Neurobiology of Addiction

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NEUROBIOLOGY
OF ADDICTION
GEORGE F. KOOB
Molecular and Integrative Neurosciences Department,
The Scripps Research Institute,
La Jolla, California, USA

MICHEL LE MOAL
Physiopathologie du Comportement
Institut National de la Sante′ et de la Recherche Me′dicale,
Institut François Magendie,
Universite′ Victor Ségalen Bordeaux 2
Bordeaux, France

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06 07 08 09 10 10 9 8 7 6 5 4 3 2 1
“Drugs don’t affect me”
Dr. Theodora J Koob
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 Contents

Preface ix 4. Opioids
Acknowledgments xi
Definitions 121
History of Opioid Use, Abuse, and Addiction 121
Medical Use and Behavioral Effects 122
1. What is Addiction Pharmacokinetics 124
Definitions of addiction 1 Abuse and Addiction Potential 126
Neuroadaptational Views of Addiction 10 Behavioral Mechanism of Action 134
Summary 19 Neurobiological Mechanism—Neurocircuitry 135
References 19 Neurobiological Mechanism—Cellular 150
Neurobiological Mechanism—Molecular 154
Summary 159
References 159
2. Animal Models of Drug Addiction
Definitions and Validation of Animal Models 23 5. Alcohol
Animal Models for the Binge/Intoxication Stage of the
Addiction Cycle 26 Definitions 173
Animal Models for the Drug Withdrawal/Negative Affect History of Alcohol Use, Abuse, and Alcoholism 174
Stage of the Addiction Cycle 38 Behavioral Effects of Alcohol 175
Animal Models for the Preoccupation/Anticipation Pharmacokinetics 178
(Craving) Stage of the Addiction Cycle 41 Abuse and Addiction Potential 181
Animal Models for the Transition to Addiction 50 Behavioral Mechanism of Action 190
Summary 60 Neurobiological Mechanism—Neurocircuitry 191
References 60 Neurobiological Mechanism—Cellular 206
Neurobiological Mechanism—Molecular 211
Summary 221
3. Psychostimulants References 221

Definitions 69
History of Psychostimulant Use, Abuse, and 6. Nicotine
Addiction 71
Definitions 243
Behavioral Effects and Medical Uses 74
History of Tobacco Use, Abuse, and Addiction 244
Pharmacokinetics 78
Medical Use and Behavioral Effects 248
Abuse and Addiction Potential 79
Pharmacokinetics 251
Behavioral Mechanisms 82
Abuse and Addiction Potential 253
Neurobiological Mechanism—Neurocircuitry 83
Behavioral Mechanism of Action 258
Neurobiological Mechanism—Cellular 96
Neurobiological Mechanism—Neurocircuitry 260
Neurobiological Mechanism—Molecular 103
Neurobiological Mechanism—Cellular 268
Summary 108
Neurobiological Mechanism—Molecular 270
References 109
Summary 275
References 276
viii CONTENTS

