The Pharmacology of Alcohol Abuse

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.- References.- 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. Brain Regional 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.- References.- 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.- References.- 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.- References.- 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 of the 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.