The Pharmacologyof Alcohol AbuseContributors

R.F. Anton, H.C. Becker, B.J. Berg, M.J. Bohn, K.E. BremnerD.A. Ciraulo, R.K. Fuller, J. Gelernter, K.A. Grant, D. HershG.A. Higgins, P.L. Hoffman, CM. Knapp, H.R. KranzlerA. Dzung Le, S.W. Leslie, R.Z. Litten, J. Littleton, P. ManuA.T. McLellan, A.K. Mehta, J. Moring, C. Miiller, C.A. NaranjoM.K. Romach, H. Rommelspacher, H.H. Samson, B.F. SandsE.M. Sellers, W.J. Shoemaker, M.K. Ticku, D.M. TomkinsJ.R. Volpicelli, N.T. Watson, T.M. Worner

Editor

Henry R. Kranzler

Springer-VerlagBerlin Heidelberg New York London ParisTokyo Hong Kong Barcelona Budapest

Contents

CHAPTER 1

The Pharmacology of Alcohol Abuse: An IntroductionH.R. KRANZLER 1References 10

CHAPTER 2

Alcohol-Induced Changes in Neuronal MembranesJ. MORING and W.J. SHOEMAKER. With 1 Figure 11

A. Introduction 11B. Historical Overview 11

I. The Meyer-Overton Hypothesis 11II. Membrane Disorder 14

C. Membrane Lipid Effects 15I. Disordering of Membranes by Acute Ethanol 15

II. Partitioning of Ethanol into Membranes 17III. Pressure Reversal of Acute Effects of Ethanol 19IV. Membrane Lipid Composition Changes

Due to Chronic Ethanol Exposure 201. Phospholipids 202. Cholesterol 213. Acyl Chain Composition 224. Do Lipid Composition Changes Cause Tolerance

or Change Membrane Function? 23V. Effects of Ethanol on Membrane Lipid Domains 24

1. Lipid Classes 242. Transbilayer Lipid Distribution 253. Annular Lipids 264. Lateral Membrane Domains 27

VI. Ethanol-Induced Hypothermia 27VII. Lipid Effects on Proteins 28

D. Membrane Protein Effects 29I. Direct Effects of Acute Ethanol on Proteins 29

XIV Contents

1. Firefly Luciferase 292. The GABAA Receptor 30

II. Protein Model of the Anesthetic Cutoff Effect 31III. Effects of Ethanol on Calcium Channels 32IV. Effects of Ethanol on Intracellular Calcium 34V. Effects of Ethanol on G-Protein-Related Systems 35

1. Acute Effects on Protein Kinase C 362. The Adenylyl Cyclase System 373. Chronic Effects 37

VI. Effects of Chronic Ethanolon Receptor Subunit Expression 391. The GABAA Receptor 402. Origin of mRNA Effects 41

E. Conclusions 41References 43

CHAPTER 3

Effects of Ethanol on Voltage-Dependent Calcium Channel FunctionS.W. LESLIE 55

A. Voltage-Dependent Calcium Channels 55I. Introduction 55

II. L Type Channels 55III. N, P, and T Type Channels 58

1. Conclusions 60B. Effects of Ethanol and Other Sedative-Hypnotic Drugs

on Voltage-Dependent Calcium Channels 60I. Ethanol Effects on Ion Channels 60

II. Ethanol Effects on Different Types of Calcium Channel. 62III. Brain Regional Differences in the Effects of Ethanol... 64IV. Chronic Ethanol Effects on Calcium Channels 65V. Calcium Channel Blockers and Ethanol Preference . . . . 66

VI. Conclusions 67C. Effects of Barbiturates and Benzodiazepines

on Calcium Channels 67I. Conclusions 69

References 69

CHAPTER 4

Effects of Alcohol on Excitatory Amino Acid Receptor FunctionP.L. HOFFMAN 75

A. Introduction 75I. Site of Action of Ethanol: Protein Versus Lipid 75

Contents XV

B. Ethanol and Excitatory Amino Acid Receptors 76I. Characteristics of Glutamate Receptors 76

II. Ethanol and NMD A Receptor Function: Acute Effects . 791. Mechanism of Action of Ethanol 812. Effects of Anesthetics and Sedative Hypnotics 813. Ethanol and the NMD A Receptor In Vivo 834. Ethanol and the NMD A Receptor

in Development 85III. Ethanol and NMD A Receptor Function:

Chronic Effects 861. Role of NMDA Receptors in Ethanol

Withdrawal (Physical Dependence) 882. Role of NMDA Receptors in Ethanol Tolerance.... 913. Role of NMDA Receptors

in Opiate Tolerance and Dependence 94C. Summary: Ethanol and the NMDA Receptor 95References 96

