Pharmacological Aspectsof Drug DependenceToward an Integrated Neurobehavioral Approach

Contributors

R.L. Balster, P.B.S. Clarke, D.R. Compton, L.A. DykstraG.I. Elmer, M.W. Fischman, R.A. Glennon, D.J. GreenblattR.R. Griffiths, L.S. Harris, K. Hellevuo, J.E. HenningfieldP.L. Hoffman, J.R. Hughes, C.-E. Johanson, R.M. KeenanH.D. Kleber, T.R. Kosten, M.J. Kreek, M.J. KuharM.C. LaBuda, F.R. Levin, A.H. Lichtman, B.R. MartinL.G. Miller, G.K. Mumford, R.W. Pickens, C.R. SchusterB. Tabakoff, G.R. Uhl, F.J. Vocci, E.A. Wallace, J. Willetts

Editors

Charles R. Schuster and Michael J. Kuhar

Springer

Contents

I. Research in the Study of Drug Action and Addiction

CHAPTER 1

Genetic Vulnerability to Substance AbuseR.W. PICKENS, G.I. ELMER, M.C. LABUDA, and G.R. UHL

With 1 Figure 3

A. Heterogeneity of Drug Abuse 3I. Etiological Influences 5

1. Risk Factors 52. Genetic Influences 6

B. Clinical Studies 8I. Family Genetic Studies 9

1. Alcoholism 92. Other Drug Abuse 12

II. Levels of Genetic Analysis 141. Factors Affecting Use 152. Metabolism 153. Subjective and Objective Effects 164. Drug Specificity 165. Alternative Modes of Transmission 176. Phenocopies 18

C. Molecular Studies 18I. Selecting Genetic Markers 19

II. Linkage Analysis 201. Dopamine D2 Receptor Locus 202. Other Genes 23

D. Animal Studies 23I. Animal Models of Drug Taking Behavior 24

1. Behavioral Pharmacology Approach 242. Behavioral Genetics Approach 26

II. Genetic Variation in Drug Self-Administrationand Drug-Reinforced Behavior 271. Two-Bottle Choice 272. Conditioned Place Preference 29

XIV Contents

3. Intracranial Self-Stimulation 294. Operant Self-Administration 30

III. Drug-Naive Behaviors as Predictors of Vulnerability 32IV. Neurobiological Markers as Predictors of Vulnerability . . . . 34V. Response to Abused Drugs as Predictors of Vulnerability. . 36

E. Summary 38References 39

CHAPTER 2

Integrative Neurobehavioral Pharmacology: Focus on CocaineM.J. KUHAR and C.R. SCHUSTER. With 8 Figures 53

A. Introduction 53B. Approaches to Drug Abuse and Dependence 54C. A Cocaine Receptor 55

I. Behavioral Models for Drug Abuse 561. Drug Self-Administration 562. Place Preference 583. Alteration of Thresholds

for Electrical Brain Stimulation Reinforcement 584. Drugs of Abuse and Endogenous Reward Systems 59

II. Receptor Binding 60III. Interdisciplinary Support for a Dopamine Hypothesis 63

D. Brain Imaging 66E. Molecular Actions of Cocaine 71

I. Cloning the Dopamine Transporter/Cocaine Receptor . . . . 71II. Effects of Chronic Cocaine Administration

and Withdrawal 74F. Conclusions 74References 75

II. Molecular, Behavioral, and Human Pharmacologyof Dependence and Consequences

CHAPTER 3

MarihuanaD.R. COMPTON, L.S. HARRIS, A.H. LICHTMAN, and B.R. MARTINWith 2 Figures 83

A. Introduction 83B. Cellular and Molecular Effects 85

I. Neurochemistry 85

Contents XV

1. Effects on Neurotransmitters 852. Receptors 903. Second Messenger

and Other Transduction Mechanisms 974. Integration of Systems 103

C. General Pharmacology 107I. Pharmacokinetics 107

1. Absorption and Distribution 1072. Metabolism and Excretion 1083. Relationship of THC Levels to Effects 109

II. Effects on Organ Systems 1101. Brain 1102. Immune System I l l3. Endocrine 1144. Cardiovascular 1185. Gastrointestinal 1196. Renal 119

