Neuron

Review

Neuroscience of Behavioral and Pharmacological

Treatments for Addictions
Marc N. Potenza,1,2,3,* Mehmet Sofuoglu,1,3 Kathleen M. Carroll,1,4 and Bruce J. Rounsaville1,4
1Department of Psychiatry
2Department of Neurobiology and Child Study Center
Yale University School of Medicine, New Haven, CT 06519, USA
3These authors contributed equally to this work
4These authors contributed equally to this work

*Correspondence: marc.potenza@yale.edu
DOI 10.1016/j.neuron.2011.02.009

Although substantial advances have been made in behavioral and pharmacological treatments for addic-
tions, moving treatment development to the next stage may require novel ways of approaching addictions,
particularly ways based on new findings regarding the neurobiological underpinnings of addictions that also
assimilate and incorporate relevant information from earlier approaches. In this review, we first briefly review
theoretical and biological models of addiction and then describe existing behavioral and pharmacologic ther-
apies for the addictions within this framework. We then propose new directions for treatment development
and targets that are informed by recent evidence regarding the heterogeneity of addictions and the neurobi-
ological contributions to these disorders.

Overview ioral engagement representing core elements (Holden, 2001;

Despite intensive research and significant advances, drug addic-
tions remain a substantial public health problem. Drug addictions
cost U.S. society hundreds of billions of dollars annually and
impact not only the addicted individuals, but also their spouses,
children, employers, and others (Uhl and Grow, 2004; Volkow
et al., 2011). Furthermore, costs may be even higher as nondrug
disorders (e.g., related to food and gambling) have recently been
conceptualized within an addiction framework, with neurobiolog-
ical data supporting similarities across substance dependences,
obesity, and pathological gambling (Frascella et al., 2010; Grant
et al., 2010b; Kenny, 2011; Potenza, 2008). Given the additional
health burdens of these conditions (e.g., obesity and tobacco
consumption represent two top causes of preventable death
[Danaei et al., 2009; Kenny, 2011]), addictions arguably represent
our nation’s (and the world’s) main health problem. Thus, the
development of improved prevention and treatment strategies
is of paramount importance.
In order to best prevent and treat addictions, it is important to
have a clear understanding of which disorders constitute addic-
tions, and this point has been debated considerably over time.
The term addiction, derived from a Latin word meaning ‘‘bound
to’’ or ‘‘enslaved by,’’ was initially not linked to substance use
(Maddux and Desmond, 2000). However, over the past several
hundred years, addiction became associated with excessive
alcohol and then drug use such by the 1980s it was largely
synonymous with compulsive drug use (O’Brien et al., 2006).
However, observations that individuals with gambling problems
share clinical, phenomenological, genetic, and other biological
similarities with people with drug dependences has prompted
reconsideration of the core features of addiction, with continued
performance of the behavior despite adverse consequences,
compulsive engagement, or diminished control over the
behavior, and an appetitive urge or craving state prior to behav-
Potenza, 2006; Shaffer, 1999). If these are considered the central
elements of addictions, then behaviors like gambling may be
considered from an addictions perspective. Consistent with
this notion and existing clinical, preclinical, and neurobiological
data, pathological gambling is being considered for reclassifica-
tion with substance use disorders into an addictions category in
DSM-V (Holden, 2010).
In addition to similarities across addictive disorders, there are
also differences relevant to individual addictions that are related
to features like the sites of action of the drugs being abused and
the social acceptability and availability of the behavior or
substance, and these represent important considerations with
respect to the neurobiologies and treatments of addictions. For
example, while compulsivity may cut across addictions, aspects
of tolerance and withdrawal may differ and reflect specific neuro-
adaptations related to individual substances or behaviors (Dalley
et al., 2011; Kenny, 2011; Sulzer, 2011). Thus, considering
the mechanisms underlying addictions in general as well as
features unique to individual disorders is important in treatment
development.
