Pharmacological Aspects of Drug Dependence: Toward an Integrated Neurobehavioral Approach

ISBN-13: 9783642646317 / Angielski / Miękka / 2011 / 658 str.

Charles R. Schuster; Michael J. Kuhar

Opis

In spite of a "war on drugs" that spans years, and in spite of increases in law enforcement efforts and to a lesser extent treatment, substance abuse and dependence continue. While the number of people who experiment with drugs has decreased in recent years, those who use drugs repeatedly, per- haps several times a week, a measure of "hard core" drug abusers, has not changed, and emergency room visits associated with substances abuse continues to rise. Considering both licit and illicit drug abuse, the number of drug abusers in, for example, the United States is very large and, accordingly, the cost to society is great. A recent Institute of Medicine study suggests that the overall cost is about $66 billion per year (1990 costs). Certainly when assessing the total cost of substance abuse, we must include of the costs of disease and behavioral disorders that are intimately associated with substance abuse. For example, sharing of needles among illicit drug abusers has been and is a critical vector in the spread of drug resistant TB, AIDS, and hepatitis. Further, the use of drugs and alcohol leads to unsafe sexual practices with the attendant risk of AIDS and other sexually transmitted diseases. Tragically, infants are born with drugs in their system and with infections and disease transmitted from the mothers who are drug abusers or their sex partners who are drug abusers.

Spis treści

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.