Pharmacological Aspects of Drug Dependence

I. Research in the Study of Drug Action and Addiction.- 1 Genetic Vulnerability to Substance Abuse.- A. Heterogeneity of Drug Abuse.- I. Etiological Influences.- 1. Risk Factors.- 2. Genetic Influences.- B. Clinical Studies.- I. Family Genetic Studies.- 1. Alcoholism.- 2. Other Drug Abuse.- II. Levels of Genetic Analysis.- 1. Factors Affecting Use.- 2. Metabolism.- 3. Subjective and Objective Effects.- 4. Drug Specificity.- 5. Alternative Modes of Transmission.- 6. Phenecopies.- C. Molecular Studies.- I. Selecting Genetic Markers.- II. Linkage Analysis.- 1. Dopamine D2 Receptor Locus.- 2. Other Genes.- D. Animal Studies.- I. Animal Models of Drug Taking Behavior.- 1. Behavioral Pharmacology Approach.- 2. Behavioral Genetics Approach.- II. Genetic Variation in Drug Self-Administration and Drug-Reinforced Behavior.- 1. Two-Bottle Choice.- 2. Conditioned Place Preference.- 3. Intracranial Self-Stimulation.- 4. Operant Self-Administration.- III. Drug-Naive Behaviors as Predictors of Vulnerability.- IV. Neurobiological Markers as Predictors of Vulnerability.- V. Response to Abused Drugs as Predictors of Vulnerability.- E. Summary.- References.- 2 Integrative Neurobehavioral Pharmacology: Focus on Cocaine.- A. Introduction.- B. Approaches to Drug Abuse and Dependence.- C. A Cocaine Receptor.- I. Behavioral Models for Drug Abuse.- 1. Drug Self-Administration.- 2. Place Preference.- 3. Alteration of Threshold for Electrical Brain Stimulation Reinforcement.- 4. Drugs of Abuse and Endogenous Reward Systems.- II. Receptor Binding.- III. Interdisciplinary Support for a Dopamine Hypothesis.- D. Brain Imaging.- E. Molecular Actions of Cocaine.- I. Cloning the Dopamine Transporter/Cocaine Receptor.- II. Effects of Chronic Cocaine Administration and Withdrawal.- F. Conclusions.- References.- II. Molecular, Behavioral, and Human Pharmacology of Dependence and Consequences.- 3 Marihuana.- A. Introduction.- B. Cellular and Molecular Effects.- I. Neurochemistry.- 1. Effects on Neurotransmitters.- 2. Receptors.- 3. Second Messenger and Other Transduction Mechanisms.- 4. Integration of Systems.- C. General Pharmacology.- I. Pharmacokinetics.- 1. Absorption and Distribution.- 2. Metabolism and Excretion.- 3. Relationship of THC Levels to Effects.- II. Effects on Organ Systems.- 1. Brain.- 2. Immune System.- 3. Endocrine.- 4. Cardiovascular.- 5. Gastrointestinal.- 6. Renal.- III. Toxicity.- 1. Respiratory Effects.- 2. Psychotic Episodes.- 3. Neurochemical and Histological Effects.- IV. Tolerance.- 1. Animals.- 2. Humans.- V. Dependence.- 1. Animals.- 2. Humans.- VI. ?9-THC During Pregnancy.- 1. Effect on Dams and Litters.- 2. Developmental Toxicity.- 3. Neural Development.- 4. Teratogenecity.- 5. Fetotoxicity — Interactions with Ethanol.- D. Behavioral Pharmacology.- I. Unlearned Behaviors/Ethology.- l. General Comments.- 2. Consummatory Behavior.- 3. Motor Behavior.- 4. Social Behavior.- II. Conditioned Effects.- 1. Drug Discrimination.- 2. Self-Administration.- 3. Performance, Memory and Learning.- E. Conclusions.- References.- 4 Cocaine.- A. History and Epidemiology.- B. General Pharmacology.- I. Pharmacokinetics.- II. Organ and System Toxicity.- III. Fetal and Developmental Toxicity.- IV. Behavioral Toxicity.- C. Neurobiology of Cocaine’s Behavioral Effects.- I. Receptor Targets.- II. Sensitization.- III. Reinforcement.- IV. Medications Development.- D. Final Comments.- References.- 5 Opioid Analgesics.- A. Background.- B. Cellular and Molecular Effects.