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.

1 The Pharmacology of Alcohol Abuse: An Introduction

References
2 Alcohol-Induced Changes in Neuronal Membranes
A. Introduction
B. Historical Overview
I. The Meyer-Overton Hypothesis
II. Membrane Disorder
C. Membrane Lipid Effects
I. Disordering of Membranes by Acute Ethanol
II. Partitioning of Ethanol into Membranes
III. Pressure Reversal of Acute Effects of Ethanol
IV. Membrane Lipid Composition Changes Due to Chronic Ethanol Exposure
1. Phospholipids
2. Cholesterol
3. Acyl Chain Composition
4. Do Lipid Composition Changes Cause Tolerance or Change Membrane Function?
V. Effects of Ethanol on Membrane Lipid Domains
1. Lipid Classes
2. Transbilayer Lipid Distribution
3. Annular Lipids
4. Lateral Membrane Domains
VI. Ethanol-Induced Hypothermia
VII. Lipid Effects on Proteins
D. Membrane Protein Effects
I. Direct Effects of Acute Ethanol on Proteins
1. Firefly Luciferase
2. The GABAa Receptor
II. Protein Model of the Anesthetic Cutoff Effect
III. Effects of Ethanol on Calcium Channels
IV. Effects of Ethanol on Intracellular Calcium
V. Effects of Ethanol on G-Protein-Related Systems
1. Acute Effects on Protein Kinase C
2. The Adenylyl Cyclase System
3. Chronic Effects
VI. Effects of Chronic Ethanol on Receptor Subunit Expression
1. The GABAa Receptor
2. Origin of mRNA Effects
E. Conclusions
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3 Effects of Ethanol on Voltage-Dependent Calcium Channel Function
A. Voltage-Dependent Calcium Channels
I. Introduction
II. L Type Channels
III. N, P, and T Type Channels
1. Conclusions
B. Effects of Ethanol and Other Sedative-Hypnotic Drugs on Voltage-Dependent Calcium Channels
I. Ethanol Effects on Ion Channels
II. Ethanol Effects on Different Types of Calcium Channel
III. BrainRegional Differences in the Effects of Ethanol
IV. Chronic Ethanol Effects on Calcium Channels
V. Calcium Channel Blockers and Ethanol Preference
VI. Conclusions
C. Effects of Barbiturates and Benzodiazepines on Calcium Channels
I. Conclusions
References
4 Effects of Alcohol on Excitatory Amino Acid Receptor Function
A. Introduction
I. Site of Action of Ethanol: Protein Versus Lipid
B. Ethanol and Excitatory Amino Acid Receptors
I. Characteristics of Glutamate Receptors
II. Ethanol and NMD A Receptor Function: Acute Effects
1. Mechanism of Action of Ethanol
2. Effects of Anesthetics and Sedative Hypnotics
3. Ethanol and the NMD A Receptor In Vivo
4. Ethanol and the NMDA Receptor in Development
III. Ethanol and NMDA Receptor Function: Chronic Effects
1. Role of NMDA Receptors in Ethanol Withdrawal (Physical Dependence)
2. Role of NMDA Receptors in Ethanol Tolerance
3. Role of NMDA Receptors in Opiate Tolerance and Dependence
C. Summary: Ethanol and the NMDA Receptor
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5 Effects of Alcohol on GABA-Mediated Neurotransmission
A. Introduction
B. Behavioral Studies
C. Binding Studies
D. Functional Studies
I. Electrophysiological Studies
II. Chloride Flux
E. Rol5-4513: Ethanol Antagonist
F. Molecular Biological Studies
G. Chronic Ethanol Treatment and GABA Receptor Gene Expression
H. Conclusions
References
6 Involvement of CNS Catecholamines in Alcohol Self-Administration, Tolerance, and Dependence: Preclinical Studies
A. Introduction
B. Acute Effects of Investigator-Administered Ethanol: Potential for Catecholamine Involvement in Ethanol Reinforcement
I. Norepinephrine
II. Dopamine
C. Oral Ethanol Seif-Administration in Nonoperant Situations
I. Limited Access Ethanol Drinking Situations
1. Norepinephrine
2. Dopamine
II. Continuous Access Ethanol Drinking Situations
1. Norepinephrine
2. Dopamine
III. Operant Paradigms of Oral Ethanol Self-Administration
1. Norepinephrine
2. Dopamine
D. Chronic Effects of Ethanol on Noradrenergic and Dopaminergic Activity