7. Cannabinoids Cellular Hypotheses of Addiction 405

Molecular Hypotheses of Addiction 408
Definitions 289 Synthesis: Common Elements of Most Neurobiological
History of Cannabinoid Use, Abuse, and Models of Addiction 414
Addiction 293 References 416
Medical Use and Behavioral Effects 296
Pharmacokinetics 299
Cannabinoid Tolerance 300
Cannabinoid Withdrawal 301
10. Drug Addiction: Transition from
Pathology and Psychopathology 304 Neuroadaptation to Pathophysiology
Behavioral Mechanism of Action 307
Common Neurobiological Elements in
Neurobiological Mechanism—Neurocircuitry 307
Addiction 429
Neurobiological Mechanism—Cellular 316
Overall Conclusions—Neurobiology of
Neurobiological Mechanism—Molecular 321
Addiction 434
Summary 323
Homeostasis versus Allostasis in Addiction 435
References 325
Drug-Seeking to Addiction—An Allostatic View 437
The Allostatic View versus Incentive
Sensitization View 444
8. Imaging A NonDopamine-centric View of Addiction 447
Pain and Addiction 448
Introduction 339 Neurocircuitry of Compulsive Drug-Seeking and
Basic Technical Principles of Neuroimaging 340 Drug-Taking 450
Brain Imaging of Drug Addiction 343 Implications of the Allostatic View for Motivation and
Integration of Imaging Studies in Humans with the Psychopathology 453
Neurocircuitry of Addiction 361 References 453
Summary 368
References 369
Appendix 1. Psychostimulants 463
Appendix 2. Opioids 471
9. Neurobiological Theories of Addiction Appendix 3. Alcohol 473
Appendix 4. Nicotine 481
Introduction 378 Appendix 5. Cannabinoids 483
Neurocircuitry Hypotheses of Addiction—
Dopamine and Reward 378
Neurocircuitry Theories of Addiction—Executive
Function 381 Index 485
Neurocircuitry Theories of Addiction—Relapse 387
Neurocircuitry Theories of Addiction—Reward and
Stress 394
 Preface

This book began with an idealistic goal to summarize, incorporated as a separate chapter to allow a view of
integrate, and synthesize the world's literature on the common elements in the imaging field and to reduce
Neurobiology of Addiction under one conceptual redundancy of technique, approach, and methodology.
framework, in one volume. As we embarked on this Towards the end of the book, there is a chapter on
journey, it became increasingly evident that this was a Neurobiological Theories of Addiction which explores the
Herculean task that required an enormous commit- different conceptual views of prominent investigators
ment to find original sources, review diverse topics, in the field, from both a neurobiological and evolving
search under conceptual stones, and select relevant historical perspective. An attempt is made to integrate
facts, papers and frameworks, and ultimately limit our the different theories into a heuristic model to account
appetite for citing every paper. for most of the stages of the addiction cycle. The last
The journey took over two years and led to the chapter, Drug Addiction: Transition from Neuroadaptation
uncovering of heretofore unknown intellectual gems to Pathophysiology, is what we unabashedly admit is our
(to us anyway) and some contradictions—but also a world view of the neurobiology of addiction; as such,
surprising number of neurobiological consistencies this final chapter may be considered parochial.
and commonalities across the spectrum of addictive Nevertheless, we believe, that after two years of intense
drugs. What evolved was, what we think, is a reason- research, we can bring a unique view to the field, as if we
ably objective view of the field, with a concerted were in a zeppelin floating above the vast sea of data.
attempt to accomplish what we set out to do. Several facts are worth noting. First, an attempt was
As a result, there is a chapter on What is Addiction? made to trace every single statement to its original
and another on Animal Models of Addiction to guide the source, and not to use secondary references. If,
reader through the conceptual and technical frame- perchance, we have failed, we welcome corrections.
work of the book. What follows are five chapters on the Second, we made a valiant attempt to fully cover the
major classes of drugs of addiction: Psychostimulants, field. If we have left out an important component of a
Opioids, Alcohol, Nicotine, and Cannabinoids. Each chap- given piece of the field, we also welcome input. Third,
ter stands on its own and integrates human use we restricted our journey to the major drugs of addic-
and addiction patterns and behavioral mechanisms tion and left out numerous other drugs of abuse and
with the neurobiology explored at three levels: neuro- drugs of dependence (with a little "d"; see Chapter 1).
circuitry (neuropharmacology), cellular (electrophy- We did not cover psychedelics, inhalants, steroids,
siology), and molecular (molecular measures and caffeine, benzodiazepines, gambling, etc. Such a
molecular genetic approaches). Appendices 1–5 broadened perspective will be saved for another day.
provide human case histories and anecdotes describ-
ing addiction profiles and personal experiences
relevant to each drug chapter. George F Koob
These levels of analysis are arbitrary and overlap
but provide a succinct framework for integration Michel Le Moal
across disciplines. Human neuroimaging has been
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 Acknowledgments