Multiple, non-mutually exclusive models (e.g., incentive
salience [Robinson and Berridge, 2001], allostasis [Edwards
and Koob, 2010; Koob and Le Moal, 2001], reward deficiency
[Blum et al., 1996]) have been proposed for addictions. While
they each have unique features, they also include common
features related to the proposed core elements of addiction
described above. Across these models, motivational neurocircui-
try functions to favor drug use (or behavioral engagement) over
other aspects of life (e.g., studying for tests, going to work, or
caring for one’s family). Consistently, addiction has been termed
a condition of motivated behavior going awry (Volkow and Li,
2004) and neurobiological models of motivational circuitry have
been proposed for addictions and addiction vulnerability

Neuron 69, February 24, 2011 ª2011 Elsevier Inc. 695


(Chambers et al., 2003; Everitt and Robbins, 2005; George and
Koob, 2010). In these models, cortico-striato-pallido-thalamo-
cortical loops form a central feature underlying motivated behav-
iors (Alexander et al., 1990; Alexander et al., 1986). Other brain
regions and circuits contribute importantly to motivated behav-
iors, with regions like the amygdala providing important affective
information, the hippocampus important contextual memory
information, the hypothalamus and septum important homeo-
static information, and the insula important information related
to interoceptive processing (Chambers et al., 2003; Everitt and
Robbins, 2005; George and Koob, 2010; Naqvi and Bechara,
2009). Additionally, cingulate cortices provide important contribu-
tions, with the anterior and posterior components contributing to
emotional regulation, cognitive control, and stress responsive-
ness (Botvinick et al., 2001; Bush et al., 2000; Sinha, 2008). While
often relatively simplistic, such models, particularly when consid-
ered from a systems perspective (i.e., these brain regions function
in circuits rather than in isolation), provide a neurobiological basis
for developing new treatments for addictions and investigating
the mechanisms by which effective therapies for addictions work.
Aspects of the development of addictions can be understood
on the basis of both positive and negative reinforcements linked
to drug use. Drug experimentation typically begins during adoles-
cence, initially resulting in hedonic experiences that generate
relatively immediate positive reinforcement for use with little or
no negative consequences (Rutherford et al., 2010; Wagner
and Anthony, 2002). Yet as drug use continues, neuroadapta-
tions occur relating to the development of drug tolerance, result-
ing in a reduction in the pleasurable sensations achieved from
a similar initial level of drug use. Although the precise adaptations
remain a topic of current investigation, motivational
neurocircuitry and multiple neurotransmitter systems, particu-
larly dopamine, are implicated (Rutherford et al., 2010; Sulzer,
2011). As this cycle continues, subjects increase the frequency
and amount of drug use to gain the same rewarding experience.
For many drugs, increased use also leads to withdrawal symp-
toms when drug use is curtailed or cut down. As withdrawal
symptoms can at least be temporarily relieved by continued,
and escalating, drug use, a vicious cycle is established. Over
time, hedonic motivations for substance use diminish while nega-
tive reinforcement motivations increase, with drug-taking behav-
iors becoming less rewarding and more compulsive or habitual
over time. This shift has been proposed to involve a progression
of involvement of ventral to dorsal cortico-striato-pallido-tha-
lamo-cortical circuitry (Brewer and Potenza, 2008; Everitt and
Robbins, 2005; Fineberg et al., 2010; Haber and Knutson,
2010). From a molecular level, dopamine function, particularly
striatal D2/D3 receptor function, appears relevant to this process
and has been implicated across addictive disorders (Kenny,
2011; Steeves et al., 2009; Wang et al., 2009). However, multiple
other neurotransmitter systems contribute and may represent
better treatment targets, particularly as D2/D3 receptor antago-
nists have not demonstrated clinical efficacy for addictions.
From a cognitive perspective, attempts to control or eliminate
addictive behaviors are usually motivated by the delayed nega-
tive consequences of use. The individual’s cognitive recognition
of these negative consequences may lead to attempts to develop
changed attitudes and drug-using behaviors. This process
696 Neuron 69, February 24, 2011 ª2011 Elsevier Inc.
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necessitates executive control, which may be mediated via
top-down control of the prefrontal cortex over subcortical
processes promoting motivations to engage in the addictive
behavior (Chambers et al., 2003; Everitt and Robbins, 2005).
Both positive reinforcement processes (e.g., seeking a drug
high) and negative reinforcement processes (e.g., seeking
relief from stressful or negative mood states) may be linked to
environmental or internal cues in fashions that are behaviorally
engrained, resistant to change, and linked to powerful motiva-
tional craving states (Chambers et al., 2007). Thus, therapies
may be needed to target strong learned associations between
drug use and immediate positive or negative reinforcements.
Phases of Treatment
The treatment for addictions can be divided into three phases:
detoxification, initial recovery, and relapse prevention. The first
phase, detoxification, has the goal of achieving abstinence that
is sufficiently sustained to yield a safe reduction in immediate
withdrawal symptoms. The second phase, initial recovery, has
goals of developing sustained motivation to avoid relapse,
learning strategies for tolerating craving induced by external or
internal cues, and developing new patterns of behavior that
entail replacement of drug-induced reinforcement with alterna-
tive rewards. The third phase, relapse prevention, takes place
after a period of sustained abstinence and requires subjects to
develop long-term strategies that will allow them to replace
past drug behaviors with new, healthy behaviors.
As discussed above, the drug addiction cycle is maintained
through repeated use and alterations to motivational neurocircui-
try, including dopaminergic systems. Given the need to disengage
from sustained patterns of use and related neuroadaptations,
detoxification frequently requires pharmacological intervention.