CHAPTER 5

Effects of Alcohol on GABA-Mediated Neurotransmission - „,M.K. TICKU and A.K. MEHTA

A. Introduction 103B. Behavioral Studies 104C. Binding Studies 105D. Functional Studies 106

I. Electrophysiological Studies 106II. Chloride Flux 107

E. Rol5-4513: Ethanol Antagonist 108F. Molecular Biological Studies 110G. Chronic Ethanol Treatment

and GABA Receptor Gene Expression 112H. Conclusions 112

References 113

CHAPTER 6

Involvement of CNS Catecholamines in Alcohol Self-Administration,Tolerance, and Dependence: Preclinical StudiesH.A. SAMSON and P.L. HOFFMAN 121

A. Introduction 121B. Acute Effects of Investigator-Administered Ethanol:

Potential for Catecholamine Involvementin Ethanol Reinforcement 121

XVI Contents

I. Norepinephrine 121II. Dopamine 123

C. Oral Ethanol Self-Administration in Nonoperant Situations 124I. Limited Access Ethanol Drinking Situations 124

1. Norepinephrine 1242. Dopamine 124

II. Continuous Access Ethanol Drinking Situations 1251. Norepinephrine 1252. Dopamine 125

III. Operant Paradigmsof Oral Ethanol Self-Administration 1261. Norepinephrine 1262. Dopamine 126

D. Chronic Effects of Ethanol on Noradrenergicand Dopaminergic Activity 127

I. Norepinephrine 127II. Dopamine 129

E. Role of Catecholamines in Ethanol Toleranceand Physical Dependence 130

I. Tolerance 130II. Physical Dependence 131

F. Summary 132References 133

CHAPTER 7

5-HT Mediation of Alcohol Self-Administration, Tolerance,and Dependence: Pre-Clinical StudiesG.A. HIGGINS, A.D. LE, and E.M. SELLERS. With 3 Figures 139

A. Introduction 139B. Overview of the 5-HT System: Morphology and Receptors 139C. 5-HT and Alcohol Self-Administration 141

I. Increasing 5-HT Function 1411. Indirect 5-HT Agonists

and Alcohol Self-Administration 1412. 5-HT Receptor Agonists

and Alcohol Self-Administration 1433. Treatments that Enhance 5-HT Function

and Other Consummatory Behaviours 1454. Treatments that Enhance 5-HT Function

and Other Drug-Reinforced Behaviour 147II. Reducing 5-HT Function 147

1. 5-HT Receptor Antagonistsand Alcohol Self-Administration 147

2. 5-HT Lesions and Alcohol Self-Administration 149

Contents XVII

3. Treatments that Reduce 5-HT Functionand Other Consummatory Behaviours 150

4. Treatments that Reduce 5-HT Functionand Other Drug-Reinforced Behaviour 150

III. Biochemical Factors 151IV. Summary 152

D. 5-HT, Alcohol Tolerance, and Physical Dependence 155I. General Aspects of Alcohol Tolerance 155

1. Definition and Classification 1552. Features of Ethanol Tolerance 156

II. Role of 5-HT in Ethanol Tolerance/Dependence 156III. Differences in 5-HT Regulation of Ethanol Drinking

and Ethanol Tolerance 157IV. 5-HT and Ethanol Dependence 158

E. Effects of Chronic Ethanol Administration on 5-HT Receptors .. 158I. Intoxication 158

F. Interaction of 5-HT and Opioids 159G. General Summary 159References 160

CHAPTER 8

Opioid Mediation of Alcohol Self-Administration: Pre-Clinical StudiesJ.R. VOLPICELLI, B.J. BERG, and N.T. WATSON 169

A. Introduction 169B. Alcohol Drinking Enhances Opioid System Activity 169

I. Opioid Peptides Are Produced in the Metabolismof Alcohol (TIQ Alkaloid Hypothesis) 169

II. Alcohol Drinking Leads to Changesin Opioid Receptor Sensitivity 170

III. Alcohol Drinking Leads to the Releaseof Endogenous Opioids 171

C. Genetic Susceptibility to Alcohol Abuse 171D. Modulating Opiate Receptor Activity

Influences Alcohol Drinking 172I. Low Doses of Opioids Increase Alcohol Drinking 173