I. Norepinephrine
II. Dopamine
E. Role of Catecholamines in Ethanol Tolerance and Physical Dependence
I. Tolerance
II. Physical Dependence
F. Summary
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7 5-HT Mediation of Alcohol Self-Administration, Tolerance, and Dependence: Pre-Clinical Studies
A. Introduction
B. Overview of the 5-HT System: Morphology and Receptors
C. 5-HT and Alcohol Self-Administration
I. Increasing 5-HT Function
1. Indirect 5-HT Agonists and Alcohol Self-Administration
2. 5-HT Receptor Agonists and Alcohol Self-Administration
3. Treatments that Enhance 5-HT Function and Other Consummatory Behaviours
4. Treatments that Enhance 5-HT Function and Other Drug-Reinforced Behaviour
II. Reducing 5-HT Function
1. 5-HT Receptor Antagonists and Alcohol Self-Administration
2. 5-HT Lesions and Alcohol Self-Administration
3. Treatments that Reduce 5-HT Function and Other Consummatory Behaviours
4. Treatments that Reduce 5-HT Function and Other Drug-Reinforced Behaviour
III. Biochemical Factors
IV. Summary
D. 5-HT, Alcohol Tolerance, and Physical Dependence
I. General Aspects of Alcohol Tolerance
1. Definition and Classification
2. Features of Ethanol Tolerance
II. Role of 5-HT in Ethanol Tolerance/Dependence
III. Differences in 5-HT Regulation of Ethanol Drinking and Ethanol Tolerance
IV. 5-HT and Ethanol Dependence
E. Effects of Chronic Ethanol Administration on 5-HT Receptors
I. Intoxication
F. Interaction of 5-HT and Opioids
G. General Summary
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8 Opioid Mediation of Alcohol Self-Administration: Pre-Clinical Studies
A. Introduction
B. Alcohol Drinking Enhances Opioid System Activity
I. Opioid Peptides Are Produced in the Metabolism of Alcohol (TIQ Alkaloid Hypothesis)
II. Alcohol Drinking Leads to Changes in Opioid Receptor Sensitivity
III. Alcohol Drinking Leads to the Release of Endogenous Opioids
C. Genetic Susceptibility to Alcohol Abuse
D. Modulating Opiate Receptor Activity Influences Alcohol Drinking
I. Low Doses of Opioids Increase Alcohol Drinking
II. Moderate to High Doses of Opioids Suppress Alcohol Drinking
III. Alcohol Drinking Increases During Opiate Withdrawal
E. Uncontrollable Stress and Alcohol Abuse
I. Post-Stress Alcohol Drinking
F. Opiate Antagonists Attenuate Alcohol Drinking
I. Why Do Organisms Abuse Alcohol?
G. Summary
References
9 Animal Models of the Alcohol Addiction Process
A. Introduction
B. Alcohol-Seeking Behavior
C. Initiation
I. Models to Assess Environmental Effects in the Initiation of Alcohol-Seeking
II. Models to Assess the Genetic Basis of Initiation of Alcohol-Seeking
III. Models to Assess the Psychopharmacological Basis of Initiation of Alcohol-Seeking
D. Transition to Abuse and Dependence (Maintenance)
I. Role of Tolerance in the Maintenance of Excessive Alcohol-Seeking
II. Role of Sensitization in the Maintenance of Excessive Alcohol-Seeking
III. Role of Dependence in the Maintenance of Excessive Alcohol-Seeking
IV. Role of Environmental Interactions in the Maintenance of Excessive Alcohol-Seeking Behavior
V. Role of Conditioned Effects in the Maintenance of Excessive Alcohol-Seeking Behavior
E. Remission/Treatment
I. Nonpharmacological Treatments to Reduce Alcohol Consumption
II. Pharmacological Treatments to Reduce Alcohol Consumption
F. Relapse
I. Role of Conditioned Withdrawal in the Relapse Process
II. Role of Conditioned Drug-Like Effects in the Relapse Process
G. Summary
References
10 Ethanol and Neurohormonal Regulation
A. Effects of Ethanol on Neurohormones
I. Hypothalamic-Pituitary-Gonadal Axis
1. Gonadotropin-Releasing Hormone Secretion
2. Gonadotropin Secretion
3. Gonadal Endocrine Secretion
4. Gonadal Steroid Metabolism
5. Consequences of Alterations in the HPG Axis
6. Hypothalamic-Pituitary-Gonadal Axis and Fetal Development
7. Conclusions
