Neurobiology of Alcohol Dependence

548 Pages·2014·32.753 MB·English

by  Antonio Noronha, Changhai Cui, Robert Adron Harris, John C. Crabbe

NEUROBIOLOGY
OF ALCOHOL
DEPENDENCE
NEUROBIOLOGY
OF ALCOHOL
DEPENDENCE
Edited by
Antonio B. C. Noronha
Division of Neuroscience and Behavior, National Institute on Alcohol Abuse and Alcoholism,
Bethesda, MD, USA
Changhai Cui
Division of Neuroscience and Behavior, National Institute on Alcohol Abuse and Alcoholism,
Bethesda, MD, USA
R. Adron Harris
Waggoner Center for Alcohol & Addiction Research, The University of Texas at Austin,
Austin, TX, USA
John C. Crabbe
Portland Alcohol Research Center, Oregon Health & Science University and VA Medical Center,
Portland, OR, USA
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Contributors
R. Adron Harris Waggoner Center for Alcohol and Addiction Christa Helms Division of Neurosciences, Oregon National
Research, University of Texas–Austin, USA Primate Research Center, USA
Somayeh Ahmadiantehrani The Gallo Research Center, Linzy M. Hendrickson Waggoner Center for Alcohol and
Department of Neurology, University of California, San Addiction Research, University of Texas, Austin, USA
Francisco, USA Andrew Holmes Laboratory of Behavioral and Genomic
Nigel S. Atkinson Waggoner Center for Alcohol & Addiction Neuroscience, National Institute on Alcohol Abuse and
Research, Department of Neuroscience, University of Alcoholism, National Institutes of Health, USA
Texas–Austin, USA Patricia H. Janak The Gallo Research Center, Department of
Erich J. Baker Computer Science Department, Baylor Univer­ Neurology, University of California, San Francisco, USA
sity, USA L. Judson Chandler Department of Neurosciences and Center
Sridevi Balaraman Texas A&M Health Science Center, College for Drug and Alcohol Programs, Medical University of
of Medicine, Department of Neuroscience and Experimental South Carolina, USA
Therapeutics, USA Thomas L. Kash The Bowles Center for Alcohol Studies and
the Department of Pharmacology, The University of North
Jacqueline M. Barker Department of Neurosciences and
Carolina at Chapel Hill, USA
Center for Drug and Alcohol Programs, Medical University
of South Carolina, USA George F. Koob Committee on the Neurobiology of Addictive
Disorders, The Scripps Research Institute, USA
Howard C. Becker Charleston Alcohol Research Center,
Departments of Psychiatry and Neurosciences, Medical Remi Legastelois The Gallo Research Center, Department of
University of South Carolina, Charleston, SC USA Neurology, University of California, San Francisco, USA
Elizabeth J. Burnett Department of Neurosciences and Center Virginia Long The Gallo Research Center, Department of
for Drug and Alcohol Programs, Medical University of Neurology, University of California, San Francisco, USA
South Carolina, USA David M. Lovinger Section on Synaptic Pharmacology,
Elissa J. Chesler The Jackson Laboratory, USA Laboratory for Integrative Neuroscience, National Institute
on Alcohol Abuse and Alcoholism, National Institutes of
John C. Crabbe Portland Alcohol Research Center, Veterans
Health, USA
Affairs Medical Center, Department of Behavioral
Emily G. Lowery-Gionta The Bowles Center for Alcohol
Neuroscience, Oregon Health & Science University, USA
Studies and the Department of Pharmacology, The
Howard J. Edenberg Department of Biochemistry and
University of North Carolina at Chapel Hill, USA
Molecular Biology, and Department of Medical and
Ketan Marballi Waggoner Center for Alcohol and Addiction
Molecular Genetics, Indiana University School of
Research, University of Texas–Austin, USA
Medicine, USA
R. Dayne Mayfield Waggoner Center for Alcohol and
Betsy Ferguson Division of Neurosciences, Oregon National
Addiction Research, University of Texas–Austin, USA
Primate Research Center, USA
Mary E. McCaul Department of Psychiatry and Behavioral
C. Fernando Valenzuela Department of Neurosciences,
Sciences, The Johns Hopkins University School of Medicine,
School of Medicine, University of New Mexico Health
USA
Sciences Center, USA
Department of Medicine, The Johns Hopkins University School
Tatiana Foroud Department of Medical and Molecular
of Medicine, USA
Genetics, Indiana University School of Medicine, USA
Megan McClintick Department of Behavioral Neurosciences,
