Neuroscience of addiction and dependence - The National Alliance

286 Pages·2004·1.82 MB·English

DepNeuroCoverFinal_CAG 19.1.2004 12:15 Page 1
Neuroscience of psychoactive
substance use and dependence
The Neuroscience of psychoactive substance use and dependence N
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provides an authoritative summary of current knowledge of the u
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biological basis of substance use and dependence, and discus-
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ses the relationship of these behaviours with environmental fac- ie
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tors. The book focuses on specific brain mechanisms governing c
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craving, tolerance, withdrawal, and dependence on a wide range
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of psychoactive substances, including tobacco, alcohol and illicit f
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drugs. The ethical implications of new developments for preven-
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tion and treatment are also discussed, and the public health h
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implications of this knowledge are translated into recommenda- a
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tions for policy and programmes at national and international tiv
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levels. Relying on contributions from many international experts,
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the best available evidence is presented from the various schools u
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of thought and areas of research in this rapidly growing field. t
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Neuroscience of psychoactive substance use and dependence is e

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written for individuals with more than a basic knowledge of the
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field, including scientists from a variety of disciplines. The book
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should be of interest to health care workers, clinicians, social
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workers, university students, science teachers and policy makers. d
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ISBN 92 4 156235 8
WHO
Neuroscience of
psychoactive substance use
and dependence
WORLD HEALTH ORGANIZATION
GENEVA
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WHO Library Cataloguing-in-Publication Data
Neuroscience of psychoactive substance use and dependence.
1. Psychotropic drugs - pharmacology 2. Substance-related disorders -
physiopathology 3. Psychopharmacology 4. Brain - drug effects
I. World Health Organization.
ISBN 92 4 156235 8 (LC/NLM classification: WM 270)
© World Health Organization 2004
All rights reserved. Publications of the World Health Organization can be obtained from Marketing
and Dissemination, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland
(tel: [phone]; fax: [phone]; email: [email protected]). Requests for
permission to reproduce or translate WHO publications – whether for sale or for noncommercial
distribution – should be addressed to Publications, at the above address (fax: [phone];
email: [email protected]).
The designations employed and the presentation of the material in this publication do not imply
the expression of any opinion whatsoever on the part of the World Health Organization concerning
the legal status of any country, territory, city or area or of its authorities, or concerning the
delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border
lines for which there may not yet be full agreement.
The mention of specific companies or of certain manufacturers’ products does not imply that
they are endorsed or recommended by the World Health Organization in preference to others of
a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary
products are distinguished by initial capital letters.
Text design by minimum graphics
Cover design by Tushita Graphic Vision
Printed in Switzerland
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Contents
Foreword ix
Acknowledgements xi
List of background papers and contributors xv
Abbreviations xvii
Chapter 1. Introduction 1
Structure of the report 1
Psychoactive substances and their sociolegal status 1
Global use of psychoactive substances 4
Tobacco 4
Alcohol 5
Illicit use of controlled substances 9
Adverse effects of psychoactive substances and their mechanisms
of action 10
Substance dependence in relation to neuroscience 12
The burden of harm to health from psychoactive substance use 16