- I. Opioid Receptors.- 1. Early Discoveries.- 2. Opioid Receptor Multiplicity.- 3. Selective Opioid Agonists and Antagonists.- 4. Distribution.- II. Postreceptor Events.- C. General Pharmacology.- I. Pharmacokinetics and Metabolism.- II. General Effects.- III. Immune Function.- IV. Analgesia.- 1. Clinical Observations.- 2. Mechanism of Action of Mu Agonists.- 3. Kappa and Delta Agonists.- V. Tolerance.- VI. Physical Dependence.- D. Behavioral Pharmacology.- I. Reinforcing Effects.- 1. Self-Administration and Place Preference.- 2. Neurobiological Mechanisms.- II. Discriminative Stimulus Characteristics.- III. Schedule-Controlled Behavior.- IV. Conditioned Drug Effects.- V. Learning and Memory.- VI. Unlearned Behaviors.- E. Summary.- References.- 6 Phencyclidine: A Drug of Abuse and a Tool for Neuroscience Research.- A. Introduction and History.- B. Overview of Pharmacological Profile.- I. Humans.- II. Animals.- C. Cellular Mechanisms of Action.- I. The Phencyclidine Receptor.- II. Phencyclidine and the Sigma Binding Site.- III. Phencyclidine and the NMDA Receptor Complex.- IV. Behavioral Correlates of Phencyclidine/NMDA Interactions.- V. Phencyclidine and Dopaminergic Effects —Direct or Indirect Interactions?.- D. Behavioral Pharmacology of Phencyclidine Abuse.- I. Discriminative Stimulus Effects.- II. Self-Administration.- III. Tolerance and Dependence.- IV. Modification of Drug Tolerance and Dependence.- V. Learning and Memory.- E. Concluding Remarks.- References.- 7 Benzodiazepine Discontinuation Syndromes: Clinical and Experimental Aspects.- A. Clinical Aspects of Benzodiazepine Discontinuation.- I. Risk Factors for Benzodiazepine Discontinuation Effects.- 1. Benzodiazepine Compounds.- 2. Dose.- 3. Duration.- 4. Personality Type.- II. Clinical Benzodiazepine Discontinuation Effects.- B. Laboratory Aspects of Benzodiazepine Discontinuation.- I. Behavioral Pharmacology.- II. Neurochemical Effects.- C. Conclusion.- References.- 8 Nicotine.- A. Introduction.- B. Abuse and Dependence in Humans.- I. Epidemiology.- II. Clinical Aspects and Pathophysiology of Nicotine Dependence.- III. Tolerance and Physical Dependence.- C. General Pharmacology.- I. Chemistry and Pharmacokinetics.- 1. Absorption.- 2. Distribution.- 3. Systemic Metabolism.- 4. Brain Metabolic Activity.- 5. Drug Interactions.- II. Pharmacodynamics.- 1. Cardiovascular Effects.- 2. Electroencephalograph Effects.- III. Systemic Effects.- 1. Immunologic Effects.- 2. Hormonal Effects.- 3. Toxicity.- IV. Abuse Liability and Dependence Potential.- 1. Discriminative Effects.- 2. Reinforcing Effects.- 3. Physical Dependence.- D. Neuropharmacology.- I. Nicotinic Receptors.- 1. Receptor Diversity.- 2. Receptor Regulation.- II. Cellular Mechanisms.- 1. Effects of Nicotine on Cell Firing.- 2. Effects of Nicotine on Nerve Terminals.- 3. Effects of Nicotine on Transmitter Release in the Whole Animal.- III. Neuronal Activity and Mechanisms of Reinforcement.- 1. Mesolimbic Dopamine.- 2. Dorsal Noradrenergic Bundle.- 3. Thalamocortical Projections.- 4. Habenulo-Interpeduncular System.- 5. 5-HT Release.- 6. Amino Acid Neurotransmitter Release.- 7. Acetylcholine Release.- 8. Other Measures of Neuronal Activity.- 9. Peripheral Effects.- E. Implications for Medications Development and Conclusions.- References.- 9 Caffeine Reinforcement, Discrimination, Tolerance and Physical Dependence in Laboratory Animals and Humans.- A. Introduction.- B. Reinforcing Effects of Caffeine in Laboratory Animals.- C. Reinforcing Effects of Caffeine in Humans.