Alfredo Ghezzi Waggoner Center for Alcohol & Addiction
Oregon Health and Science University, USA
Research, Department of Neuroscience, University of
Rajesh C. Miranda Texas A&M Health Science Center, College
Texas–Austin, USA
of Medicine, Department of Neuroscience and Experimental
Nicholas W. Gilpin Department of Physiology, Louisiana State Therapeutics, USA
University Health Sciences Center, USA
Hitoshi Morikawa Waggoner Center for Alcohol and
William B. Glen Department of Neurosciences and Center for Addiction Research, University of Texas, Austin, USA
Drug and Alcohol Programs, Medical University of South
Russell A. Morton Department of Neurosciences, School of
Carolina, USA
Medicine, University of New Mexico Health Sciences Center,
Kathleen A. Grant Division of Neurosciences, Oregon National USA
Primate Research Center, USA
Subhash C. Pandey Department of Psychiatry, University of
Department of Behavioral Neurosciences, Oregon Health and Illinois at Chicago and Jesse Brown VA Medical Center,
Science University, USA Chicago, Illinois, USA
ix
x Contributors
Matthew J. Pava Section on Synaptic Pharmacology, Laboratory Department of Cell Biology and Physiology, Neuroscience
for Integrative Neuroscience, National Institute on Alcohol Center, Bowles Center for Alcohol Studies, University of
Abuse and Alcoholism, National Institutes of Health, USA North Carolina, USA
Adolf Pfefferbaum Neuroscience Program, SRI International, Edith V. Sullivan Department of Psychiatry and Behavioral
USA Sciences, Stanford University School of Medicine, USA
Department of Psychiatry and Behavioral Sciences, Stanford Karen Szumlinski Department of Psychological and Brain
University School of Medicine, USA Sciences, University of California–Santa Barbara, USA
Charles L. Pickens Laboratory of Behavioral and Genomic Steven N. Treistman Institute of Neurobiology, University of
Neuroscience, National Institute on Alcohol Abuse and Puerto Rico Medical Sciences Campus, San Juan, Puerto
Alcoholism, National Institutes of Health, USA Rico, USA
Igor Ponomarev Waggoner Center for Alcohol and Addiction Benjamin R. Troutwine Waggoner Center for Alcohol &
Research, University of Texas–Austin, USA Addiction Research, Department of Neuroscience, Univer­
sity of Texas–Austin, USA
Anna K. Radke Laboratory of Behavioral and Genomic
Neuroscience, National Institute on Alcohol Abuse and Gary S. Wand Department of Psychiatry and Behavioral
Alcoholism, National Institutes of Health, USA Sciences, The Johns Hopkins University School of Medicine,
USA
Marisa Roberto Committee on the Neurobiology of Addictive
Disorders, The Scripps Research Institute, USA Department of Medicine, The Johns Hopkins University School
of Medicine, USA
Dorit Ron The Gallo Research Center, Department of
Neurology, University of California, San Francisco, USA Vincent Warnault The Gallo Research Center, Department of
Neurology, University of California, San Francisco, USA
Adrian Rothenfluh Department of Psychiatry, Program in
Neuroscience, UT Southwestern Medical Center, USA Leslie R. Whitaker Intramural Research Program, National
Institute on Drug Abuse, National Institutes of Health, USA
Garrett E. Seale Institute of Neurobiology, University of
Puerto Rico Medical Sciences Campus, Puerto Rico, USA John J. Woodward Department of Neurosciences and Center
for Drug and Alcohol Programs, Medical University of
Dongju Seo Department of Psychiatry, Yale University School
South Carolina, USA
of Medicine, USA
F. Woodward Hopf Ernest Gallo Clinic and Research Center,
Rajita Sinha Department of Psychiatry, Yale University School
Department of Neurology, University of California, San
of Medicine, USA
Francisco, USA
Mary Ann C. Stephens Department of Psychiatry and
Henry H. Yin Department of Psychology and Neuroscience
Behavioral Sciences, The Johns Hopkins University School
and Neurobiology, Center for Cognitive Neuroscience,
of Medicine, USA
Duke University, USA
Garret D. Stuber Departments of Psychiatry & Cell and
Molecular Physiology, Bowles Center for Alcohol Studies,
University of North Carolina, USA
Preface
Alcohol dependence is mediated by complex neural and functional changes contributing to the alteration of
mechanisms that involve multiple brain circuits and brain networks associated with alcohol dependence.