II. Moderate to High Doses of Opioids SuppressAlcohol Drinking 174

III. Alcohol Drinking Increases During Opiate Withdrawal . 175E. Uncontrollable Stress and Alcohol Abuse 175

I. Post-Stress Alcohol Drinking 176F. Opiate Antagonists Attenuate Alcohol Drinking 176

I. Why Do Organisms Abuse Alcohol? 178G. Summary 180References 181

XVIII Contents

CHAPTER 9

Animal Models of the Alcohol Addiction ProcessK.A. GRANT 185

A. Introduction 185B. Alcohol-Seeking Behavior 186C. Initiation 188

I. Models to Assess Environmental Effectsin the Initiation of Alcohol-Seeking 189

II. Models to Assess the Genetic Basis of Initiationof Alcohol-Seeking 192

III. Models to Assess the Psychopharmacological Basisof Initiation of Alcohol-Seeking 195

D. Transition to Abuse and Dependence (Maintenance) 201I. Role of Tolerance in the Maintenance

of Excessive Alcohol-Seeking 202II. Role of Sensitization in the Maintenance

of Excessive Alcohol-Seeking 204III. Role of Dependence in the Maintenance

of Excessive Alcohol-Seeking 206IV. Role of Environmental Interactions in the Maintenance

of Excessive Alcohol-Seeking Behavior 208V. Role of Conditioned Effects in the Maintenance

of Excessive Alcohol-Seeking Behavior 211E. Remission/Treatment 212

I. Nonpharmacological Treatmentsto Reduce Alcohol Consumption 213

II. Pharmacological Treatmentsto Reduce Alcohol Consumption 213

F. Relapse 215I. Role of Conditioned Withdrawal

in the Relapse Process 215II. Role of Conditioned Drug-Like Effects

in the Relapse Process 216G. Summary 218References 218

CHAPTER 10

Ethanol and Neurohormonal RegulationJ. LITTLETON 231

A. Effects of Ethanol on Neurohormones 231I. Hypothalamic-Pituitary-Gonadal Axis 233

1. Gonadotropin-Releasing Hormone Secretion 234

Contents XIX

2. Gonadotropin Secretion 2343. Gonadal Endocrine Secretion 2354. Gonadal Steroid Metabolism 2365. Consequences of Alterations in the HPG Axis 2376. Hypothalamic-Pituitary-Gonadal Axis

and Fetal Development 2377. Conclusions 239

II. Hypothalamic-Pituitary-Adrenal Axis 2391. Corticotropin-Releasing Hormone Secretion 2402. Adrenocorticotropic Hormone Secretion 2403. Adrenal Steroids 2414. Consequences of Alterations in the HP A Axis 2425. Hypothalamic-Pituitary-Adrenal Axis

and Fetal Development 2436. Conclusions 244

III. Hypothalamic-Pituitary-Thyroid Axis 2441. Thyrotropin-Releasing Hormone

and TSH Secretion 2442. Thyroid Hormones 2453. Consequences of Alterations in the HPT Axis 2464. Conclusions 246

IV. Other Neurohormonal Systems 2461. Growth Hormone 247

B. Role of Neurohormonal Alterations in Ethanol Consumption.... 248I. Opioid Peptides 249

II. Hypothalamic-Pituitary-Adrenal Axis 250III. Appetitive Systems 252

C. Overall Conclusions 253References 254

CHAPTER 11

Clinical Application of Findings from Animal Researchon Alcohol Self-Administration and DependenceM.K. ROMACH and D.M. TOMKINS 261

A. Overview 261B. Alcohol Consumption 261

I. Clinical Aspects of Alcoholism 261II. Animal Models of Alcoholism 265

1. Self-Administration 2662. Drug Discrimination 2673. Genetic Strains 268

III. Preclinical Studies 2681. Serotonin 268

XX Contents

2. Opioids 2703. Dopamine 271

IV. Clinical Studies 2721. Serotonin 2722. Opioids 2753. Dopamine 277

C. Alcohol Withdrawal 277I. Preclinical Studies 277

II. Clinical Studies 279D. Comorbidity 281

I. Overview 281II. Animal Models 282

III. Clinical Studies 2831. Depression 2832. Anxiety 284

E. Conclusions 285References 287

CHAPTER 12

Genetic Factors in Alcoholism: Evidence and ImplicationsJ. GELERNTER 297

A. Introduction 297B. Clinical Studies: Familial Patterns in Alcohol Use 298

I. Adoption Studies 298II. Twin Studies 301

III. Other Clinical Data Bearing on Genetics 303IV. Trait Markers and Differences Between Familial

and Nonfamilial Alcoholism 303C. Laboratory Studies: Search for a Molecular Basis

for a Complex Behavior 303I. Linkage Studies 304

II. Association Studies 3041. Alcohol-Metabolizing Enzymes 3052. D2 Dopamine Receptor Gene 306

D. Conclusions 308References 309

CHAPTER 13

Pharmacotherapy and Pathophysiology of Alcohol WithdrawalR.F. ANTON and H.C. BECKER. With 3 Figures 315