- D. Discriminative Stimulus Effects of Caffeine in Laboratory Animals.- I. Pharmacologic Mechanisms in Drug Discrimination.- E. Subjective and Discriminative Stimulus Effects of Caffeine in Humans.- I. Qualitative Subjective Effects of Caffeine.- II. Demonstration of Caffeine Discrimination.- III. Acquisition of Caffeine Discrimination.- IV. Thresholds for Caffeine Discrimination.- V. Cross-Generalization with Other Drugs.- VI. Relationship Between Caffeine Discriminative and Subjective Effects.- VII. Relationship Between Discrimination and Physical Dependence.- VIII. Relationship Between Discrimination and Reinforcement.- F. Tolerance to Caffeine in Laboratory Animals.- I. Role of Adenosine in Tolerance.- G. Tolerance to Caffeine in Humans.- H. Caffeine Physical Dependence in Laboratory Animals.- I. Role of Adenosine in Physical Dependence.- I. Caffeine Physical Dependence in Humans.- J. Conclusions.- References.- 10 Classical Hallucinogens.- A. Introduction.- B. Definitions.- C. Human vs Nonhuman Investigations.- D. Models and Assay Methods for Hallucinogenic Activity.- I. Animal Models.- II. Nonanimal Models.- III. The Drug Discrimination Paradigm.- E. Structure-Activity Relationships.- I. Indolylalkylamines.- II. Phenylalkylamines.- F. Mechanism of Action of Classical Hallucinogens.- I. The 5-HT Hypothesis.- II. The 5-HT2Hypothesis.- III. The 5-HT1c Hypothesis.- IV. 5-HT2A vs 5-HT2c Receptors.- 1. Studies with Selective Antagonists.- 2. Studies with Lisuride.- 3. Studies with TFMPP.- 4. Radioligand Binding Studies.- V. Involvement of Other 5-HT Receptors.- VI. Involvement of Dopamine Receptors.- G. Structurally Related Agents and Designer Drugs.- H. Molecular Modeling of Hallucinogen-Receptor Interactions.- I. Summary.- References.- 11 Alcohol.- A. Introduction.- B. The Metabolism of Ethanol.- I. Ethanol-Induced Metabolic Anomalies.- II. Alcohol Dehydrogenase and Microsomal Ethanol Oxidizing Systems.- III. Aldehyde Dehydrogenase.- IV. Acetate Metabolism and the Metabolic Effects of Acetate.- C. Actions of Ethanol on the CNS.- I. Membrane Hypothesis of Ethanol’s Actions.- II. Voltage-Sensitive Calcium Channels.- III. Neurotransmitter Release.- 1. Dopamine.- 2. Serotonin, Norepinephrine and Acetylcholine.- IV. Neuropeptides.- 1. Opiates.- 2. Arginine Vasopressin.- 3. Neurotensin.- V. Postsynaptic Receptors.- 1. Receptor-Effector Coupling Systems.- VI. Ligand-Gated Ion Channels.- 1. GABAA Receptors.- 2. Glutamate Receptors.- 3. 5-HT3 Receptors.- D. Conclusion.- References.- III. Advances in the Pharmacotherapy of Addiction.- 12 Pharmacotherapy of Addiction: Introduction and Principles.- A. Introduction.- B. Pharmacologic Interventions.- I. Agonist.- 1. General Principles and Clinical Indications.- 2. Drug Classes.- II. Antagonists.- 1. General Principles and Clinical Indications.- 2. Drug Classes.- III. Anti-withdrawal Agents.- 1. General Principles and Clinical Indications.- 2. Drug Classes.- IV. Anti-craving Agents.- C. Conclusion.- References.- 13 Development of Medications for Addictive Disorders.- A. History of the Regulatory System for New Drugs.- B. Scheme of New Drug Development.- C. Phases of Clinical Investigations.- D. Special Considerations Related to Medications Development for Addictive Disorders.- E. l-a-Acetylmethadol: Selected Clinical Studies.- F. Other Necessary Regulatory Actions Regarding l-a-Acetylmethadol.- G. Summary.- References.- 14a Long-Term Pharmacotherapy for Opiate (Primarily Heroin) Addiction: Opioid Agonists.- A. Introduction.