neuroadaptive changes in a variety of neurotransmitter Section III bridges genetic factors to behavioral phe-
and neuropeptide systems. Recent research advances at notypes related to alcohol dependence. It emphasizes
the molecular, cellular, neurocircuitry, and behavioral the importance of both genes and epigenetic modifica-
levels have provided substantial information for our tions of gene expression contributing to alcohol depen-
understanding of the neurobiological mechanisms con- dence and alcohol-related traits. It discusses different
tributing to various aspects of alcohol dependence (such experimental paradigms for studying alcohol depen-
as craving, tolerance, withdrawal, and relapse). The goal dence in laboratories and highlights advances in under-
of this book is to integrate that current information and standing risk factors for developing alcohol dependence,
knowledge and provide a comprehensive and updated tolerance, and relapse using model systems. Collectively,
overview of the neurobiological mechanisms underly- these three sections summarize our current understand-
ing alcoholism. ing of the neurobiological mechanisms underlying alco-
Neurobiology of Alcohol Dependence presents a breadth hol dependence at the molecular, cellular, circuitry, and
of topics on neurocircuitry, neuroplasticity, genes, and behavioral levels.
behaviors; these topics stem from both preclinical and Although this book provides a rather comprehensive
clinical studies of alcohol dependence. It comprises overview of neurobiological mechanisms of alcohol
three main sections. Section I focuses on the neurocir- dependence, it is not intended to be all inclusive. Several
cuitries of alcohol dependence. Alcohol has a profound areas, including neuroimmune signaling, sleep disor-
impact on multiple neurocircuits related to reward, ders, and pain, are not covered as independent chapters
stress, habit formation, and executive function, which but are briefly mentioned in the text. The close relevance
work in concert to contribute to alcohol dependence. of these topics to alcohol dependence warrants future
The chapters in this section depict how dysfunction of discussion and further research efforts.
various neurocircuits may be responsible for behavioral Neurobiology of Alcohol Dependence will appeal to sci-
phenotypes associated with alcohol dependence, the entists, students, and educators who are interested in
developmental effects of alcohol on the central nervous this topic, particularly those in the research fields of
system, and, lastly, the whole brain structural and func- alcohol-use disorders and addiction. Readers will bene-
tional changes associated with alcohol dependence. fit from critical insights provided by leading alcohol
Section II provides critical reviews of the neurosignal- researchers. We would like to thank all the scientists
ing and neuroplasticity associated with alcohol depen- who have contributed chapters to this book and those
dence. Unlike other drugs of abuse, alcohol does not who have provided constructive comments and sugges-
have a specific receptor target in the brain. Instead, it tions for the manuscripts.