III. Toxicity 1191. Respiratory Effects 1192. Psychotic Episodes 1203. Neurochemical and Histological Effects 121

IV. Tolerance 1221. Animals 1222. Humans 123

V. Dependence 1231. Animals...: 1232. Humans 125

VI. A9-THC During Pregnancy 1271. Effect on Dams and Litters 1272. Developmental Toxicity 1273. Neural Development 1284. Teratogenicity 1285. Fetotoxicity - Interactions with Ethanol 129

D. Behavioral Pharmacology 129I. Unlearned Behaviors/Ethology 129

1. General Comments 1292. Consummatory Behavior 1303. Motor Behavior 1304. Social Behavior 132

II. Conditioned Effects 1331. Drug Discrimination 1332. Self-Administration 1343. Performance, Memory and Learning 135

E. Conclusions 138References 138

XVI Contents

CHAPTER 4

CocaineM.W. FISCHMAN and C.-E. JOHANSON 159

A. History and Epidemiology 159B. General Pharmacology 161

I. Pharmacokinetics 161II. Organ and System Toxicity 163

III. Fetal and Developmental Toxicity 165IV. Behavioral Toxicity 167

C. Neurobiology of Cocaine's Behavioral Effects 167I. Receptor Targets 168

II. Sensitization 169III. Reinforcement 174IV. Medications Development 178

D. Final Comments 182References 182

CHAPTER 5

Opioid AnalgesicsL. DYKSTRA. With 4 Figures 197

A. Background 197B. Cellular and Molecular Effects 200

I. Opioid Receptors 2001. Early Discoveries 2002. Opioid Receptor Multiplicity 2003. Selective Opioid Agonists and Antagonists 2024. Distribution 204

II. Postreceptor Events 204C. General Pharmacology 205

I. Pharmacokinetics and Metabolism 205II. General Effects 205

HI. Immune Function 206IV. Analgesia 207

1. Clinical Observations 2072. Mechanism of Action of Mu Agonists 2073. Kappa and Delta Agonists 208

V. Tolerance 209VI. Physical Dependence 210

D. Behavioral Pharmacology 211I. Reinforcing Effects 211

1. Self-Administration and Place Preference 2112. Neurobiological Mechanisms 214

Contents XVII

II. Discriminative Stimulus Characteristics 215HI. Schedule-Controlled Behavior 217IV. Conditioned Drug Effects 219V. Learning and Memory 219

VI. Unlearned Behaviors 220E. Summary 221References 221

CHAPTER 6

Phencyclidine: A Drug of Abuseand a Tool for Neuroscience Research 233R.L. BALSTER and J. WILLETTS. With 1 Figure

A. Introduction and History 233B. Overview of Pharmacological Profile 234

I. Humans 234II. Animals 236

C. Cellular Mechanisms of Action 237I. The Phencyclidine Receptor 237

II. Phencyclidine and the Sigma Binding Site 238III. Phencyclidine and the NMD A Receptor Complex 239IV. Behavioral Correlates

of Phencyclidine/NMDA Interactions 241V. Phencyclidine and Dopaminergic Effects

- Direct or Indirect Interactions? 243D. Behavioral Pharmacology of Phencyclidine Abuse 244

I. Discriminative Stimulus Effects 244II. Self-Administration 245

III. Tolerance and Dependence 246IV. Modification of Drug Tolerance and Dependence 247V. Learning and Memory 247

E. Concluding Remarks 248References 249

CHAPTER 7

Benzodiazepine Discontinuation Syndromes:Clinical and Experimental AspectsL.G. MILLER and D.J. GREENBLATT 263