- B. dl-Methadone (and 1-Methadone) as Used in Long-Term Pharmacotherapy of Opiate Addiction.- I. Chemistry, Pharmacokinetics, Pharmacodynamics, and Mechanisms of Action.- 1. Methadone Disposition in Setting of Chronic Diseases.- 2. Methadone Disposition in Pregnancy.- 3. Drug and Alcohol Interactions with Methadone.- II. Use of Methadone in Long-Term Pharmacotherapy of Opiate Addiction: “Methadone Maintenance”.- 1. Safety, Efficacy, and Effectiveness.- III. Neuroendocrine Immune and Gastroenterological Effects of Methadone (As Contrasted with Heroin Addiction).- 1. Neuroendocrine Function.- 2. Immune Function.- 3. Gastrointestinal Function.- IV. Special Issues Related to Methadone Maintenance and All Other Long-Term Treatments of Opiate (Heroin) Addicts.- 1. Codependency: Alcoholism, Cocaine, and Other Addictions.- 2. Psychiatric Comorbidity.- 3. Chronic Liver Disease, HIV Infection, and AIDS: Preexisting Medical Problems in Heroin Addicts and Impact of Methadone Treatment.- C. l-a-Acetylmethadol (LAAM).- I. Chemistry, Pharmacokinetics, Pharmacodynamics, and Mechanisms of Action in Humans.- II. Use of LAAM in Long-Term Pharmacotherapy of Opiate Addiction: Safety, Efficacy, and Effectiveness.- III. Neuroendocrine Effects of LAAM.- References.- 14b Long-Term Pharmacotherapy for Opiate (Primarily Heroin) Addiction: Opioid Antagonists and Partial Agonists.- A. Naloxone, Naltrexone, and Nalmefene (Mixed Agonists and Antagonists).- I. Chemistry, Pharmacokinetics, Pharmacodynamics, and Mechanisms of Action in Humans.- II. Use of Naltrexone and Other Opioid Antagonists: Safety, Efficacy, and Effectiveness.- III. Neuroendocrine Effects of Opioid Antagonists.- B. Buprenorphine.- I. Chemistry, Pharmacokinetics, Pharmacodynamics, and Mechanisms of Action in Humans.- II. Use of Buprenorphine: Safety, Efficacy, and Effectiveness.- III. Neuroendocrine Effects of Partial Agonists (Mixed Agonists/Antagonists).- References.- 15 Pharmacotherapy of Nicotine Dependence.- A. Introduction.- I. A Brief History of Treatment for Smoking Cessation.- II. Why Pharmacotherapy?.- III. Methodological Issues.- 1. Paradigms to Test Efficacy.- 2. Traditions of Testing Medications for Smoking vs for Other Drug Dependencies.- IV. Comparing Medications.- B. Medications to Aid Smoking Cessation.- I. Nicotine Replacement.- 1. Nicotine Polacrilex (Nicotine Gum).- 2. Transdermal Nicotine Systems (Nicotine Patches).- 3. Patient Selection for Nicotine Replacement.- 4. Other Nicotine Replacement Medications.- 5. Lobeline.- 6. Future Studies on Nicotine Replacement.- II. Blocking Agents.- 1. Mecamylamine.- 2. Naltrexone.- III. Clonidine.- IV. Agents That Make Smoking Aversive.- 1. Silver Acetate.- 2. Other Aversive Agents.- V. Medications to Abate Withdrawal or Replace the Reinforcing Effects of Nicotine.- 1. Anxiolytics.- 2. Antidepressants.- 3. Stimulants.- 4. Anorectics.- 5. Other Medications.- C. Use of Adjunctive Psychological Therapies.- I. Psychological Therapies for Smoking Cessation.- II. Combining Psychological Therapies and Medications.- D. Treating Smoking Among Alcohol/Drug Abusers.- E. Conclusions: Typical Quit Rates.- References.- 16 Pharmacotherapies for Cocaine Dependence.- A. Introduction.- B. Pharmacologic Treatment of Cocaine Dependence.- I. Introduction.- II. Medications Employed in the Treatment of Cocaine Dependence.- 1. Acute Withdrawal Agents.- 2. Chronic Treatment Agents.- 3. Comorbid Psychiatric Disorders.- III. Clinical Considerations.- 1. Indications for Treatment.- 2. Length of Treatment.- 3. Precautions in Treatment.- References.