interacts with multiple neurobiological systems. This
section highlights alcohol’s actions on various neuro- Antonio Noronha
transmitters, neuropeptides, and signaling systems as Changhai Cui
well as the neuroplasticity of these systems implicated Adron Harris
in alcohol dependence. It also discusses the structural John Crabbe
xi
C H A P T E R
1
Frameworks of Alcohol Addiction
Alcohol Addiction as a Reward Deficit and Stress Surfeit Disorder
George F. Koob
Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, USA
O U T L I N E
Definitions and Conceptual Framework for Negative Protracted Withdrawal 17
Reinforcement in Alcoholism 3
Stress-Induced Reinstatement 17
Motivation, Withdrawal, Opponent Process, and
Corticotropin-Releasing Factor, Stress, and the
Compulsive Use 6
Frontal Cortex 18
Animal Models for Compulsive Alcohol Seeking 8
Cellular Mechanisms that Mediate the
Neural Substrates of the Negative Emotional State
Neuroplasticity of the Dark Side in the
Associated With Alcoholism 10
Extended Amygdala 19
Within-System Neuroadaptations that Contribute
to the Compulsivity Associated with the Negative Reinforcement in Alcoholism:
Dark Side of Alcoholism 10 An Allostatic View 20
Between-System Neuroadaptations that Contribute
Acknowledgments 22
to Compulsivity Associated with the
Dark Side of Alcoholism 12 References 22
DEFINITIONS AND CONCEPTUAL anxiety, or irritability) reflecting a motivational with-
FRAMEWORK FOR NEGATIVE drawal syndrome when access to the drug (alcohol) is
REINFORCEMENT IN ALCOHOLISM prevented (Koob & Le Moal, 1997). Clinically and in
animal models, the occasional but limited use of alcohol
Alcoholism has many symptoms that vary from generally does not lead to escalated alcohol intake and
behavioral and social dysfunction to physiological the emergence of a chronic compulsive alcohol-seeking
changes (tolerance and withdrawal) embedded in state that is termed alcoholism. Alcoholism and drug
the diagnosis of Alcohol Use Disorders defined in the addiction in general have been hypothesized to be com-
Diagnostic and Statistical Manual of the American Psychiatric posed of multiple stages that feed into each other in a
Association, fifth edition (DSM-V; American Psychiatric three-stage cycle: binge/intoxication, withdrawal/negative
Association, 2013). Alcohol Use Disorder is a composite affect, and preoccupation/anticipation (“craving”; Figure
of the previous abuse and dependence criteria outlined 1.1). The three stages are conceptualized as interacting
in the DSM-IV (American Psychiatric Association, 1994). with each other, becoming more intense, and ultimately
Alcoholism, and more generically drug addiction, can be leading to the pathological state known as addiction
defined as a chronically relapsing disorder characterized (Koob & Le Moal, 1997).
by (i) compulsion to seek and take the drug (alcohol), (ii) The thesis to be argued in the present synthesis is that
loss of control in limiting (alcohol) intake, and (iii) emer- alcoholism is a reward-deficit disorder and a stress-surfeit
gence of a negative emotional state (such as dysphoria, disorder and that the compulsivity observed in alcoholism
Neurobiology of Alcohol Dependence 3
© 2014 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/B978-0-12-405941-2.00001-8
4 1. FRAmEwORkS OF ALCOHOL ADDICTION
FIGURE 1.1 (Top left) Diagram showing the stages of impulse-control disorder and compulsive disorder cycles related to the sources of rein-
forcement. In impulse-control disorders, an increasing tension and arousal occurs before the impulsive act, with pleasure, gratification, or relief
during the act. Following the act, there may or may not be regret or guilt. In compulsive disorders, there are recurrent and persistent thoughts
(obsessions) that cause marked anxiety and stress followed by repetitive behaviors (compulsions) that are aimed at preventing or reducing dis-
tress (American Psychiatric Association, 1994). Positive reinforcement (pleasure/gratification) is more closely associated with impulse-control
disorders. Negative reinforcement (relief of anxiety or relief of stress) is more closely associated with compulsive disorders. [Taken with permission
from Koob, 2013.] (Top right) Collapsing the cycles of impulsivity and compulsivity results in the addiction cycle, conceptualized as three major
components: preoccupation/anticipation, binge/intoxication, and withdrawal/negative affect. [Taken with permission from Koob, 2008.] (Bottom) Change in
the relative contribution of positive and negative reinforcement constructs during the development of substance dependence on alcohol. [Taken
with permission from Koob, 2013.]