These initial drug treatments may involve choosing a replacement
substance that has a similar mode of action on the neurobiological
substrate, while having a slower and more sustained effect.
Behaviorally speaking, this results in withdrawal symptoms that
are made less acute but more prolonged and gradual. For
example, drugs with longer half-lives than herion (e.g., metha-
done) can be used in addicted individuals during detoxification.
Successful resolution of detoxification requires sustained
motivation to tolerate withdrawal symptoms. The second phase,
initial recovery, is often aided by external, structural controls
(e.g., hospitalization) that limit access to drugs once withdrawal
symptoms have been alleviated. Yet, ultimately, the initial
recovery phase must teach the addicted individual ways to
sustain motivations to avoid relapse, learn strategies for toler-
ating and resisting drug cravings induced by external or internal
cues, and develop new patterns of behavior that entail replace-
ment of drug-induced reinforcement with alternative rewards.
Learning these new behavioral strategies can also be aided by
the longer-term administration of medications such as those
used in the detoxification process (e.g., drugs that block or
reduce drug rewards, reduce craving by substituting for drug
effects) or by the additional augmentation with drugs that help
to reduce mental and physical symptoms not necessarily related
to drug use (e.g., independent depression or anxiety disorders).
The third phase, relapse prevention, is perhaps the most
difficult to achieve given the long-term brain adaptations
Neuron
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resulting from sustained drug abuse. Indeed, relapses often
occur and many relapse prevention programs involve
a continued support system (e.g., Alcoholics Anonymous) to
aid in maintaining new behaviors developed during initial
recovery. Threats to recovery involve both external and internal
cues that lead to waning motivation, attenuation of external or
internal controls, and revival of associative learning cues linking
drug use to hedonic experiences and can be triggered by both
external cues and internal cues. External cues include exposure
to drugs or to people, places, or things associated with drug use.
Internal cues include hedonic experiences that may be
enhanced by resumed drug use or dysphoric experiences that
may be mediated by such factors as stress, interpersonal
conflict, or symptoms of comorbid mental disorders such as
depression.
At all three phases, social processes can improve executive
functioning through a variety of mechanisms, including
enhancing motivation, reducing friction and stress, providing
alternative rewards associated with avoiding drug use, and
providing external constraints. These factors can be conceived
of as enhancing cortically mediated executive control over
addictive behaviors (Volkow et al., 2011).
In the next sections, we will briefly review the major behavioral
and pharmacological treatments for addictions and describe the
targets of these treatments. In a simplified description, the neural
processes targeted by treating addictions can be characterized
as ‘‘top-down’’ or ‘‘bottom-up.’’ Top-down interventions attempt
to change cognitions and behaviors mediated by enhanced
prefrontal cortical function and altered executive control.
Bottom-up interventions target the subcortical processes,
including the striatal reward pathways, that mediate dysphoric
symptoms and learned association pathways that do not require
or necessarily involve cortical activity. As a broad generalization,
current behavioral treatments appear strongest at changing
top-down activity while pharmacological treatments tend to
target bottom-up processes (Figure 1).
Figure 1. The Brain Regions Proposed
to Mediate the Behavioral and
Pharmacological Treatments of Addictions
For simplicity, only a few key brain regions are
included in the figure. See text for details. Abbrevi-
ations: AD, adrenergic receptors; CBT, cognitive
behavioral therapy; CM, contingency manage-
ment; DA, dopamine; DAT, dopamine transporter;
GABA, gamma-aminobutyric acid; Glu, glutamate;
l.cer, locus ceruleus; MI, motivational interviewing;
Nac, nucleus accumbens; nAChR, nicotinic cholin-
ergic receptor; NE, norepinephrine; NET, norepi-
nephrine transporter; VTA, ventral tegmental area.
Behavioral Therapies Strategies
and Targets
Compulsive drug use despite negative
consequences and despite the desire to
quit can be understood as entailing two
processes that are targets for behavioral
therapies: (1) the excessive desire to
use or craving for substances; and (2)
insufficient impulse control associated
with neurocognitive impairment. In the sections below we briefly
review three broad categories of behavioral interventions that
have achieved consistent empirical support for substance use
problems through randomized controlled trials. These are (1)
brief and motivational models, (2) contingency management
models, and (3) cognitive behavioral models.
Brief Motivational Models
A surprising revelation of the past 20 years of treatment research
in the addictions has been the efficacy and durability of brief
behavioral therapies for many individuals with substance use
problems (Burke et al., 2003; Miller and Rollnick, 2002). Rela-
tively brief, focused interventions consisting of as little of a single
session have not only been demonstrated to be effective, but in
several studies have also been shown to be as effective as
lengthier, more intensive approaches. The efficacy of brief
motivational approaches appears to extend to addictions that
do not involve ingested substances (Burke et al., 2003), including
pathological gambling and eating disorders (Brewer et al.,
2008b; Frascella et al., 2010), suggesting that similar neural
mechanisms may underlie therapeutic effects across addictions.