A. Introduction 315

Contents XXI

B. Clinical Syndrome 316I. Phenomenology and Description 316

II. Drinking Variables Relatedto the Alcohol Withdrawal Syndrome 318

III. Protracted Alcohol Withdrawal 319IV. Psychiatric Comorbidity and Alcohol Withdrawal 320

C. Pathophysiology of Alcohol Dependence and Withdrawal 322I. GABA-A Receptor System 322

II. NMDA Receptor System 325III. Voltage-Operated Calcium Channels 326IV. Monoamine Systems 328V. Second Messenger Systems and Adenosine 330

VI. Summary 331D. Repeated Episodes of Alcohol Withdrawal:

The "Kindling" Hypothesis 332E. Treatment of Alcohol Withdrawal 337F. Measurement of the Alcohol Withdrawal Syndrome 337G. Nonpharmacologic Treatment of Alcohol Withdrawal 338H. Pharmacologic Treatment 339

I. Complicated Alcohol Withdrawal 339II. Uncomplicated Alcohol Withdrawal 341

III. Benzodiazapines 341IV. Alpha- and Beta-Adrenergic Blockers 347V. Anticonvulsants 348

VI. Miscellaneous Treatments 349I. Treatment of Alcohol Withdrawal Seizures 350J. Biologic Aspects of Alcohol Withdrawal in Man 352References 354

CHAPTER 14Drugs to Decrease Alchol Consumption in Humans: Aversive AgentsR.K. FULLER and R.Z. LITTEN 369

A. Introduction 369B. Absorption, Metabolism, and Excretion 370C. Pharmacokinetics 370D. Mechanism of Disulfiram: Ethanol Reaction 371E. Clinical Use 371F. Efficacy 372G. Enhancing Disulfiram Compliance 374H. Toxicity 377I. Contraindications to Disulfiram Treatment 378J. Calcium Carbamide 378K. Future Research Directions 379References 379

XXII Contents

CHAPTER 15

Drugs Attenuating Alcohol Consumption in Humans Through Effectson Various Neurotransmitter SystemsC. A. NARANJO and K. E. BREMNER 383

A. Introduction 383B. Serotonin 383C. Dopamine 388D. Opioids 388E. Medications Acting on Other Neurotransmitter Systems 389F. Conclusions 390References 391

CHAPTER 16

Pharmacology of Gastrointestinal Comorbidity in AlcoholicsT.M. WORNER and P. MANU 395

A. Introduction 395B. Drug Therapy for Alcohol-Induced Liver Disease 396

I. Steatosis 396II. Alcoholic Hepatitis 396

1. Insulin and Glucagon 3972. Corticosteroids 3973. Anabolic Steroids 3984. Colchicine 3985. Propylthiouracil 398

III. Cirrhosis 3991. Ascites 4002. Encephalopathy 4003. Esophageal Varices 402

IV. Liver Transplantation 403C. Drug Therapy of Acute Alcoholic Pancreatitis 403

1. Cimetidine 4032. Somatostatin 4043. Pirenzepine 405

D. Drug Therapy of Chronic Alcoholic Gastritis 406E. Summary 407References 407

CHAPTER 17

Drugs for the Treatment of Psychiatric Comorbidity in Alcoholics:Recent DevelopmentsM.J. BOHN and D. HERSH 415

Contents XXIII

A. Introduction 415B. Depression 416

I. Assessment 419II. Treatment 419

III. Pharmacotherapy 4201. Cyclic Antidepressants 4212. Monoamine Oxidase Inhibitors 4233. Serotonin Uptake Inhibitors 4244. Lithium 424

C. Anxiety Disorders 425I. Assessment 427

II. Treatment 427III. Pharmacotherapy 427

D. Bipolar Affective Disorder 429I. Assessment 430

II. Treatment 431III. Pharmacotherapy 431

E. Schizophrenia 433I. Assessment 434

II. Treatment 435III. Pharmacologic Treatment 435

F. Conclusions 436References 437

CHAPTER 18Clinical Markers of Alcohol AbuseH. ROMMELSPACHER and C. MULLER 443

A. Introduction 443I. Definition of the Term "Marker" 443

B. Ethanol, Acetaldehyde, and Acetate 445I. Ethanol 445

II. Acetaldehyde 446III. Acetaldehyde-Hemoglobin Adduct 446IV. Acetate 448

C. Monoamine Oxidase 448I. Regulation of Enzyme Activity 448

II. In Vitro Effects of Ethanol 449III. Enzyme Activity in Alcoholics and Nonalcoholics 449IV. In Vitro Studies of Platelets from Alcoholics 451