has an important negative reinforcement component that allostatic state that perpetuates dependence. Alcoholism
perpetuates alcoholism. Positive reinforcement is defined as also involves substantial neuroadaptations that persist
the process by which the presentation of a stimulus (usu- beyond acute withdrawal and trigger relapse and defi-
ally appetitive) increases the probability of a response. cits in cognitive function that can also fuel compulsive
Negative reinforcement can be defined as the process by drinking. However, the argument here is that a core defi-
which the removal of an aversive stimulus increases the cit in reward function and stress function sets up vulner-
probability of a response. Note that negative reinforce- ability to relapse in alcoholism and possibly even deficits
ment is not punishment, although both involve an aver- in cognitive function that perpetuate compulsive use
sive stimulus. In punishment, the aversive stimulus and relapse to compulsive use.
suppresses behavior, including drug taking (e.g., disulfi- To support this hypothesis, a compelling negative
ram [Antabuse]). Negative reinforcement can be perhaps reinforcement view of alcoholism will be presented with
described in lay terms as reward via relief (i.e., relief the following key points. A negative emotional state is a
reward), such as the removal of pain or, in the case of alco- common presentation in most alcoholics during with-
holism, removal of the negative emotional state associated drawal and protracted abstinence. Much is known about
with acute withdrawal or protracted abstinence. the neurobiological mechanisms that drive such negative
Negative reinforcement will be argued to be driven by emotional states. From this perspective, the neurobio-
negative emotional states that derive from genetic, epi- logical substrates that underlie the compulsive motiva-
genetic, or excessive alcohol intake. Such negative emo- tion to seek alcohol will be reviewed. An argument will
tional states become sensitized over time and set up an be presented that it is the loss of reward function and
I. NEUROCIRCUITRY OF ALCOHOL DEPENDENCE
DEFINITIONS AND CONCEPTUAL FRAmEwORk FOR NEgATIvE REINFORCEmENT IN ALCOHOLISm 5
gain of brain stress function that mediate the negative first representative case history, an individual progressed
emotional state outlined as key to alcoholism. from a point at which he stated, “I drank when I was
Drug addiction has generally been conceptualized as happy and I drank when I was anxious and I drank when
a disorder that involves elements of both impulsivity I was bored and I drank when I was depressed, which
and compulsivity. Impulsivity can be defined behavior- was often, (Knapp, 1996, p. 3)” to, “I loved the way drink
ally as “a predisposition toward rapid, unplanned reac- made me feel, and I loved its special power of deflection,
tions to internal and external stimuli without regard for its ability to shift my focus away from my own awareness
the negative consequences of these reactions to them- of self and onto something else, something less painful
selves or others” (Moeller, Barratt, Dougherty, Schmitz, than my own feelings, (ibid, p. 7)” and, “There’s a sense
& Swann, 2001, p. 1784). Impulsivity is a core deficit in of deep need, and the response is a grabbiness, a compul-
substance abuse disorders and is represented by DSM-V sion to latch on to something outside yourself in order to
symptoms, such as recurrent alcohol use in situations in assuage some deep discomfort” (ibid, p. 54). Similarly, in
which it is physically hazardous or having a craving or a a second representative case history, “Alcohol seemed to
strong desire or urge to use alcohol. Compulsivity can be satisfy some specific need I had, which I can’t describe,
defined as elements of behavior that result in the perse- (Goodwin, 1981, p. 29)” and, “There were always reasons
veration of responding in the face of adverse conse- to drink. I was low, tense, tired, mad, happy, (ibid, p. 29)”
quences or perseveration in the face of incorrect and, “The goal, always, was to maintain a glow, not
responses in choice situations. Compulsivity is analo- enough, I hoped, that people would notice, but a glow,
gous to the symptoms of Substance Use Disorder out- (ibid, p. 29)” and, “By now I was hooked and knew it, but
lined by the American Psychiatric Association: continued desperately did not want others to know it. I had been
substance use despite knowledge of having persistent or sneaking drinks for years—slipping out to the kitchen
recurrent social or interpersonal problems or despite during parties and such—but now I began hiding alco-
knowledge of having a persistent or recurrent physical hol, in my desk, bedroom, car glove compartment, so it
or psychological problem and a great deal of time spent would never be far away, ever. I grew panicky even
in activities necessary to obtain the substance (American thinking I might not have alcohol when I needed it, which
Psychiatric Association, 2013). Collapsing the cycles of was just about always, (ibid, p. 30)” and, “I loathed
impulsivity and compulsivity yields a composite addic- myself. I was waking early and thinking what a mess I
tion cycle that consists of three stages noted above— was, how I had hurt so many others and myself. The
preoccupation/anticipation, binge/intoxication, and with- words ’guilty’ and ‘depression’ sound superficial in
drawal/negative affect—in which impulsivity often domi- trying to describe how I felt. The loathing was almost
nates at the early stages and compulsivity dominates at physical—a dead weight that could be lifted in only one
terminal stages (Figure 1.1). As an individual moves way, and that was by having a drink” (ibid, p. 30); see the
from impulsivity to compulsivity, a shift occurs from Appendix in Koob & Le Moal, 2006, for full quotations).