A. Clinical Aspects of Benzodiazepine Discontinuation 263I. Risk Factors

for Benzodiazepine Discontinuation Effects 2631. Benzodiazepine Compounds 263

XVIII Contents

2. Dose 2643. Duration 2644. Personality Type 264

II. Clinical Benzodiazepine Discontinuation Effects 264B. Laboratory Aspects of Benzodiazepine Discontinuation 265

I. Behavioral Pharmacology 265II. Neurochemical Effects 266

C. Conclusion 267References 267

CHAPTER 8

NicotineJ.E. HENNINGFIELD, R.M. KEENAN, and P.B.S. CLARKE 271

A. Introduction 271B. Abuse and Dependence in Humans 271

I. Epidemiology 271II. Clinical Aspects and Pathophysiology

of Nicotine Dependence 273III. Tolerance and Physical Dependence 274

C. General Pharmacology 276I. Chemistry and Pharmacokinetics 276

1. Absorption 2762. Distribution 2783. Systemic Metabolism 2784. Brain Metabolic Activity 2795. Drug Interactions 280

II. Pharmacodynamics 2811. Cardiovascular Effects 2812. Electroencephalograph Effects 282

III. Systemic Effects 2831. Immunologic Effects ' 2832. Hormonal Effects 2843. Toxicity 284

IV. Abuse Liability and Dependence Potential 2851. Discriminative Effects 2852. Reinforcing Effects 2863. Physical Dependence 287

D. Neuropharmacology 288I. Nicotinic Receptors 288

1. Receptor Diversity 2882. Receptor Regulation 289

II. Cellular Mechanisms 2891. Effects of Nicotine on Cell Firing 290

Contents XIX

2. Effects of Nicotine on Nerve Terminals 2903. Effects of Nicotine on Transmitter Release

in the Whole Animal 291III. Neuronal Activity and Mechanisms of Reinforcement 291

1. Mesolimbic Dopamine 2922. Dorsal Noradrenergic Bundle 2943. Thalamocortical Projections 2954. Habenulo-Interpeduncular System 2955. 5-HT Release 2956. Amino Acid Neurotransmitter Release 2967. Acetylcholine Release 2968. Other Measures of Neuronal Activity 2979. Peripheral Effects 298

E. Implications for Medications Developmentarid Conclusions 299

References 300

CHAPTER 9

Caffeine Reinforcement, Discrimination, Toleranceand Physical Dependence in Laboratory Animals and HumansR.R. GRIFFITHS and G.K. MUMFORD. With 2 Figures 315

A. Introduction 315B. Reinforcing Effects of Caffeine in Laboratory Animals 316C. Reinforcing Effects of Caffeine in Humans 317D. Discriminative Stimulus Effects of Caffeine

in Laboratory Animals 318I. Pharmacologic Mechanisms in Drug Discrimination 320

E. Subjective and Discriminative Stimulus Effects of Caffeinein Humans 322

I. Qualitative Subjective Effects of Caffeine 322II. Demonstration of Caffeine Discrimination 324

III. Acquisition of Caffeine Discrimination 324IV. Thresholds for Caffeine Discrimination 325V. Cross-Generalization with Other Drugs 325

VI. Relationship Between Caffeine Discriminativeand Subjective Effects 325

VII. Relationship Between Discriminationand Physical Dependence 327

VIII. Relationship Between Discriminationand Reinforcement 327

F. Tolerance to Caffeine in Laboratory Animals 327I. Role of Adenosine in Tolerance 329

G. Tolerance to Caffeine in Humans 329

XX Contents

H. Caffeine Physical Dependence in Laboratory Animals 330I. Role of Adenosine in Physical Dependence 332

I. Caffeine Physical Dependence in Humans 333J. Conclusions 334References 335

CHAPTER 10

Classical HallucinogensR.A. GLENNON. With 7 Figures 343

A. Introduction 343B. Definitions 345C. Human vs Nonhuman Investigations 346D. Models and Assay Methods for Hallucinogenic Activity 347