This book would not have been possible without the Scripps Research Institute Kresge Library) and Hélène
following contributions. First and foremost, without Renaud (Institut François Magendie Library) for their
the tireless efforts of Michael A. Arends, we would still diligent interlibrary loan support. We acknowledge
be writing. Mike found and tracked down references the following fellows and students for their varied
(sometimes literally hundreds of years old) from the editing contributions: Sheila Drnec, Thomas Greenwell,
world over, coordinated all tables, figures, figure Simon Katner, Maegan Mattock, Beth Maxwell Boyle,
legends, and references, and leant his incredibly thor- Cindy Reiter-Funk, Bryant Silbaugh, and Brendan
ough editing skill. Walker. We also thank K. Noelle Gracy for soliciting
All figures for the book were redrawn from their this work, and Johannes Menzel, Pauline Sones, and
original sources by Janet Hightower of The Scripps Maureen Twaig of Elsevier for their support and
Research Institute Biomedical Graphics department. enduring patience.
We cannot thank them enough. Finally, we owe a debt of gratitude to many
We appreciate Isabelle Batby and Mellany Santos colleagues for providing encouragement, suggestions,
for their editorial contributions and many excursions references, and their own personal interpretations of
to the library. We thank Marisela Perez-Meza (The studies:

Nora Abrous Athina Markou

Serge Ahmed Remi Martin-Fardon
James Anthony Barbara Mason
Gary Aston-Jones Charles O’Brien
Tamas Bartfai Loren Parsons
Floyd Bloom Pier Vincenzo Piazza
Al Collins John Pierce
Véronique Deroche-Gamonet Linda Porrino
Barry Everitt Heather Richardson
Eliot Gardner Trevor Robbins
Jacques Glowinski Marisa Roberto
Howard Gutstein Bernard Roques
R. Adron Harris Saul Shiffman
Markus Heilig George Siggins
Jack Henningfield Hervé Simon
Ralph Hingson Guy Simonnet
Reese Jones Luis Stinus
Pierre Karli Jean-Pol Tassin
Conan Kornetsky Anne-Marie Thierry
Robin Kroft Tamara Wall
Charles Ksir Friedbert Weiss
Jean-Paul Laulin Sam Zakhari
Rong Lee Eric Zorrilla
Ting-Kai Li
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 C H A P T E R

What is Addiction?

O U T L I N E

Definitions of Addiction Neuroadaptational Views of Addiction

Drug use, drug abuse, and drug addiction Behavioral sensitization
Diagnostic criteria of addiction Counteradaptation–opponent-process
Dependence view of addiction Motivational view of addiction
Psychiatric view of addiction Allostasis and neuroadaptation
Psychodynamic view of addiction
Summary
Social psychological / Self-regulation view of addiction
Vulnerability to addiction References