II. Hypothalamic-Pituitary-Adrenal Axis
1. Corticotropin-Releasing Hormone Secretion
2. Adrenocorticotropic Hormone Secretion
3. Adrenal Steroids
4. Consequences of Alterations in the HPA Axis
5. Hypothalamic-Pituitary-Adrenal Axis and Fetal Development
6. Conclusions
III. Hypothalamic-Pituitary-Thyroid Axis
1. Thyrotropin-Releasing Hormone and TSH Secretion
2. Thyroid Hormones
3. Consequences of Alterations in the HPT Axis
4. Conclusions
IV. Other Neurohormonal Systems
1. Growth Hormone
B. Role of Neurohormonal Alterations in Ethanol Consumption
I. Opioid Peptides
II. Hypothalamic-Pituitary-Adrenal Axis
III. Appetitive Systems
C. Overall Conclusions
References
11 Clinical Application of Findings from Animal Research on Alcohol Self-Administration and Dependence
A. Overview
B. Alcohol Consumption
I. Clinical Aspects of Alcoholism
II. Animal Models of Alcoholism
1. Self-Administration
2. Drug Discrimination
3. Genetic Strains
III. Preclinical Studies
1. Serotonin
2. Opioids
3. Dopamine
IV. Clinical Studies
1. Serotonin
2. Opioids
3. Dopamine
C. Alcohol Withdrawal
I. Preclinical Studies
II. Clinical Studies
D. Comorbidity
I. Overview
II. Animal Models
III. Clinical Studies
1. Depression
2. Anxiety
E. Conclusions
References
12 Genetic Factors in Alcoholism: Evidence and Implications
A. Introduction
B. Clinical Studies: Familial Patterns in Alcohol Use
I. Adoption Studies
II. Twin Studies
III. Other Clinical Data Bearing on Genetics
IV. Trait Markers and Differences Between Familial and Nonfamilial Alcoholism
C. Laboratory Studies: Search for a Molecular Basis for a Complex Behavior
I. Linkage Studies
II. Association Studies
1. Alcohol-Metabolizing Enzymes
2. D2 Dopamine Receptor Gene
D. Conclusions
References
13 Pharmacotherapy and Pathophysiology of Alcohol Withdrawal
A. Introduction
B. Clinical Syndrome
I. Phenomenology and Description
II. Drinking Variables Related to the Alcohol Withdrawal Syndrome
III. Protracted Alcohol Withdrawal
IV. Psychiatric Comorbidity and Alcohol Withdrawal
C. Pathophysiology of Alcohol Dependence and Withdrawal
I. GABA-A Receptor System
II. NMDA Receptor System
III. Voltage-Operated Calcium Channels
IV. Monoamine Systems
V. Second Messenger Systems and Adenosine
VI. Summary
D. Repeated Episodes of Alcohol Withdrawal: The "Kindling" Hypothesis
E. Treatment of Alcohol Withdrawal
F. Measurement of the Alcohol Withdrawal Syndrome
G. Nonpharmacologic Treatment of Alcohol Withdrawal
H. Pharmacologic Treatment
I. Complicated Alcohol Withdrawal
II. Uncomplicated Alcohol Withdrawal
III. Benzodiazapines
IV. Alpha- and Beta-Adrenergic Blockers
V. Anticonvulsants
VI. Miscellaneous Treatments
I. Treatment of Alcohol Withdrawal Seizures
J. Biologic Aspects of Alcohol Withdrawal in Man
References
14 Drugs to Decrease Alchol Consumption in Humans:Aversive Agents
A. Introduction
B. Absorption, Metabolism, and Excretion
C. Pharmacokinetics
D. Mechanism of Disulfiram: Ethanol Reaction
E. Clinical Use
F. Efficacy
G. Enhancing Disulfiram Compliance
H. Toxicity
I. Contraindications to Disulfiram Treatment
J. Calcium Carbamide
K. Future Research Directions
References
15 Drugs Attenuating Alcohol Consumption in Humans Through Effects on Various Neurotransmitter Systems
A. Introduction
B. Serotonin
C. Dopamine
D. Opioids
E. Medications Acting on Other Neurotransmitter Systems
F. Conclusions
References
16 Pharmacology of Gastrointestinal Comorbidity in Alcoholics
A. Introduction
B. Drug Therapy for Alcohol-Induced Liver Disease
I. Steatosis
II. Alcoholic Hepatitis
1. Insulin and Glucagon
2. Corticosteroids
3. Anabolic Steroids
4. Colchicine
5. Propylthiouracil
III. Cirrhosis
1. Ascites
2. Encephalopathy
3. Esophageal Varices
IV. Liver Transplantation
C. Drug Therapy of Acute Alcoholic Pancreatitis
1. Cimetidine
2. Somatostatin
3. Pirenzepine
