Animal and Translational Models for CNS Drug Discovery: Reward Deficit Disorders (eBook)

Front Cover 1
Animal and Translational Models for CNS Drug Discovery 4
Copyright Page 5
Contents 8
Preface 16
Acknowledgements 40
List of Contributors 42
CHAPTER 1 Impulse and Reward Deficit Disorders: Drug Discovery and Development 44
Introduction 45
The Key Messages of Epidemiology: What should be Modeled? 45
Drug Addiction 46
Behavioral Addictions 46
Comorbid Associations 48
From Epidemiology to Unmet Medical Needs to Drug Discovery and Development 50
Challenges Facing Drug Discovery and Development in Impulse and Reward Deficit Disorders 51
Toward Translational Value of Animal Models in Impulse and Reward Deficit Disorders 53
Key Neurosystems Relevant to Drug Discovery and Development 53
Key Experimental Paradigms with Translational Potential for Drug Discovery and Development 54
Compulsive/Impulsive Behaviors 56
Target Validation and Throughput Limitations 57
Target Validation, Validity, Reliability, and Automation 58
Conclusions 58
References 59
CHAPTER 2 Drug Discovery and Development for Reward Disorders: Views from Government 66
Introduction and Contextual Issues 66
Division of Pharmacotherapies and Medical Consequences of Drug Abuse 67
Drug Discovery Program – Initial Operations 67
Drug Discovery Program – Current Status 69
Development of Medications for Opiate and Cocaine Addiction 70
Animal Models in the Discovery of Drug Addiction Treatments 73
The Validity of Animal Models in the Field of Drug Addiction 73
Use of Data from Animal Models for "Go/No Go" Decisions 73
Avoiding False Positives in Drug Self-administration and Relapse Model Testing 74
Translational Research, Human Laboratory Models, and the Bridge between Animal Models and Clinical Efficacy Trials 77
References 81
CHAPTER 3 Issues in Designing and Conducting Clinical Trials for Reward Disorders: A Clinical View 84
Introduction 84
Utility of Research using Animal Models 85
Advantages of Animal Research 85
Drug Exposure 85
Behavioral Techniques in Animal Research 86
Drug Self-administration 87
Human Testing Paradigms for New Medications 88
Human Laboratory 88
Self-administration 89
Neuroimaging 89
Methodological Issues in Clinical Trials 90
Target Population and Subject Selection 90
General Design Issues 92
Statistical Issues 94
Conclusions 95
Acknowledgments 96
References 96
CHAPTER 4 The Role of Animal Models in Reward Deficit Disorders: Views from Academia 102
Introduction and Definitions 103
Face and Construct Validity of Animal Models of Reward Deficits in Psychiatric Illness 104
Face Validity and Construct Validity of Animal Models of Reward Deficits in Psychiatric Disorders 105
Brain Stimulation Reward 105
Sucrose Consumption/Sucrose Preference 108
Progressive-Ratio Responding 108
Drug Withdrawal Model of Dependence 109
Brain Stimulation Reward As a Measure of the Reward Deficits Associated with Drug Dependence 110
Sucrose Intake/Preference As a Measure of the Reward Deficits Associated with Drug Dependence 110
Progressive-Ratio Responding As a Measure of Reward Deficits Associated with Drug Dependence 111
Chronic Mild Stress and Depression 113
Brain Stimulation Reward As a Measure of the Reward Deficits Associated with the Chronic Mild Stress Model of Depression 113
Sucrose Intake/Preference As a Measure of the Reward Deficits Associated with the Chronic Mild Stress Model of Depression 114
Progressive-Ratio Responding As a Measure of the Reward Deficits Associated with the Chronic Mild Stress Model of Depression 118
Validity of Animal Models of Reward Deficits 118
Common Neurobiological Substrates for the Reward Deficits in Addiction and Depression 119
Neurochemical Substrates in Dependence 119
Neurochemical Substrates in Depression 120
Extended Amygdala 121
Allostasis in Reward Function 122
Translational Value of these Models and Procedures for the Study of Reward Deficits in Man 123
Prospects for the Development of New Therapeutics of Reward Deficit Disorders 124
Summary and Conclusions 124
Acknowledgments 125
References 125
CHAPTER 5 Pharmacotherapy of Alcohol Dependence: Improving Translation from the Bench to the Clinic 134
Introduction 135
Epidemiology/Clinical and Societal Impact 135
Types of Alcoholism 137
Diagnostic Features of Alcohol Dependence 138
Clinical Diagnostic Criteria for Alcohol Dependence and Their Importance in the Development of Animal Models 139
Important Non-diagnostic Components of Alcohol Dependence 142
Current Treatment of Alcohol Dependence 145
Human Pharmacology and Experimental Medicine Approaches to the Treatment of Alcohol Dependence 150
Review of Clinical Trial Design 150
Behavioral Models of Alcohol Dependence 152
Voluntary Drinking Choice Model 152
Forced Alcohol Consumption 160
Effects of Clinically Effective and Novel Drugs on Alcohol Withdrawal 160
Alcohol Place Conditioning 161
Changes in Alcohol Place Conditioning After Chronic Treatment and Reinstatement of Conditioned Place Preference 163
Effects of Aversive Consequences on Alcohol Place Conditioning 163
Effects of Clinically Effective and Novel Drugs on Alcohol Place Conditioning 164
Family History of Alcohol Dependence 175
Genes Associated with Risk of Alcohol Dependence 177
Correspondence of Efficacy of Established and Novel Treatments for Alcohol Dependence in Animals and Humans 184