Although the precise neural mechanisms mediating the effects of
brief motivational interventions are not known, processes
involving the receipt of health-related information and recom-
mendations from a professional may prompt individuals to alter
their decision-making processes to focus on more future-
oriented goals. Thus, brain motivational circuitry in general and
specific regions implicated in risk-reward decision making
(e.g., ventromedial prefrontal cortex), cognitive control (e.g.,
anterior cingulate cortex), and planning and executive func-
tioning (e.g., dorsolateral prefrontal cortex) in particular may
represent important brain regions for consideration (Bechara,
2003; Bush et al., 2002; Dalley et al., 2011).
Contingency Management Models
Another major development in the treatment of substance
use problems has involved findings regarding the efficacy of
contingency management interventions (Dutra et al., 2008;
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Lussier et al., 2006). Based on principles of behavioral pharma-
cology and operant conditioning, contingency management
approaches recognize that abused substances are powerful
reinforcers and are implemented with the idea that immediate
reinforcement of abstinence (or other behaviors incompatible
with substance use) can reliably, and comparatively easily,
interrupt substance use for a large number of individuals. In the
case of substance dependence, individuals are provided
concrete rewards, often cash, that generally escalate in value
and are contingent on submitting drug-free urine specimens
(Higgins et al., 1991). Beyond producing some of the largest
and most consistent effect sizes in substance abuse treatment
(Dutra et al., 2008), these approaches have broad utility
and can be targeted to improve treatment adherence, including
medication compliance that often undercuts the efficacy of
available pharmacotherapies (Carroll et al., 2004).
Contingency management for addictions can be conceptual-
ized within a behavioral neuroeconomic framework (Glimcher
and Rustichini, 2004). Individuals with addictions as compared
to those without typically place comparably greater values on
immediate rewards, and future rewards are more rapidly deval-
ued, a process termed delay or temporal discounting. This rapid
discounting has been observed across groups of individuals with
different addictions, both substance and nonsubstance, in
active and remitted addictions, and with respect to both drugs
and money (Johnson et al., 2007; Johnson et al., 2010; Petry,
2001a, 2001b; Ross et al., 2009). From a neurobiological
perspective, the selection of small immediate rewards typically
activates ‘‘reward’’ regions like the ventral striatum and ventro-
medial prefrontal cortex whereas the selection of larger, delayed
rewards activates more dorsal cortical regions (Kable and
Glimcher, 2007; McClure et al., 2004). Steep temporal discount-
ing has been associated with poor treatment outcome for
addictions (Krishnan-Sarin et al., 2007), may be amenable to
treatment (Bickel et al., 2011), and may involve cortical and
subcortical systems involved in decision making (Bickel and Yi,
2008) (see also Balleine et al. (2007) and related articles in the
volume).
Cognitive Behavioral Models
Another set of approaches that has emerged with strong support
from randomized trials includes cognitive behavioral therapies
(CBTs), which seek to help the individual recognize behavioral
patterns and cognitions that maintain substance use and to
learn and then implement skills and strategies to change
those patterns and interrupt substance use (Dutra et al., 2008;
Irvin et al., 1999; Magill and Ray, 2009; Tolin, 2010). These
approaches are based on principles of operant as well as clas-
sical conditioning, for example, seeking to heighten the individ-
uals’ awareness of cues previously paired with substance use,
reduction of exposure to such cues, and implementation of skills
to be aware of and tolerate cue-induced craving. CBT
approaches emphasize the development of cognitive strategies
to countervail the strong drives for drugs associated with condi-
tioned cravings, as well as to fortify behavioral controls through
learning to employ alternative coping mechanisms or to seek and
value alternative, socially sanctioned rewards that are incompat-
ible with drug abuse. CBT approaches appear to have particu-
larly durable effects in that substance use often continues to
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decrease even after CBT treatment concludes, so-called
‘‘sleeper effects’’ (Carroll et al., 1994).
As with other behavioral therapies, the neural mechanisms
underlying CBT remain poorly understood and, in comparison
to brief motivational interventions and contingency manage-
ment, may be particularly complex given the multifaceted nature
of CBT. For example, CBT typically consists of multiple sessions
or modules, with each having a specific focus (Carroll et al.,
1998; Petry, 2005). Accordingly, different modules may prefer-
entially induce changes in specific neural circuits. For example,
modules that teach coping strategies for managing cravings
may specifically influence or involve brain regions implicated in
cue-induced drug craving (e.g., medial prefrontal and anterior
cingulate cortices in cocaine dependence [Childress et al.,
1999; Wexler et al., 2001]) and/or work through altering func-
tional connectivity within brain circuits related to craving.