DEFINITIONS OF ADDICTION over drug-seeking and drug-taking that defines chronic

addiction (Koob and Le Moal, 1997).
The critical nature of the distinction between drug
Drug Use, Drug Abuse, and Drug Addiction
use, abuse and dependence has been illuminated
Drug addiction, also known as Substance Dependence by data showing that approximately 15.6 per cent
(American Psychiatric Association, 1994), is a chron- (29 million) of the U.S. adult population will go on
ically relapsing disorder that is characterized by (1) to engage in nonmedical or illicit drug use at some
compulsion to seek and take the drug, (2) loss of time in their lives, with approximately 3.1 per cent
control in limiting intake, and (3) emergence of a nega- (5.8 million) of the U.S. adult population going on to
tive emotional state (e.g., dysphoria, anxiety, irritability) drug abuse and 2.9 per cent (5.4 million) going on to
when access to the drug is prevented (defined here as Substance Dependence on illicit drugs (Grant and
dependence) (Koob and Le Moal, 1997). The occa- Dawson, 1998; Grant et al., 2005). For alcohol, 51 per
sional but limited use of an abusable drug clinically is cent (120 million) of people over the age of 12 were
distinct from escalated drug use, loss of control over current users, 23 per cent (54 million) engaged in binge
limiting drug intake, and the emergence of chronic drinking, and 7 per cent (16 million) were defined
compulsive drug-seeking that characterizes addiction. as heavy drinkers. Of these current users, 7.7 per cent
Modern views have focused on three types of drug (18 million) met the criteria for Substance Abuse or
use: (1) occasional, controlled or social use, (2) drug Dependence on Alcohol (see Alcohol chapter). For
abuse or harmful use, and (3) drug addiction. An tobacco, 30 per cent (71.5 million) of people aged 12 and
important goal of current neurobiological research on older reported past-month use of a tobacco product.
addiction is to understand the neuropharmacological Also, 19 per cent (45 million) of persons in the
and neuroadaptive mechanisms within specific neuro- U.S. smoked every day in the past month. From the
circuits that mediate the transition between occasional, 1992 National Comorbidity Survey, 75.6 per cent of
controlled drug use and the loss of behavioral control 15–54-year-olds ever used tobacco, with 24.1 per cent
Neurobiology of Addiction, by George F. Koob and Michel Le Moal. Copyright © 2006, Elsevier Inc. All rights reserved.
ISBN – 13: 978-0-12-419239-3 ISBN – 10: 0-12-419239-4
1
2 1. WHAT IS ADDICTION?

TABLE 1.1 Estimated Prevalence Among 15–54-Year-Olds of Nonmedical Use and Dependence Among Users (1990–1992)
from The National Comorbidity Survey

Prevalence of Dependence among

Ever used (%) dependence (%) users (%)

Tobacco 75.6 24.1 31.9

Alcohol 91.5 14.1 15.4
Illicit Drugs 51.0 7.5 14.7
Cannabis 46.3 4.2 9.1
Cocaine 16.2 2.7 16.7
Stimulants 15.3 1.7 11.2
Anxiolytics 12.7 1.2 9.2
Analgesics 9.7 0.7 7.5
Psychedelics 10.6 0.5 4.9
Heroin 1.5 0.4 23.1
Inhalants 6.8 0.3 3.7

[Reproduced with permission from Anthony et al., 1994.]

meeting the criteria for Dependence (Anthony et al., use to abuse to addiction. Drug addiction is a disease
1994) (see Nicotine chapter). and, more precisely, a chronic disease (Meyer, 1996).
The number of individuals meeting the criteria for As such, it can be defined by its diagnosis, etiology,
Substance Dependence on a given drug as a function and pathophysiology as a chronic relapsing disorder
of ever having used the drug varies between drugs. (Fig. 1.2). The associated medical, social, and occupa-
According to data from the 1990–1992 National tional difficulties that usually develop during the
Comorbidity Survey, the percentage addicted to a course of addiction do not disappear after detoxifica-
given drug, of those people who ever used the drug, tion. Addictive drugs are hypothesized to produce
decreased in the following order: tobacco > heroin > changes in brain pathways that endure long after
cocaine > alcohol > marijuana (Anthony et al., 1994) the person stops taking them. These protracted brain
(Table 1.1). More recent data derived from the National changes and the associated personal and social diffi-
Household Survey on Drug Abuse (Substance Abuse culties put the former patient at risk of relapse
and Mental Health Services Administration, 2003) (O’Brien and McLellan, 1996), a risk higher than
showed that the percentage addicted to a given drug, 60 per cent within the year that follows discharge
of those who ever used, decreases in the following (Finney and Moos, 1992; Hubbard et al., 1997;
order: heroin > cocaine > marijuana > alcohol (Fig. 1.1).
These more recent data suggest unsettling evidence of
an overall trend for a significant increase in Substance
Dependence with marijuana (see Cannabinoids chapter).
The cost to society of drug abuse and drug addic-
tion is prodigious in terms of both direct costs and
indirect costs associated with secondary medical
events, social problems, and loss of productivity. In the
United States alone, it is estimated that illicit drug
abuse and addiction cost society $161 billion (Office of
National Drug Control Policy, 2001; see also Uhl and
Grow, 2004). It is estimated that alcoholism costs soci-
ety $180 billion per year (Yi et al., 2000), and tobacco
addiction $155 billion (Centers for Disease Control and
Prevention, 2004). In France, the total cost of drug
use is USD 41 billion (including $22 billion for alcohol,
$16 billion for tobacco, and nearly $3 billion for illicit
drugs) (Kopp and Fenoglio, 2000).
FIGURE 1.1 Dependence or abuse of specific substances
Addiction and Substance Dependence will be used among past-year users of substance (Substance Abuse and Mental
interchangeably throughout this text and will refer to Health Services Administration, 2003). Heroin: 57.4% (0.2 million),
a final stage of a usage process that moves from drug Cocaine: 25.6% (1.5 million), Marijuana: 16.6% (4.2 million).
 DEFINITIONS OF ADDICTION 3

