: Familial Patterns in Alcohol Use. . . . . . . . . . . . . . 298
I. Adoption Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298 II. Twin Studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301
III. Other Clinical Data Bearing on Genetics. . . . . . . . . . . . . 303 IV. Trait Markers and Differences Between Familial
and Nonfamilial Alcoholism. . . . . . . . . . . . . . . . . . . . . . . . 303 C. Laboratory Studies: Search for a Molecular Basis
for a Complex Behavior . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303 I. Linkage Studies .................................. 304
II. Association Studies ............................... 304 1. Alcohol-Metabolizing Enzymes .................. 305 2. D2 Dopamine Receptor Gene. . . . . . . . . . . . . . . . . . . . 306
D. Conclusions .............................................. 308 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309
CHAPTER 13
Pharmacotherapy and Pathophysiology of Alcohol Withdrawal R.F. ANTON and H.C. BECKER. With 3 Figures. . . . . . . . . . . . . . . . . . . . 315
A. Introduction.............................................. 315
Contents XXI
B. Clinical Syndrome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316 I. Phenomenology and Description. . . . . . . . . . . . . . . . . . . . 316
II. Drinking Variables Related to the Alcohol Withdrawal Syndrome. . . . . . . . . . . . . . . . 318
III. Protracted Alcohol Withdrawal. . . . . . . . . . . . . . . . . . . . . 319 IV. Psychiatric Comorbidity and Alcohol Withdrawal ..... 320
C. Pathophysiology of Alcohol Dependence and Withdrawal. . . . . . . 322 I. GAB A-A Receptor System.. . . . .. . . . . . . . . . . .. . . . .. 322
II. NMDA Receptor System. . . . . . . . . . . . . . . . . . . . . . . .. . 325 III. Voltage-Operated Calcium Channels. . . . . . . . . . . . . . . . 326 IV. Monoamine Systems. . . . . . . .. . . . . . . . . . . . . . . . .. . . . . 328 V. Second Messenger Systems and Adenosine. . . . . . . . . . . 330
VI. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331 D. Repeated Episodes of Alcohol Withdrawal:
The "Kindling" Hypothesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332 E. Treatment of Alcohol Withdrawal ........................... 337 F. Measurement of the Alcohol Withdrawal Syndrome. . . . . . . . . . . . 337 G. Nonpharmacologic Treatment of Alcohol Withdrawal. . . . . . . . . . 338 H. Pharmacologic Treatment .................................. 339
I. Complicated Alcohol Withdrawal . . . . . . . . . . . . . . . . . . . 339 II. Uncomplicated Alcohol Withdrawal. . . . . . . . . . . . . . . . . 341
III. Benzodiazapines.................................. 341 IV. Alpha- and Beta-Adrenergic Blockers. . . . . . . . . . . . . . . 347 V. Anticonvulsants .................................. 348
VI. Miscellaneous Treatments. . . . . . . . . . . . . . . . . . . . . . . . . . 349 I. Treatment of Alcohol Withdrawal Seizures. . . . . . . . . . . . . . . . . . . . 350 J. Biologic Aspects of Alcohol Withdrawal in Man. . . . . . . . . . . . . . . 352 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 354
CHAPTER 14 Drugs to Decrease Alchol Consumption in Humans: Aversive Agents R.K. FULLER and R.Z. LITIEN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369
A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369 B. Absorption, Metabolism, and Excretion. . . . . . . . . . . . . . . . . . . . . . 370 C. Pharmacokinetics.......................................... 370 D. Mechanism of Disulfiram: Ethanol Reaction .................. 371 E. Clinical Use. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 371 F. Efficacy.................................................. 372 G. Enhancing Disulfiram Compliance. . . . . . . .. . . . . . . . . . . . . . . . . . . 374 H. Toxicity.................................................. 377 I. Contraindications to Disulfiram Treatment. . . . . . . . . . . . . . . . . . . . 378 J. Calcium Carbamide. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378 K. Future Research Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 379 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 379
XXII Contents
CHAPTER 15
Drugs Attenuating Alcohol Consumption in Humans Through Effects on Various Neurotransmitter Systems C. A. NARANJO and K. E. BREMNER ............................. 383
A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383 B. Serotonin ................................................ 383 C. Dopamine................................................ 388 D. Opioids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 388 E. Medications Acting on Other Neurotransmitter Systems ........ 389 F. Conclusions .............................................. 390 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391
CHAPTER 16
Pharmacology of Gastrointestinal Comorbidity in Alcoholics T.M. WORNER and P. MANU. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395
A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395 B. Drug Therapy for Alcohol-Induced Liver Disease. . . . . . . . . . . . . . 396
I. Steatosis......................................... 396 II. Alcoholic Hepatitis ............................... 396
1. Insulin and Glucagon . . . . . . . . . . . . . . . . . . . . . . . . . . . 397 2. Corticosteroids ................................ 397 3. Anabolic Steroids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398 4. Colchicine..................................... 398 5. Propylthiouracil................................ 398