Consistent with this notion, an fMRI study investigating cue-
induced craving and using instructions based on CBT cognitive
strategies to focus on long-term consequences of tobacco use
rather than short-term pleasurable tobacco associations found
that dorsolateral prefrontal cortical regions exerted control
over ventral striatal activation in the regulation of craving (Kober
et al., 2010). These findings are reminiscent of a study of
tobacco smokers who were exposed to tobacco cues in an
emotional Stroop task and received a combination of behavioral
therapy and nicotine replacement (Janes et al., 2010). Individ-
uals who showed greater functional connectivity between
prefrontal cortical regions and brain areas involved in craving
and interoceptive processing (anterior cingulate cortex and
insula) demonstrated greater success in treatment (Janes
et al., 2010).
Other aspects of CBT may involve the recruitment and
strengthening of other circuits. For example, consider the
learning of alternate coping strategies. Training on a visual
perception learning task led to strengthened connectivity of
circuitry involved in spatial attention, and these changes were
observed in brain activity during rest (Lewis et al., 2009). Restful
waking brain activity has been termed the default mode network,
and although changes in default mode processing have been
proposed to underlie both effective behavioral and pharmaco-
logical treatment of nicotine dependence (Costello et al.,
2010), the relationship between default mode processing and
learning changes in CBT has not been examined.
Other CBT modules (for example, those relating to financial
management in pathological gambling) may more closely involve
neurocircuitry implicated in the processing of monetary rewards
or financial decision making (Kable and Glimcher, 2007; Knutson
and Greer, 2008). As individuals with addictions typically differ
from control subjects in the function of such circuitry (Tanabe
et al., 2007; Wrase et al., 2007), it is tempting to speculate that
effective CBT might ‘‘normalize’’ these circuits and that such
normalization would be related to completion of the correspond-
ing CBT module. CBT-related changes over a longer time period,
including ‘‘sleeper effects,’’ may involve circuitry underlying
cognitive function and affective control, as has been observed
with CBT in other disorders like depression and obsessive-
compulsive disorder (Goldapple et al., 2004; Ritchey et al.,
2010; Saxena et al., 2009; Siegle et al., 2006).
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The Future of Behavioral Therapies
Several novel approaches to achieving recovery from addictions
are receiving empirical support, and in some cases these may
complement existing strategies through more efficient targeting
of cognitive, emotional, and behavioral domains or deficits, as
well as their neural correlates. Novel cognitive remediation strat-
egies, aimed at strengthening brain function, may have potential
in addiction treatment. Cognitive remediation strategies involve
repeated intensive exposure to computerized exercises in-
tended to strengthen memory, attention, planning, and other
aspects of executive functioning. Given its novelty, this
approach has promise and is consistent with adult neuroplastic-
ity (Ersche and Sahakian, 2007) and findings in nonaddicted
populations. For example, cognitive remediation strategies
improve not only neurocognitive functioning in individuals with
schizophrenia, but also their general social and occupational
functioning (Bell et al., 2001). Specifically, measures of neuro-
cognition (assessing attention, memory, and problem solving)
and measures of social cognition and adjustment were improved
over a two-year period (Hogarty et al., 2004). There is preliminary
evidence that computerized cognitive remediation improves
cognitive functioning in substance users with neuropsycho-
logical deficits and also improves treatment engagement
and outcome (Bickel et al., 2011; Grohman et al., 2006; Wexler,
2011). For example, working memory training was found to
reduce impulsive choice measures of temporal discounting
in substance abusers (Bickel et al., 2011). The extent to
which such changes reflect increased top-down control
through enhanced prefrontal cortical function requires direct
investigation.
Other approaches receiving empirical support in addictions
treatment are mindfulness-based therapies. Based in part on
Buddhist tenets and practices, mindfulness-based therapies
have been developed to target stress and negative mood states
in depression and examined in preliminary studies of addictions
(Brewer et al., 2010). In a pilot study, mindfulness training,
compared with CBT, demonstrated comparable efficacy on
measures of retention and abstinence and was more effective
in diminishing subjective and biological stress responsiveness
(self-reported anxiety following personalized stress exposure
and sympathetic/vagal ratios, respectively) (Brewer et al.,
2009). These findings suggest that mindfulness-based therapies
may be particularly helpful in targeting negative reinforcement
processes, like stress-induced cravings, in addictions, and this
may be of particular relevance to relapse prevention as stress-
induced cravings measures predict relapse (Sinha et al., 2006).