I. Animal Models 347II. Nonanimal Models 348

III. The Drug Discrimination Paradigm 349E. Structure-Activity Relationships 350

I. Indolylalkylamines 351II. Phenylalkylamines 352

F. Mechanism of Action of Classical Hallucinogens 352I. The 5-HT Hypothesis 352

II. The 5-HT2 Hypothesis 353III. The 5-HT lc Hypothesis 355IV. 5-HT2A vs 5-HT2C Receptors 356

1. Studies with Selective Antagonists 3562. Studies with Lisuride : 3573. Studies with TFMPP 3584. Radioligand Binding Studies 358

V. Involvement of Other 5-HT Receptors 360VI. Involvement of Dopamine Receptors 362

G. Structurally Related Agents and Designer Drugs 363H. Molecular Modeling

of Hallucinogen-Receptor Interactions 365I. Summary 368References 369

CHAPTER 11

AlcoholB. TABAKOFF, K. HELLEVUO, and P.L. HOFFMAN. With 1 Figure 373

A. Introduction 373B. The Metabolism of Ethanol 374

I. Ethanol-Induced Metabolic Anomalies 376

Contents XXI

II. Alcohol Dehydrogenaseand Microsomal Ethanol Oxidizing Systems 379

III. Aldehyde Dehydrogenase 381IV. Acetate Metabolism and the Metabolic Effects

of Acetate 382C. Actions of Ethanol on the CNS 383

I. Membrane Hypothesis of Ethanol's Actions 383II. Voltage-Sensitive Calcium Channels 387

III. Neurotransmitter Release 3911. Dopamine 3912. Serotonin, Norepinephrine and Acetylcholine 394

IV. Neuropeptides 3961. Opiates 3962. Arginine Vasopressin 4003. Neurotensin 401

V. Postsynaptic Receptors 4021. Receptor-Effector Coupling Systems 403

VI. Ligand-Gated Ion Channels 4151. GABAA Receptors 4152. Glutamate Receptors 4213. 5-HT3 Receptors 430

D. Conclusion 431References 433

III. Advances in the Pharmacotherapy of Addiction

CHAPTER 12

Pharmacotherapy of Addiction: Introduction and PrinciplesF.R. LEVIN and H.D. KLEBER 461

A. Introduction 461B. Pharmacologic Interventions 462

I. Agonists 4631. General Principles and Clinical Indications 4632. Drug Classes 463

II. Antagonists 4651. General Principles and Clinical Indications 4652. Drug Classes 466

III. Anti-withdrawal Agents 4671. General Principles and Clinical Indications 4672. Drug Classes 468

IV. Anti-craving Agents 469C. Conclusion 470References 470

XXII Contents

CHAPTER 13

Development of Medications for Addictive DisordersF.I. Vocci. With 3 Figures 473

A. History of the Regulatory System for New Drugs 473B. Scheme of New Drug Development 473C. Phases of Clinical Investigations 476D. Special Considerations Related to Medications Development

for Addictive Disorders 479E. /-a-Acetylmethadol: Selected Clinical Studies 479F. Other Necessary Regulatory Actions

Regarding /-a-Acetylmethadol • 483G. Summary 483References 484

CHAPTER 14a

Long-Term Pharmacotherapy for Opiate (Primarily Heroin)Addiction: Opioid AgonistsM.J. KREEK 487

A. Introduction 487B. d/-Methadone (and /-Methadone) as Used in Long-Term

Pharmacotherapy of Opiate Addiction 493I. Chemistry, Pharmacokinetics, Pharmacodynamics,

and Mechanisms of Action 4931. Methadone Disposition in Setting

of Chronic Diseases 5012. Methadone Disposition in Pregnancy 5023. Drug and Alcohol Interactions with Methadone 503

II. Use of Methadone in Long-Term Pharmacotherapyof Opiate Addiction: "Methadone Maintenance" 5061. Safety, Efficacy, and Effectiveness 506

III. Neuroendocrine Immune and Gastroenterological Effectsof Methadone (As Contrasted with Heroin Addiction) . . . . 5231. Neuroendocrine Function 5232. Immune Function 5283. Gastrointestinal Function 530