III. Cirrhosis......................................... 399 1. Ascites ....................................... 400 2. Encephalopathy................................ 400 3. Esophageal Varices. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 402
IV. Liver Transplantation ............................. 403 C. Drug Therapy of Acute Alcoholic Pancreatitis. . . . . . . . . . . . . . . . . 403
1. Cimetidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403 2. Somatostatin .................................. 404 3. Pirenzepine ................................... 405
D. Drug Therapy of Chronic Alcoholic Gastritis . . . . . . . . . . . . . . . . . . 406 E. Summary................................................. 407 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407
CHAPTER 17
Drugs for the Treatment of Psychiatric Comorbidity in Alcoholics: Recent Developments M.J. BOHN and D. HERSH...................................... 415
Contents XXIII
A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 415 B. Depression............................................... 416
I. Assessment..................................... 419 II. Treatment...................................... 419
III. Pharmacotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 420 1. Cyclic Antidepressants. . . . . . . . . . . . . . . . . . . . . . . . . . 421 2. Monoamine Oxidase Inhibitors. . . . . . . . . . . . . . . . . . . 423 3. Serotonin Uptake Inhibitors. . . . . . . . . . . . . . . . . . . . . 424 4. Lithium....................................... 424
C. Anxiety Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 425 I. Assessment ...................................... 427
II. Treatment....................................... 427 III. Pharmacotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427
D. Bipolar Affective Disorder. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429 I. Assessment ...................................... 430
II. Treatment....................................... 431 III. Pharmacotherapy................................. 431
E. Schizophrenia............................................. 433 I. Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 434
II. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 435 III. Pharmacologic Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . 435
F. Conclusions .............................................. 436 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 437
CHAPTER 18 Clinical Markers of Alcohol Abuse H. ROMMELSPACHER and C. MOLLER. . . . . . . . . . .. . . . .. . . . .. . . . .. . . 443
A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 443 I. Definition of the Term "Marker" ................... 443
B. Ethanol, Acetaldehyde, and Acetate. . . . . . . . . . . . . . . . . . . . . . . . . 445 I. Ethanol ......................................... 445
II. Acetaldehyde.................................... 446 III. Acetaldehyde-Hemoglobin Adduct. . . . . . . . . . . . . . . . . . 446 IV. Acetate..................... . . . . . . . . . . . . . . . . . . . . . 448
C. Monoamine Oxidase. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 448 I. Regulation of Enzyme Activity ..................... 448
II. In Vitro Effects of Ethanol. . . . . . . . . . . . . . . . . . . . . . . . . 449 III. Enzyme Activity in Alcoholics and Nonalcoholics ..... 449 IV. In Vitro Studies of Platelets from Alcoholics. . . . . . . . . . 451
D. Guanine Nucleotide Binding Proteins and Adenylylcyclase . . . . . . 451 I. Acute Effects of Ethanol. . . . . . . . . . . . . . . . . . . . . . . . . . . 452
II. Chronic Effects of Ethanol . . . . . . . . . . . . . . . . . . . . . . . . . 452 E. Serum Enzymes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 453
I. y-Glutamyltransferase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 454
XXIV Contents
II. Aspartate Aminotransferase. . . . . . . . . . . . . . . . . . . . . . . . 454 III. Other Enzymes, Indices, and Test Combinations. . . . . . 455
F. Tetrahydroisoquinolines and p-Carbolines .................... 455 I. Tetrahydroisoquinolines .. . . . . . . . . . . . . . . . . . . . . . . . . . 456
II. p-Carbolines ..................................... 457 G. Immune System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 458
I. Blood Groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 458 II. Immunoglobulins................................. 458
III. Human Leukocyte Antigens. . . . . . . . . . . . . . . . . . . . . . . . 458 IV. Cell-Mediated Immune Function. . . . . . . . . . . . . . . . . . . . 459
H. Alcohol Intake and Serum Trace Elements. . . . . . . . . . . . . . . . . . . . 459 I. Trace Elements and Electrolytes . . . . . . . . . . . . . . . . . . . . 459
II. Thiamine (Vitamin B1) ............................ 459 I. Carbohydrate-Deficient Transferrin. . . . . . . . . . . . . . . . . . . . . . . . . . 460
I. Biochemistry..................................... 460 II. Methodological Approaches. . . . . . . . . . . . . . . . . . . . . . . . 461
III. Performance: Sensitivity and Specificity. . . . . . . . . . . . . . 462 J. Conclusion............................................... 463 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 464
CHAPTER 19
Interaction of Alcohol with Therapeutic Drugs and Drugs of Abuse B.F. SANDS, C.M. KNAPP, and D.A. CIRAULO. .. .. . . . .. . . . . . . . . . . . 475
A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475 B. Pharmacokinetic Mechanisms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 476
I. Bioavailability and Absorption. . . . . . . . . . . . . . . . . . . . . . 476 II. Distribution...................................... 477
III. Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 478 C. Pharmacodynamic Mechanisms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 480 D. Individual Drugs .......................................... 484
I. Acetaminophen .................................. 484 II. Angiotensin-Converting Enzyme Inhibitors. . . . . . . . . . . 484
1. Enalapril...................................... 484 III. Anticonvulsants .................................. 484
1. Phenytoin..................................... 484 IV. Antidepressants .................................. 485
1. Amitriptyline.................................. 485 2. Imipramine.................................... 485 3. Clomipramine................................. 486 4. Desipramine................................... 486 5. Doxepin ...................................... 486 6. Nortriptyline .................................. 486
V. Serotonin Selective Reuptake Inhibitors. . . . . . . . . . . . . . 487
Contents XXV
VI. Antipyrine....................................... 487 VII. Ascorbic Acid. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 487
VIII. Barbiturates...................................... 488 1. Phenobarbital ................................. 488 2. Pentobarbital.................................. 488
IX. Benzodiazepines.................................. 488 1. Chlordiazepoxide.............................. 488 2. Diazepam..................................... 488 3. Flurazepam ................................... 490 4. Lorazepam.................................... 490 5. Triazolam..................................... 490
X. Bromocriptine.................................... 491 XI. Ca2+ Blockers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 491
1. Nifedipine..................................... 491 2. Nimodipine ................................... 491 3. Verapamil..................................... 491
XII. Cannabis........................................ 492 XIII. Cocaine......................................... 492 XIV. Sodium Warfarin ................................. 494 XV. Cromoglycate ................................. . . . 494
XVI. Disulfiram . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 494 XVII. H2 Blockers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 495
1. Cimetidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 495 2. Famotidine.................................... 495 3. Ranitidine..................................... 495
XVIIII. Lithium Carbonate. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 496 XIX. Methylxanthines.................................. 496
1. Caffeine ...................................... 496 2. Theophylline .................................. 496
XX. Metoclopramide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497 XXI. Neuroleptics ..................................... 497
1. Chlorpromazine................................ 497 2. Remoxipride .................................. 497 3. Thioridazine................................... 497
XXII. Nitrates ......................................... 498 1. Nitroglycerin .......................... . . . . . . . . 498
XXIII. Opioids.......................................... 498 1. Methadone.................................... 499 2. Propoxyphene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 499
XXIV. Oral Contraceptives. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 499 XXV. Oral Hypoglycemics. . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . 500
1. Chlorpropramide............................... 500 2. Tolbutamide...... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 500
XXVI. Sedative-Hypnotics ............................... 500 1. Chloral Hydrate ............................... 500
XXVI Contents
2. Glutethimide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501 3. Meprobamate................................. 501
XXVII. Salicylates ....................................... 501 XXVIII. Tobacco......................................... 501
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 502
CHAPTER 20
Pharmacotherapies for Alcoholism: Theoretical and Methodological Perspectives H.R. KRANZLER, A.T. McLELLAN, and M.J. BOHN ................ 513
A. Pharmacologic Approaches to Relapse Prevention in Alcoholics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 513
B. Treatment Matching. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 514 I. Matching Based Upon Comorbid Psychopathology. . . . 514
1. Anxiety and Alcoholism. . . . . . . . . . . . . . . . . . . . . . . . . 515 2. Depression and Alcoholism. . . . . . . . . . . . . . . . . . . . . . 515
II. Matching Based Upon Other Patient Characteristics. . . 516 1. Cloninger's Typology . . . . . . . . . . . . . . . . . . . . . . . . . . . 517 2. The "Type A/Type B" Distinction of Babor
and Colleagues ................................ 518 C. Methodologic Issues in Clinical Trials with Alcoholics .......... 520
I. Patient Assessment and Outcome Measurement: "For Whom Is One Drink Too Many?" . . . . . . . . . . . . . . 522
II. Treatment Retention and "How Much Additional Treatment Is Too Much Treatment?" . . . . . . . . . . . . . . . . 524 1. Preventing Attrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . 525 2. Analysis of Outcomes When Attrition Occurs. . . . . . 527
III. Maximizing Compliance and Determining "How Well You've Done" . . . . . . . . . . . . . . . . . . . . . . . . . 527
IV. "How Long to Treat? Then What?" . . . . . . . . . . . . . . . . . 530 D. What May the Future Hold? ................................ 531 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 532
Subject Index ................................................ 539