Given the neurobiology of stress responsiveness and increased
cortico-striato-limbic activations to stress in addicted individuals
(Koob and Zorrilla, 2010; Sinha, 2008), it is tempting to speculate
that mindfulness-based therapies may normalize stress-related
responses in addicted individuals. Mindfulness-based therapies
may be particularly applicable to women, as cocaine-dependent
women as compared to cocaine dependent men demonstrate
relatively increased cortico-striato-limbic activations to stress
cues (Potenza et al., 2007). Changes related to mindfulness-
based therapies may involve white matter changes in brain
regions implicated in emotional regulation and cognitive control
as meditation, a component of mindfulness-based therapies,
has been reported to induce white matter integrity changes in
the corona radiata, a tract connecting the anterior cingulate
cortex to other brain structures (Tang et al., 2010).
Additional behavioral therapeutic advances might be gleaned
from considering approaches to nonsubstance addictions. For
example, imaginal desensitization has shown some efficacy in
the treatment of pathological gambling (Brewer et al., 2008b;
Grant et al., 2009), and this approach of controlled exposure to
gambling-related cues may help uncouple cues from engage-
ment in addictive behaviors and thus might be anticipated to
influence prefrontal control over motivation (George and Koob,
2010). Participation in 12-step programs (e.g., Alcoholics
Anonymous) may also induce specific neuroadaptations. Like
CBT, 12-step programs have multiple components (steps) (Alco-
holics Anonymous, 1986), and these may be differentially linked
to specific brain circuits. For example, step eight involves
a willingness to make amends to those harmed, and performing
such behaviors may involve changes neurocircuitry implicated in
social reciprocity and moral decision making (Moll et al., 2005;
Potenza, 2009a). Although a 12-step program is not a behavioral
therapy per se, many individuals receiving formal treatment for
addictions also attend 12-step programs. Thus, considering
the contributions of 12-step participation to treatment outcome
and corresponding changes in neurocircuitry is important.
Pharmacological Treatments and Targets
Multiple pharmacological targets have been identified for the
treatment of addictive disorders. ‘‘Classic’’ approaches tend to
target the drug ‘‘reward’’ system, such as normalization of func-
tion through agonist approaches and negative reinforcement
strategies. These approaches are informed by study of neuro-
transmitters affected by substances of abuse (Koob and Volkow,
2010; Reissner and Kalivas, 2010; Sulzer, 2011), with recent
approaches emphasizing the targeting of individual vulnerabil-
ities and cognitive function (George and Koob, 2010).
Medications Targeting Positive Reinforcement
or Drug Reward
Positive reinforcement is defined as any stimulus that increases
the probability of the preceding behavior and typically involves
a hedonic reward. Self-administration is the primary measure
for drug reinforcement, and almost all reinforcing drugs induce
subjective drug reward or ‘‘liking’’ in humans. The exact function
of dopamine in addictive behavior continues to be debated
(Dalley and Everitt, 2009; Kenny, 2011; Lajtha and Sershen,
2010; Schultz, 2010, 2011). According to Robinson and Berridge,
dopamine mainly mediates incentive-salience or ‘‘wanting’’ while
drug pleasure or ‘‘liking’’ is mediated by other neurotransmitters
including endogenous opioids, gamma-aminobutyric acid
(GABA), and endocannabinoids (Berridge et al., 2009; Horder
et al., 2010; Robinson and Berridge, 1993). The hypothesis is sup-
ported by a human PET imaging study in which dopamine release
by amphetamine was correlated with drug ‘‘wanting’’ but not with
mood elevation (Leyton et al., 2002). In addition, acute phenylal-
anine-tyrosine depletion, which reduces the precursor levels for
dopamine, resulted in attenuated cue and cocaine-induced
drug craving but not euphoria or self-administration of cocaine
(Leyton et al., 2005). Further, dopamine receptor antagonists
do not consistently block cocaine-induced ‘‘high’’ in humans
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Table 1. Pharmacotherapies Used for the Treatment of Addictive Disorders

Medication Delivery System Mechanism of action Type of Addiction Efficacy
Methadone Oral solution or tablet m opioid agonist Opioid Effective in retaining patients
in treatment and reducing
heroin use (Mattick et al.,
2003)
Buprenorphine Sublingual tablet alone or Partial m opioid agonist and k Opioid Effective in retaining patients
with naltrexone opioid antagonist and reducing heroin use
(Mattick et al., 2004)
Naltrexone Oral tablet, Opioid antagonist Opioid Better opioid use outcomes
Extended-release injectable in high retention groups
suspension (Johansson et al., 2006)
Alcohol Significantly reduces
relapses but not to drinking
(Srisurapanont and
Jarusuraisin, 2005)
Disulfiram Oral tablet Increases acetaldehyde by Alcohol May reduce drinking in
inhibition of aldehyde compliant patients.