Chapter 2. Brain Mechanisms: Neurobiology and Neuroanatomy 19
Introduction 19
Organization of the brain 19
The neuron 25
Cell body 26
Dendrites 26
Axon 28
Terminal buttons 28
Neurotransmission 29
Action potential 29
Neurotransmitter release 30
Receptors 31
Neurotransmitters 32
Acetylcholine 33
γ-aminobutyric acid 33
Glutamate 33
Dopamine 34
Norepinephrine 34
iii
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NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE
Serotonin 35
Peptides 35
Genes 35
Cellular and neuronal effects of psychoactive substances 36
Cellular effects 36
Neuronal effects 38
Conclusion 39
Chapter 3. Biobehavioural Processes Underlying Dependence 43
Introduction 43
Defining terms 44
Classical or Pavlovian conditioning 44
Instrumental or operant conditioning 46
Reinforcer 47
Reward 47
Incentive 47
Motivation 48
Incentive-motivational responding 48
Drug reward alone does not explain drug dependence 48
Drug dependence as a response to incentive-motivation 49
Drug dependence as a response to drug withdrawal 50
Dopamine and reinforcement learning 50
Dependence-producing drugs as surrogates of conventional
reinforcers 51
Dopamine and incentive sensitization 52
Psychomotor sensitization 53
Sensitization and drug reward 53
Sensitization and tolerance 54
Individual differences 55
Summary 58
Chapter 4. Psychopharmacology of Dependence for Different
Drug Classes 67
Introduction 67
Alcohol (ethanol) 69
Introduction 69
Behavioural effects 69
Mechanism of action 70
Tolerance and withdrawal 70
Neurobiological adaptations to prolonged use 72
Pharmacological treatment of alcohol dependence 72
Sedatives and hypnotics 73
Introduction 73
Behavioural effects 73
Mechanism of action 74
iivv
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CONTENTS
Tolerance and withdrawal 74
Neurobiological adaptations to prolonged use 75
Tobacco 75
Introduction 75
Behavioural effects 75
Mechanism of action 76
Tolerance and withdrawal 77
Pharmacological treatment of nicotine dependence 78
Opioids 79
Introduction 79
Behavioural effects 79
Mechanism of action 80
Tolerance and withdrawal 80
Neurobiological adaptations to prolonged use 81
Pharmacological treatment of opioid dependence 81
Cannabinoids 84
Introduction 84
Behavioural effects 85
Mechanism of action 86
Tolerance and withdrawal 87
Neurobiological adaptations to prolonged use 88
Cocaine (hydrochloride and crack) 89
Introduction 89
Behavioural effects 89
Mechanism of action 89
Tolerance and withdrawal 91
Neurobiological adaptations to prolonged use 91
Pharmacological treatment of cocaine dependence 92
Amphetamines 93
Introduction 93
Behavioural effects 94
Mechanism of action 95
Tolerance and withdrawal 95
Neurobiological adaptations to prolonged use 96
Ecstasy 96
Introduction 96
Behavioural effects 99
Mechanism of action 99
Tolerance and withdrawal 100
Neurobiological adaptations to prolonged use 100
Volatile solvents 100
Introduction 100
Behavioural effects 101
Mechanism of action 102
v
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NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE
Tolerance and withdrawal 103
Neurobiological adaptations to prolonged use 103
Hallucinogens 104
Introduction 104
Behavioural effects 105
Mechanism of action 105
Tolerance and withdrawal 105
Neurobiological adaptations to prolonged use 106
Summary 106
Chapter 5. Genetic Basis of Substance Dependence 125
Introduction 125
Family, twin and adoption studies: estimations of heritability 127
Identifying chromosomal locations of interest: linkage studies 127
Candidate gene approach 128
Animal studies 128
Genetics of tobacco dependence 130
Heritability of tobacco dependence 130
Tobacco dependence and linkage studies 131
Candidate genes for tobacco dependence 131
Genetics of alcohol dependence 132
Heritability of alcohol dependence 132
Alcohol dependence and linkage studies 133
Candidate genes for alcohol dependence 134
Genetics of opioid dependence 136
Heritability of opioid dependence 136
Opioid dependence and linkage studies 136
Candidate genes for opioid dependence 136
Genetics of the combined risk of dependence on tobacco, alcohol,
opioids and other psychoactive substances 138
Heritability of substance dependence 138
Linkage studies of substance dependence 139
Candidate genes involved in substance dependence 140
Confounding issues in linkage and candidate gene studies 147
Environment 147
Genetice heterogeneity 147
Phenotype 148
Comorbidity 148
Methodological issues 148
Future directions 149
Social and cultural aspects 150
Risk factors and protective factors for dependence: an overview 150
Summary 151
vi
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CONTENTS
Chapter 6. Concurrent Disorders 169
Introduction 169