positive reinforcement driving the m otivated behavior These case histories illustrate numerous key points
to negative reinforcement driving the motivated regarding the present thesis, but the main point to be
behavior (Koob, 2004). elaborated is that there is a transition from drinking to
In alcoholism, a pattern of oral drug taking evolves feel good to drinking to avoid feeling bad. To some
that is often characterized by binges of alcohol intake extent, the likelihood of such a transition is driven by
that can be daily episodes or prolonged days of heavy inherent personality differences and personality differ-
drinking and which are characterized by a severe emo- ences that are shaped not only by genetics but also by
tional and somatic withdrawal syndrome. Many alco- developmental and social factors. As Khantzian
holics continue with such a binge/withdrawal pattern cogently argued, seeking and taking drugs in addiction
for extended periods of time, but some individuals can can be argued to be sources of self-medication for nega-
evolve into a situation akin to opioid addiction in which tive emotional-distress syndromes that vary with the
they must have alcohol available at all times to avoid the individual from physical and emotional pain to chronic
negative consequences of abstinence. Here, intense pre- dysphoria to stress and anxiety to interpersonal diffi-
occupation with obtaining alcohol (craving) develops culties (Khantzian, 1997). Additionally, he argued that
that is linked not only to stimuli associated with obtain- self-medication may be drug-specific—patients may
ing the drug but also to stimuli associated with with- have a preferential use of drugs that fits with the nature
drawal and the aversive motivational state. A pattern of the painful feeling states that they are self-medicat-
develops in which alcohol must be obtained to avoid the ing (such as opiates to counter intense anger and rage,
severe dysphoria and discomfort of abstinence. stimulants as augmenting agents for high-energy indi-
The pattern of alcohol addiction, related to reward viduals, energizing agents for low-energy individuals,
dysfunction, can be illustrated by excerpts from two case and depressants [e.g., alcohol] for individuals who are
histories from Knapp (1996) and Goodwin (1981). In the tense and anxious). The common element argued by
I. NEUROCIRCUITRY OF ALCOHOL DEPENDENCE
6 1. FRAmEwORkS OF ALCOHOL ADDICTION
Khantzian is that each class of drugs serves as an anti- Thus, we define dependence or the manifestation of a
dote or corrective to a dysphoric state and acts as a withdrawal syndrome after the removal of chronic drug
“replacement for a defect in the psychological struc- administration in terms of motivational symptoms, such
ture” (Kohut, 1971, p. 46) of such individuals (Khantzian, as the emergence of a negative emotional state (e.g., dys-
2003). However, even more importantly, as such “self- phoria, anxiety, or irritability) when access to the drug is
medication” evolves, the excessive taking of drugs prevented (Koob & Le Moal, 2001), which can be exacer-
changes the brain such that the withdrawal from the bated or even caused by the physical signs of withdrawal.
drug itself creates or exacerbates the state that requires Indeed, some have argued that the development of such
self-medication (see “Negative reinforcement in alco- a negative affective state can define dependence as it
holism: an allostatic view” ahead). relates to addiction (Baker, Piper, McCarthy, Majeskie, &
Flore, 2004; Koob, Stinus, & Le Moal, 1989; Russell, 1976).