D. Guanine Nucleotide Binding Proteins and Adenylylcyclase 451I. Acute Effects of Ethanol 452

II. Chronic Effects of Ethanol 452E. Serum Enzymes 453

I. y-Glutamyltransferase 454

XXIV Contents

II. Aspartate Aminotransferase 454III. Other Enzymes, Indices, and Test Combinations 455

F. Tetrahydroisoquinolines and /?-Carbolines 455I. Tetrahydroisoquinolines 456

II. /?-Carbolines 457G. Immune System 458

I. Blood Groups 458II. Immunoglobulins 458

III. Human Leukocyte Antigens 458IV. Cell-Mediated Immune Function 459

H. Alcohol Intake and Serum Trace Elements 459I. Trace Elements and Electrolytes 459

II. Thiamine (Vitamin Bi) 459I. Carbohydrate-Deficient Transferrin 460

I. Biochemistry 460II. Methodological Approaches 461

III. Performance: Sensitivity and Specificity 462J. Conclusion 463References 464

CHAPTER 19

Interaction of Alcohol with Therapeutic Drugs and Drugs of AbuseB.F. SANDS, CM. KNAPP, and D.A. CIRAULO 475

A. Introduction 475B. Pharmacokinetic Mechanisms 476

I. Bioavailability and Absorption 476II. Distribution 477

III. Metabolism 478C. Pharmacodynamic Mechanisms 480D. Individual Drugs 484

I. Acetaminophen 484II. Angiotensin-Converting Enzyme Inhibitors 484

1. Enalapril 484III. Anticonvulsants 484

1. Phenytoin 484IV. Antidepressants 485

1. Amitriptyline 4852. Imipramine 4853. Clomipramine 4864. Desipramine 4865. Doxepin 4866. Nortriptyline 486

V. Serotonin Selective Reuptake Inhibitors 487

Contents XXV

VI. Antipyrine 487VII. Ascorbic Acid 487

VIII. Barbiturates 4881. Phenobarbital 4882. Pentobarbital 488

IX. Benzodiazepines 4881. Chlordiazepoxide 4882. Diazepam 4883. Flurazepam 4904. Lorazepam 4905. Triazolam 490

X. Bromocriptine 491XL Ca2+ Blockers 491

1. Nifedipine 4912. Nimodipine 4913. Verapamil 491

XII. Cannabis 492XIII. Cocaine 492XIV. Sodium Warfarin 494XV. Cromoglycate 494

XVI. Disulfiram 494XVII. H2 Blockers 495

1. Cimetidine 4952. Famotidine 4953. Ranitidine 495

XVIIII. Lithium Carbonate 496XIX. Methylxanthines 496

1. Caffeine 4962. Theophylline 496

XX. Metoclopramide 497XXI. Neuroleptics 497

1. Chlorpromazine 4972. Remoxipride 4973. Thioridazine 497

XXII. Nitrates 4981. Nitroglycerin 498

XXIII. Opioids 4981. Methadone 4992. Propoxyphene 499

XXIV. Oral Contraceptives 499XXV. Oral Hypoglycemics 500

1. Chlorpropramide 5002. Tolbutamide 500

XXVI. Sedative-Hypnotics 5001. Chloral Hydrate 500

XXVI Contents

2. Glutethimide 5013. Meprobamate 501

XXVII. Salicylates 501XXVIII. Tobacco 501

References 502

CHAPTER 20

Pharmacotherapies for Alcoholism: Theoreticaland Methodological PerspectivesH.R. KRANZLER, A.T. MCLELLAN, and M.J. BOHN 513

A. Pharmacologic Approaches to Relapse Preventionin Alcoholics 513

B. Treatment Matching 514I. Matching Based Upon Comorbid Psychopathology . . . . 514

1. Anxiety and Alcoholism 5152. Depression and Alcoholism 515

II. Matching Based Upon Other Patient Characteristics . .. 5161. Cloninger's Typology 5172. The "Type A/Type B" Distinction of Babor

and Colleagues 518C. 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 AdditionalTreatment Is Too Much Treatment?" 5241. Preventing Attrition 5252. 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?" 530D. What May the Future Hold? 531References 532

Subject Index 539