dehydrogenase Overall efficacy is
questionable (Mann, 2004)
Acamprosate Oral tablet NMDA receptor modulator Alcohol Two-fold increase in
abstinence rates at 1 year
(Mason and Heyser, 2010)
Nicotine Replacement Transdermal patch, gum, nAChR agonist Nicotine Two-fold increase in the
Treatments lozenge, nasal spray, and odds of quitting smoking
oral inhaler (Fiore et al., 2008)
Bupropion Oral tablet DA and NE reuptake blocker, Nicotine Two-fold increase in the
and nAChR antagonist odds of quitting smoking
(Eisenberg et al., 2008)
Varenicline Oral tablet Partial agonist for the a4b2 Nicotine 2- to 3-fold increase in the
and full agonist for the a7 odds of quitting smoking at
nAChR 6 months (Cahill et al., 2010)
Abbreviations: DA, dopamine; nAChR, nicotinic cholinergic receptor; NE, norepinephrine; NMDA, n-methyl-d-aspartate.

(Brauer and De Wit, 1997; Haney et al., 2001). Additional support
also comes from the food literature where differences in dopa-
mine-related neural responses to highly versus less palatable
foods are observed (Kenny, 2011). These clinical as well as other
preclinical findings (Berridge et al., 2009) provide indirect
evidence for a limited role of dopamine for drug ‘‘liking.’’ Identi-
fying the neurotransmitter mechanisms that mediate drug
‘‘wanting’’ and ‘‘liking’’ responses may facilitate development of
new pharmacotherapy targets for addictive disorders.
1. Agonist approaches. Agonist medications have their main
impact on the same types of neurotransmitter receptors as those
stimulated by abused substances. The general strategy of
agonist treatments is to substitute a safer, longer-acting drug
for a more risky, short-acting one. Examples of agonist treatment
include methadone for opioid dependence and nicotine replace-
ment treatment for smoking cessation (Table 1). Agonist treat-
ment approaches have also been examined for cocaine depen-
dence (Herin et al., 2010). Most notably, dextroamphetamine
has reduced drug use in short-term clinical trials in cocaine
(Grabowski et al., 2004; Shearer et al., 2003) and methamphet-
amine users (Longo et al., 2010; Shearer et al., 2001). Amphet-
amines, similar to cocaine, increase synaptic dopamine levels
by inhibiting monoamine transporters and also by disrupting
the storage of dopamine in intracellular vesicles (Partilla et al.,
2006; Sulzer, 2011). The long-term safety and abuse liability of
amphetamines as a treatment for cocaine addiction remain to
be determined.
Another example of an agonist approach for cocaine depen-
dence is modafinil, which has stimulant-like effects. Modafinil
is a weak dopamine transporter inhibitor and increases synaptic
dopamine levels (Volkow et al., 2009). It also stimulates hypotha-
lamic orexin neurons, reduces GABA release, and increases
glutamate release (Martı́nez-Raga et al., 2008). While initial
randomized clinical trials with modafinil were promising for
cocaine addiction (Dackis et al., 2005), a multisite clinical trial
was negative (Anderson et al., 2009). However, modafinil may
act as a cognitive enhancing agent in stimulant-dependent indi-
viduals, improving learning through neural regions (insula and
ventromedial prefrontal and anterior cingulate cortices) impli-
cated in learning and cognitive control (Ghahremani et al., 2011).
2. Antagonist approaches. Antagonists block the effects of
drugs by either pharmacological or pharmacokinetic mecha-
nisms. Antagonist treatment approaches have been especially
useful for opioid drugs. An example of pharmacological antago-
nism is blockage of opioid effects by the m opioid antagonist
naltrexone or by buprenorphine, a partial m opioid agonist and

700 Neuron 69, February 24, 2011 ª2011 Elsevier Inc.

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k opioid antagonist. Buprenorphine and naltrexone block the
rewarding effects of opioids and are effective for the treatment
for opioid addiction. Naltrexone also attenuates the rewarding
effects of alcohol by presumably blocking m opioid receptors
(Ray et al., 2008), and this mechanism probably contributes to
naltrexone’e efficacy for the treatment of alcohol addiction
(Sulzer, 2011). Similarly, varenicline, a partial agonist for the
alpha4beta2 nicotinic receptor, attenuates the rewarding effects
of nicotine (Patterson et al., 2009; Sofuoglu et al., 2009; West
et al., 2008) and is effective for the treatment of nicotine depen-
dence (Table 1).
More recently, immunotherapies have been developed for the
treatment of cocaine, methamphetamine, and nicotine addic-
tions (Orson et al., 2008). Immunotherapies antagonize drug
effects via pharmacokinetic mechanisms (LeSage et al., 2006).
