The Pharmacology of Alcohol Abuse

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.

Inhalt
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. 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.- 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 Alc…