MOTIVATION, WITHDRAWAL, The notion of dependence on a drug, object, role, activity
OPPONENT PROCESS, AND or any other stimulus-source requires the crucial feature of
COMPULSIVE USE negative affect experienced in its absence. The degree of depen-
dence can be equated with the amount of this negative affect,
Motivation is a state that involves arousal, expecta- which may range from mild discomfort to extreme distress, or
tion, and emotion, all of which direct behavior. William it may be equated with the amount of difficulty or effort
James wrote, “Some expectation of consequences must required to do without the drug, object, etc. (Russell, 1976)
in every case like this be aroused; and this expecta-
tion, according as it is, that of something desired or of Alcoholics show dramatic evidence of dysphoric
something disliked, must necessarily either reinforce or states during acute withdrawal that persist into pro-
inhibit the mere impulse” (James, 1918, p. 390), and moti- tracted abstinence. Alcohol withdrawal in humans pro-
vation can be defined as a “tendency of the whole ani- duces well-documented physical (somatic) symptoms,
mal to produce organized activity” (Hebb, 1972). Such such as tremor, autonomic hyperactivity, nausea, vomit-
motivational states are not constant but rather vary over ing, and seizures, but more importantly produces sig-
time. The concept of motivation was inextricably linked nificant affective symptoms of anxiety, dysphoria, and
with hedonic, affective, or emotional states in addic- depression-like symptoms. Acute withdrawal (i.e., the
tion in the context of temporal dynamics by Solomon’s first week postalcohol) is characterized by Beck
opponent process theory of motivation (Solomon, 1980; Depression Inventory scores of approximately 20, which
Solomon & Corbit, 1974). Solomon and Corbit (1974) is categorized within the range of moderate depression
postulated that hedonic, affective, or emotional states, (15–30; Potokar et al., 1997), and Hamilton Depression
once initiated, are automatically modulated by the cen- Scale scores of 18, which is close to 20 (the cutoff for anti-
tral nervous system through mechanisms that reduce depressant medication in affective disorder; Brown &
the intensity of hedonic feelings. For drugs, the a-process Schuckit, 1988). Depression scores decline during subse-
includes affective or hedonic habituation (or tolerance), quent weeks of treatment but remain at close to 10 for
and the b-process includes affective or hedonic with- Hamilton Depression Scale scores for up to four weeks
drawal (abstinence). The a-process in drug use consists of an inpatient treatment program (Brown & Schuckit,
of positive hedonic responses, occurs shortly after the 1988). In another study of inpatient alcoholics during
presentation of a stimulus, correlates closely with the withdrawal, the Beck Depression Inventory score was 15
intensity, quality, and duration of the reinforcement at withdrawal and remained at 12.8 two days into with-
(alcohol), and shows tolerance. In contrast, the b-process drawal and at 9.4 two weeks postwithdrawal (de Timary,
in drug use appears after the a-process has terminated, Luts, Hers, & Luminet, 2008). Similar results were
consists of negative hedonic responses, and is sluggish in obtained for anxiety measures (de Timary et al., 2008;
onset, slow to build up to an asymptote, slow to decay, Potokar et al., 1997). In another study with a long-term
and gets larger with repeated exposure. The thesis follow-up six months after a four-week inpatient detoxi-
elaborated here is that there are neurocircuitry changes fication, Beck Depression Inventory scores remained at
of specific neurochemical systems that account for the approximately 6, and trait anxiety scores (STAI-X2)
b-process. Such opponent processes are hypothesized to remained above 33, even in subjects without comorbid
begin early in drug taking, reflecting not only deficits anxiety or depression (Driessen et al., 2001). Independent
in brain reward-system function but also recruitment of of comorbidity status, individuals who relapsed had
the function of brain stress systems. Furthermore, we higher trait anxiety scores than those who abstained
hypothesize that recruitment of the brain stress systems (Driessen et al., 2001). Therefore, although alcoholics
forms one of the major sources of negative reinforcement show significant decreases in measures of depression
in alcoholism. and anxiety during withdrawal, there is a measurable
I. NEUROCIRCUITRY OF ALCOHOL DEPENDENCE