D. Drug Therapy of Chronic Alcoholic Gastritis
E. Summary
References
17 Drugs for the Treatment of Psychiatric Comorbidity in Alcoholics: Recent Developments
A. Introduction
B. Depression
I. Assessment
II. Treatment
III. Pharmacotherapy
1. Cyclic Antidepressants
2. Monoamine Oxidase Inhibitors
3. Serotonin Uptake Inhibitors
4. Lithium
C. Anxiety Disorders
I. Assessment
II. Treatment
III. Pharmacotherapy
D. Bipolar Affective Disorder
I. Assessment
II. Treatment
III. Pharmacotherapy
E. Schizophrenia
I. Assessment
II. Treatment
III. Pharmacologic Treatment
F. Conclusions
References
18 Clinical Markers of Alcohol Abuse
A. Introduction
I. Definition ofthe Term "Marker"
B. Ethanol, Acetaldehyde, and Acetate
I. Ethanol
II. Acetaldehyde
III. Acetaldehyde-Hemoglobin Adduct
IV. Acetate
C. Monoamine Oxidase
I. Regulation of Enzyme Activity
II. In Vitro Effects of Ethanol
III. Enzyme Activity in Alcoholics and Nonalcoholics
IV. In Vitro Studies of Platelets from Alcoholics
D. Guanine Nucleotide Binding Proteins and Adenylylcyclase
I. Acute Effects of Ethanol
II. Chronic Effects of Ethanol
E. Serum Enzymes
I. ?-Glutamyltransferase
II. Aspartate Aminotransferase
III. Other Enzymes, Indices, and Test Combinations
F. Tetrahydroisoquinolines and ?-Carbolines
I. Tetrahydroisoquinolines
II. ?-Carbolines
G. Immune System
I. Blood Groups
II. Immunoglobulins
III. Human Leukocyte Antigens
IV. Cell-Mediated Immune Function
H. Alcohol Intake and Serum Trace Elements
I. Trace Elements and Electrolytes
II. Thiamine (Vitamin B1)
I. Carbohydrate-Deficient Transferrin
I. Biochemistry
II. Methodological Approaches
III. Performance: Sensitivity and Specificity
J. Conclusion
References
19 Interaction of Alcohol with Therapeutic Drugs and Drugs of Abuse
A. Introduction
B. Pharmacokinetic Mechanisms
I. Bioavailability and Absorption
II. Distribution
III. Metabolism
C. Pharmacodynamic Mechanisms
D. Individual Drugs
I. Acetaminophen
II. Angiotensin-Converting Enzyme Inhibitors
1. Enalapril
III. Anticonvulsants
1. Phenytoin
IV. Antidepressants
1. Amitriptyline
2. Imipramine
3. Clomipramine
4. Desipramine
5. Doxepin
6. Nortriptyline
V. Serotonin Selective Reuptake Inhibitors
VI. Antipyrine
VII. Ascorbic Acid
VIII. Barbiturates
1. Phenobarbital
2. Pentobarbital
IX. Benzodiazepines
1. Chlordiazepoxide
2. Diazepam
3.Flurazepam
4. Lorazepam
5. Triazolam
X. Bromocriptine
XI. Ca2+ Blockers
1. Nifedipine
2. Nimodipine
3. Verapamil
XII. Cannabis
XIII. Cocaine
XIV. Sodium Warfarin
XV. Cromoglycate
XVI. Disulfiram
XVII. H2 Blockers
1. Cimetidine
2. Famotidine
3. Ranitidine
XVIIII. Lithium carbonate
XIX. Methylxanthines
1. Caffeine
2. Theophylline
XX. Metoclopramide
XXI. Neuroleptics
1. Chlorpromazine
2. Remoxipride
3. Thioridazine
XXII. Nitrates
1. Nitroglycerin
XXIII. Opioids
1. Methadone
2. Propoxyphene
XXIV. Oral Contraceptives
XXV. Oral Hypoglycemics
1. Chlorpropramide
2. Tolbutamide
XXVI. Sedative-Hypnotics
1. Chloral Hydrate
2. Glutethimide
3. Meprobamate
XXVII. Salicylates
XXVIII. Tobacco
References
20 Pharmacotherapies for Alcoholism: Theoretical and Methodological Perspectives
A. Pharmacologic Approaches to Relapse Prevention in Alcoholics
B. Treatment Matching
I. Matching Based Upon Comorbid Psychopathology
1. Anxiety and Alcoholism
2. Depression and Alcoholism
II. Matching Based Upon Other Patient Characteristics
1. Cloninger's Typology
2. The "Type A/Type B" Distinction of Babor and Colleagues
C. Methodologic Issues in Clinical Trials with Alcoholics
I. Patient Assessment and Outcome Measurement: "For Whom Is One Drink Too Many?"
II. Treatment Retention and "How Much Additional Treatment Is Too Much Treatment?"
1. Preventing Attrition
2. Analysis of Outcomes When Attrition Occurs
III. Maximizing Compliance and Determining "How Well You've Done"
IV. "How Long to Treat? Then What?"
D. What May the Future Hold?
References.