chronic relapsing disorders such as diabetes, asthma,

and hypertension (McLellan et al., 2000). The purpose
of current neuroscientific drug abuse research is to
understand the cellular and molecular mechanisms
that mediate the transition from occasional, controlled
drug use to the loss of behavioral control over drug-
seeking and drug-taking that defines chronic addic-
tion (Koob and Le Moal, 1997).

Diagnostic Criteria of Addiction

The diagnostic criteria for addiction as described by the
Diagnostic and Statistical Manual of Mental Disorders, 4th
edition (DSM-IV) (American Psychiatric Association,
1994), also have evolved over the past 30 years with a
FIGURE 1.2 Stages of addiction to drugs of abuse. Drug-taking
invariably begins with social drug-taking and acute reinforcement
shift from the emphasis and necessary criteria of toler-
and often, but not exclusively, then moves in a pattern of use ance and withdrawal to other criteria directed more at
from escalating compulsive use to dependence, withdrawal, and compulsive use. In the DSM-IV, tolerance and with-
protracted abstinence. During withdrawal and protracted abstin- drawal form two of seven potential criteria. The criteria
ence, relapse to compulsive use is likely to occur with a repeat of the for Substance Dependence outlined in the DSM-IV
cycle. Genetic factors, environmental factors, stress, and condition-
ing all contribute to the vulnerability to enter the cycle of
closely resemble those outlined by the International
abuse/dependence and relapse within the cycle. Statistical Classification of Diseases and Related Health
Problems (ICD-10) (World Health Organization, 1992)
(Tables 1.2 and 1.3). The number of criteria met by drug
McLellan and McKay, 1998; McLellan et al., 2000). addicts vary with the severity of the addiction, the stage
While much of the initial study of the neurobiology of of the addiction process, and the drug in question
drug addiction focused on the acute impact of drugs of (Chung and Martin, 2001). For example, in adolescents,
abuse (analogous to comparing no drug use to drug the most frequently observed criteria are much time
use), the focus is now shifting to chronic administra- getting or recovering from use (DSM-IV criteria #5 and #7),
tion and the acute and long-term neuroadaptive continued use despite problems in social and occupational
changes in the brain that result in relapse. Cogent functioning (DSM-IV criterion #6), and tolerance or with-
arguments have been made which support the drawal (DSM-IV criteria #1 and #2) (Crowley et al., 1998)
hypothesis that addictions are similar in their chronic (see Cannabinoids chapter).
relapsing properties and treatment efficacy to other

TABLE 1.2 DSM-IV and ICD-10 Diagnostic Criteria for Alcohol and Drug Abuse/Harmful Use