Consensus Statement Regarding Animal Models of Alcohol Dependence 185
References 187
CHAPTER 6 Contribution of Animal Models and Preclinical Human Studies to Medication: Development for Nicotine Dependence 222
Introduction 223
The Problem of Tobacco Smoking 223
Tobacco Addiction and Nicotine Dependence 223
Criteria for Defining Nicotine Dependence in Humans 227
Animal Models of Nicotine Dependence 228
What is a Model? 228
Models of Various Aspects of Nicotine Withdrawal 231
Models of Reinstatement of Nicotine-Seeking Behavior with Relevance to Relapse 232
Animal Models of Motivation for Nicotine 233
Historical Background: Why Drug Discovery on Nicotine Dependence Was Different from that on Other Drugs of Abuse 234
Preclinical Animal Models of Nicotine Dependence in Drug Discovery 236
Limitations of Drug Discovery Assays and Models for Nicotine Dependence 239
Human Preclinical and Clinical Studies 242
Ad Libitum Smoking Studies 243
Studies of Withdrawal Symptoms and "Craving" During Abstinence 244
Short-Term Abstinence Studies 245
Small-Scale Open-Label Studies 246
Commentary 246
Successes, Failures and Serendipity in Translational Research 247
Challenges, Opportunities, and Perspectives 248
Translational Medicine: From Mechanism of Action to Clinical Efficacy 248
Product Profile and Return-of-Research-Investment 249
Experimental Medicine Paradigm Shift and Translational Research 249
Acknowledgements 250
References 250
CHAPTER 7 Development of Medications for Heroin and Cocaine Addiction and Regulatory Aspects of Abuse Liability Testing 264
Introduction 265
Opioid and Cocaine Addiction 268
Pharmacotherapy for Drug Addiction and Abuse Potential of New Compounds 271
Animal Laboratory Models 271
Human Laboratory Models 280
Assessment of Abuse Liability of Compounds: the Regulatory Environment 285
Regulatory Environment in the United States and the EU 285
World Health Organization 287
Approved and Proposed Medications to Treat Opioid and Cocaine Addiction 288
Heroin (Opioid) Addiction 288
Cocaine Addiction 292
Concordance Between Animal and Human Laboratory Studies and Clinical Outcome 297
Improving the Predictive Value of Existing Models 298
Improving the Predictive Value of Existing Models in the Assessment of Abuse Liability 300
References 301
CHAPTER 8 Anti-obesity Drugs: From Animal Models to Clinical Efficacy 314
Introduction 315
Clinical Aspects of Obesity and Cardiometabolic Disease 316
Background – Do We Need Drugs for Obesity? 316
Current Drugs for Obesity and Their Limitations 317
Other Drugs – Withdrawn or No Longer Recommended for Routine Clinical Use 318
The Need for New Drugs 318
Biology and Genetics of Energy Regulation and Implications for Obesity 319
Short-Term (Episodic) Signals 319
Long-Term (Tonic) Signals 321
CNS Integrating Pathways 322
Biomarkers of Energy Regulation and Obesity 323
Anthropometric Measures 323
Measures of Adiposity 324
Measures of Energy Expenditure 324
Risk Factors 325
Insulin Resistance and Systemic Inflammation 325
The Psychobiology of Appetite Expression 326
Episodic Signals in the Regulation of Appetite Expression 326
Tonic Signals in the Regulation of Appetite Expression 326
Psychological and Behavioral Aspects of Obesity 326
Genetics Versus Environment? 327
Obese Eating Style? 327
Trait Hunger, Disinhibition, and Binge Eating 329
Behavioral Indices for Assessing the Action and Efficacy of Anti-obesity Drugs 330
Susceptibility to Obesity and Hyperphagia 330
Structure of Feeding Behavior 331
Assessing the Effects of Drugs on Human Feeding Behavior 331
Microstructure of Human Eating Behavior: Eating Rate, Cumulative Intake Curves and Deceleration 332
Molecular Targets for Anti-obesity Drugs 333
Lipase Inhibitors 333
Serotonin/Noradrenaline Reuptake Inhibitors 334
Selective Serotonin Receptor Ligands 335
Cannabinoid Receptor Ligands 338
Neuropeptide Receptor Ligands 338
Screening Strategies from Molecular Target to Initial Clinical Trial 340
Proof of Concept for Novel Anti-obesity Drugs: The Role of Experimental Medicine Studies to Determine Drug Efficacy and Side-effects 342
Measurement of Anti-Obesity Drug Efficacy in Experimental Medicine Studies: The UEM Approach 342
Measurement of Anti-Obesity Drug Efficacy and CNS Side-Effects in Experimental Medicine Studies: The Emotional Test Battery Approach 343
Summary 345
References 345
CHAPTER 9 Current Concepts in the Classification, Treatment and Modeling of Pathological Gambling and Other Impulse Control Disorders 360
Introduction 361
Neurobiology of Pathological Gambling 362
Biochemistry of Neurotransmitters 362
Stress Response Systems 365
Opioidergic Pathways 366
Neuroimaging 367
Genetic Considerations 368
Conclusions 369
Treatment 369
Pathological Gambling 369
Trichotillomania 374
Compulsive Buying/Shopping 376
Intermittent Explosive Disorder 377
Kleptomania 378
Insight from Animal Models 380
Animal Models of Gambling Behavior 380
The Feasibility of Modeling Gambling in Animals 381
Considerations for a Model of Pathological Gambling 383
Summary 385
Conclusions and Recommendations 385
References 386
EPILOGUE: Translational Models for the 21st Century: Reminiscence, Reflections and Some Recommendations 402
Introduction 402
References 412
Index 420
A 420
B 421
C 421
D 422
E 422
F 423
G 423
H 423
I 423
K 423
L 424
M 424
N 424
O 425
P 425
Q 425
R 426
S 426
T 426
U 426
V 426
W 426