Hypotheses that may explain the observed comorbidity 170
Schizophrenia 171
Tobacco smoking and schizophrenia 171
Psychostimulant (cocaine and amphetamine) dependence and
schizophrenia 174
Alcohol use and schizophrenia 176
Neurobiological interactions between schizophrenia and the effects
of psychoactive substances 176
Depression 180
Tobacco smoking and depression 181
Psychostimulant dependence and depression 182
Alcohol use and depression 183
Neurobiological interactions between depression and the effects
of psychoactive substances 184
Discussion and conclusions 188
Chapter 7. Ethical Issues in Neuroscience Research on Substance
Dependence Treatment and Prevention 209
Introduction 209
Types of research on neuroscience of substance dependence 209
Animal experiments 209
Epidemiological research on substance dependence 209
Experimental studies in humans 210
Clinical trials of pharmacotherapy for substance dependence 210
Trials of pharmacotherapies to prevent substance dependence 211
Approach to ethical analysis 211
Principles of biomedical ethics 216
Human rights 217
Ethics of animal experimentation in neuroscience research 218
Ethical principles in human biomedical research 219
Independent ethical review of risks and benefits 219
Informed consent 220
Recruitment of subjects 220
Privacy and confidentiality 221
Emerging ethical issues in neuroscience research 222
Research on vulnerable persons 222
Are substance dependent people vulnerable persons? 223
Provocation studies 223
Ethical issues in epidemiological research on substance dependence 224
Ethical issues in clinical trials of pharmacological treatments
for substance dependence 225
Trial design 225
vii
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NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE
Distributive justice 226
Conflicts of interest 226
Trials of preventive pharmacological interventions for substance
dependence 227
Early intervention studies 227
Preventive use of drug immunotherapies 229
Implications of neuroscience research for models of substance
dependence 231
Implications of neuroscience research for the treatment of substance
dependence 232
Access to treatment 232
Legally coerced treatment 232
Summary and conclusions 235
Chapter 8. Conclusion and Implications for Public Health Policy 241
Introduction 241
Advances in the neuroscience of psychoactive substance use and
dependence and their implications 241
Potential advances in policy, prevention and treatment 243
Ethical issues in the application of neuroscience findings 244
Implications for public health policy 247
Conclusion 248
Index 251
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Foreword
Substance use and dependence cause a significant burden to individuals and
societies throughout the world. The World Health Report 2002 indicated that
8.9% of the total burden of disease comes from the use of psychoactive
substances. The report showed that tobacco accounted for 4.1%, alcohol 4%,
and illicit drugs 0.8% of the burden of disease in 2000. Much of the burden
attributable to substance use and dependence is the result of a wide variety
of health and social problems, including HIV/AIDS, which is driven in many
countries by injecting drug use.
This neuroscience report is the first attempt by WHO to provide a
comprehensive overview of the biological factors related to substance use
and dependence by summarizing the vast amount of knowledge gained in
the last 20-30 years. The report highlights the current state of knowledge of
the mechanisms of action of different types of psychoactive substances, and
explains how the use of these substances can lead to the development of
dependence syndrome.
Though the focus is on brain mechanisms, the report nevertheless
addresses the social and environmental factors which influence substance
use and dependence. It also deals with neuroscience aspects of interventions
and, in particular, the ethical implications of new biological intervention
strategies.
The various health and social problems associated with use of and
dependence on tobacco, alcohol and illicit substances require greater
attention by the public health community and appropriate policy responses
are needed to address these problems in different societies. Many gaps remain
to be filled in our understanding of the issues related to substance use and
dependence but this report shows that we already know a great deal about
the nature of these problems that can be used to shape policy responses.
This is an important report and I recommend it to a wide audience of health
care professionals, policy makers, scientists and students.
LEE Jong-wook
Director General
World Health Organization
ix
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