IV. Special Issues Related to Methadone Maintenanceand All Other Long-Term Treatmentsof Opiate (Heroin) Addicts 5311. Codependency: Alcoholism, Cocaine,

and Other Addictions 5312. Psychiatric Comorbidity 532

Contents XXIII

3. Chronic Liver Disease, HIV Infection, and AIDS:Preexisting Medical Problems in Heroin Addictsand Impact of Methadone Treatment 533

C. /-a-Acetylmethadol (LAAM) 534I. Chemistry, Pharmacokinetics, Pharmacodynamics,

and Mechanisms of Action in Humans 534II. Use of LAAM in Long-Term Pharmacotherapy

of Opiate Addiction: Safety, Efficacy, and Effectiveness . . . 536III. Neuroendocrine Effects of LAAM 540

References 541

CHAPTER 14b

Long-Term Pharmacotherapy for Opiate (Primarily Heroin)Addiction: Opioid Antagonists and Partial AgonistsM.J. KREEK 563

A. Naloxone, Naltrexone, and Nalmefene(Mixed Agonists and Antagonists) 563

I. Chemistry, Pharmacokinetics, Pharmacodynamics,and Mechanisms of Action in Humans 563

II. Use of Naltrexone and Other Opioid Antagonists:Safety, Efficacy, and Effectiveness 567

III. Neuroendocrine Effects of Opioid Antagonists 574B. Buprenorphine 575

I. Chemistry, Pharmacokinetics, Pharmacodynamics,and Mechanisms of Action in Humans 575

II. Use of Buprenorphine: Safety, Efficacy,and Effectiveness 578

III. Neuroendocrine Effects of Partial Agonists(Mixed Agonists/Antagonists) 590

References 592

CHAPTER 15

Pharmacotherapy of Nicotine DependenceJ.R. HUGHES 599

A. Introduction 599I. A Brief History of Treatment for Smoking Cessation 599

II. Why Pharmacotherapy? 599III. Methodological Issues 600

1. Paradigms to Test Efficacy 6002. Traditions of Testing Medications for Smoking

vs for Other Drug Dependencies 601

XXIV Contents

IV. Comparing Medications 601B. Medications to Aid Smoking Cessation 602

I. Nicotine Replacement 6021. Nicotine Polacrilex (Nicotine Gum) 6022. Transdermal Nicotine Systems

(Nicotine Patches) 6053. Patient Selection for Nicotine Replacement 6084. Other Nicotine Replacement Medications 6085. Lobeline 6086. Future Studies on Nicotine Replacement 609

II. Blocking Agents 6101. Mecamylamine 6102. Naltrexone 611

III. Clonidine 611IV. Agents That Make Smoking Aversive 612

1. Silver Acetate 6122. Other Aversive Agents 612

V. Medications to Abate Withdrawal or Replacethe Reinforcing Effects of Nicotine 6131. Anxiolytics 6132. Antidepressants 6133. Stimulants 6144. Anorectics 6155. Other Medications 615

C. Use of Adjunctive Psychological Therapies 616I. Psychological Therapies for Smoking Cessation 616

II. Combining Psychological Therapiesand Medications 616

D. Treating Smoking Among Alcohol/Drug Abusers 617E. Conclusions: Typical Quit Rates 617References 618

CHAPTER 16

Pharmacotherapies for Cocaine DependenceE.A. WALLACE and T.R. KOSTEN 627

A. Introduction 627B. Pharmacologic Treatment of Cocaine Dependence 627

I. Introduction 627II. Medications Employed in the Treatment

of Cocaine Dependence 6281. Acute Withdrawal Agents 6282. Chronic Treatment Agents 6323. Comorbid Psychiatric Disorders 635

Contents XXV

III. Clinical Considerations 6361. Indications for Treatment 6362. Length of Treatment 6373. Precautions in Treatment 638

References 639

Subject Index 645