DSM-IV ICD-10
Alcohol and drug abuse Harmful use of alcohol and drugs

A. A maladaptive pattern of substance use leading to clinically A. A pattern of substance use that is causing damage to health.
significant impairment or distress, as manifested by one The damage may be physical or mental.
(or more) of the following occurring within a 12-month period: The diagnosis requires that actual damage should have been
1. recurrent substance use resulting in a failure to caused to the mental or physical health of the user.
fulfil major role obligations at work, school, or home. B. No concurrent diagnosis of the substance dependence syndrome
2. recurrent substance use in situations in which use is physically for same class of substance.
hazardous.
3. recurrent substance-related legal problems.
4. continued substance use despite having persistent or recurrent
social or interpersonal problems caused or exacerbated by the
effects of the drug.
B. The symptoms have never met the criteria for substance
dependence for the same class of substance.
4 1. WHAT IS ADDICTION?

TABLE 1.3 DSM-IV and ICD-10 Diagnostic Criteria for Alcohol and Drug Dependence

DSM-IV ICD-10

Clustering criterion A. A maladaptive pattern of substance use, leading A. Three or more of the following have
to clinically significant impairment or distress been experienced or exhibited at some
as manifested by three or more of the following time during the previous year:
occurring at any time in the same 12-month
period:
Tolerance 1. Need for markedly increased amounts of 1. Evidence of tolerance, such that
a substance to achieve intoxication or desired increased doses are required in order
effect; or markedly diminished effect with to achieve effects originally produced
continued use of the same amount of the by lower doses.
substance.
Withdrawal 2. The characteristic withdrawal syndrome for a 2. A physiological withdrawal state
substance or use of a substance (or a closely when substance use has ceased or
related substance) to relieve or avoid been reduced as evidenced by the
withdrawal symptoms. characteristic substance withdrawal
syndrome, or use of substance (or a
closely related substance) to relieve or
avoid withdrawal symptoms.
Impaired control 3. Persistent desire or one or more unsuccessful 3. Difficulties in controlling substance
efforts to cut down or control substance use. use in terms of onset, termination, or
levels of use.
4. Substance used in larger amounts or over a
longer period than the person intended.
Neglect of activities 5. Important social, occupational, or recreational 4. Progressive neglect of alternative
activities given up or reduced because of pleasures or interests in favor of
substance use. substance use; or
Time spent 6. A great deal of time spent in activities necessary A great deal of time spent in
to obtain, to use, or to recover from the activities necessary to obtain, to use,
effects of substance used. or to recover from the effects of
substance use.
Inability to fulfil roles None None
Hazardous use None None
Continued use despite problems 7. Continued substance use despite knowledge 5. Continued substance use despite
of having a persistent or recurrent physical clear evidence of overtly harmful
or psychological problem that is likely to physical or psychological
be caused or exacerbated by use. consequences.
Compulsive use None 6. A strong desire or sense of
compulsion to use substance.
Duration criterion B. No duration criterion separately specified. B. No duration criterion separately specified.
However, several dependence criteria must
occur repeatedly as specified by duration
qualifiers associated with criteria (e.g., ‘often’,
‘persistent’, ‘continued’).
Criterion for subtyping dependence With physiological dependence: Evidence of None
tolerance or withdrawal (i.e., any of items A-1
or A-2 above are present).
Without physiological dependence: No evidence
of tolerance or withdrawal (i.e., none of items
A-1 or A-2 above are present).

previous prolonged use, become requisite to physio-

Dependence View of Addiction
logic equilibrium. Since it is not yet possible to diag-
Historically, definitions of addiction began with def- nose physical dependence objectively without
initions of dependence. Himmelsbach defined physical withholding drugs, the sine qua non of physical
dependence as: dependence remains the demonstration of a character-
istic abstinence syndrome’ (Himmelsbach, 1943).
‘... an arbitrary term used to denote the presence of an
acquired abnormal state wherein the regular adminis- Eventually this definition evolved into the defin-
tration of adequate amounts of a drug has, through ition for physical dependence or ‘intense physical