The antibodies produced by immunotherapies sequester the
drug in the circulation and reduce the amount of drug and the
speed at which it reaches the brain. This results in attenuated
rewarding effects of the drug of abuse (Haney et al., 2010). While
initial clinical trials suggest some promise (Martell et al., 2005,
2009), to date the efficacy of vaccines has been undercut by
a substantial induction period required to achieve clinically
significant levels of circulating antibodies and only partial
blockade of drug effects even when antibody levels are maxi-
mized. An important limitation of vaccines is that the antibodies
produced are specific for a given drug of abuse, a characteristic
that will limit their clinical efficacy in polydrug abusers. The most
promising use of vaccine may be to prevent relapse in individual
whose drug use is limited to a single agent.
A potentially promising target for agonist and antagonist treat-
ment of cocaine addiction is the D3 dopamine receptor (Heid-
breder and Newman, 2010). Like the D2 dopamine receptor,
the D3 dopamine receptor is expressed at high levels in the stria-
tum, but compared to the D2 dopamine receptor, it is particularly
highly expressed in the ventral striatum. While D3 agonists
partially reproduce cocaine reinforcement, D3 antagonists or
partial agonists attenuate cocaine reinforcement (Achat-Mendes
et al., 2010). D3 partial agonists (CJB090, BP 897, and others)
can act like agonists and stimulate dopamine receptors when
endogenous levels of dopamine are low, as in cocaine with-
drawal. In contrast, when dopamine receptors are stimulated
after cocaine use, D3 partial agonists can act like antagonists
in blocking the effects of cocaine (Martelle et al., 2007). However,
drugs with D2 and D3 antagonistic properties have not demon-
strated clinical efficacy for drug or nonsubstance addictions
(Fong et al., 2008), D2/D3 antagonists have been associated
with promoting of gambling-related motivations in pathological
gambling (Zack and Poulos, 2007), and dopamine agonists
(including D3-preferring drugs) have been associated with
nonsubstance addictions like pathological gambling in the treat-
ment of Parkinson’s disease (Weintraub et al., 2010). As such,
the efficacies and tolerabilities of D3 partial agonists need careful
examination in people with addictions. Additionally, drugs that
target striatal dopamine function through indirect manners
(e.g., through serotonin 1B receptors) also warrant consideration
for treatment development (Hu et al., 2010).
3. Medications targeting negative reinforcement of drugs. Drug
addiction is associated with adaptive changes in multiple neuro-
transmitter systems in the brain including dopamine, norepi-
nephrine, corticotrophin releasing hormone (CRH), GABA, and
glutamate (Chen et al., 2010; Koob and Le Moal, 2005). These
adaptive changes are thought to underlie the negative reinforc-
ing effects of abstinence from drug use that are clinically
observed as withdrawal symptoms, craving for drug use, and
negative mood states like anhedonia and anxiety. Increased
norepinephrine activity is associated especially with opioid and
alcohol withdrawal states. Development of sensitization to
drug-related cues, perceived as craving induced by drug cues,
probably involve adaptive changes in the dopamine, GABA,
and glutamate systems (Schmidt and Pierce, 2010). Reduction
in dopamine levels in the ‘‘reward’’ circuit is thought to mediate
anhedonia commonly observed following abstinence from drugs
(Treadway and Zald, 2011). Examples of medications targeting
negative reinforcement of drugs include methadone or bupre-
norphine, drugs that relieve opioid withdrawal symptoms.
Nicotine replacement products, bupropion, and the partial nico-
tinic agonist varenicline relieve nicotine withdrawal symptoms
and attenuate the negative mood states after smoking cessation
(Patterson et al., 2009; Sofuoglu et al., 2009). Acamprosate, an
approved medication for the treatment of alcohol dependence,
attenuates withdrawal symptoms and craving for alcohol (Gual
and Lehert, 2001).
Medications targeting the noradrenergic system have shown
promising results for treatments targeting withdrawal or relapse.
Preclinical and human laboratory studies suggest that lofexidine,
an alpha2-adrenergic agonist, may attenuate stress-induced
relapse in cocaine and opioid users (Highfield et al., 2001; Sinha
et al., 2007). Cocaine users with more severe withdrawal symp-
toms respond more favorably to propranolol, a beta-adrenergic
antagonist (Kampman et al., 2006). Clinical trials are underway to
test the efficacies of carvedilol, an alpha and beta-adrenergic
antagonist, and guanfacine, an alpha2-adrenergic agonist, in
treating cocaine or methamphetamine addiction.
Several agents targeting glutamate system are also under
investigation as potential treatment medications. Memantine,
a noncompetitive n-methyl-d-aspartate (NMDA) glutamate
receptor antagonist, has also shown efficacy in reducing cue-
induced craving for alcohol in alcohol dependent patients (Kru-
pitsky et al., 2007). In pathological gambling, memantine may
be efficacious and operate by reducing cognitive measures of
compulsivity (Grant et al., 2010). However, clinical trials with
memantine have demonstrated negative findings for alcohol
(Evans et al., 2007) and cocaine dependence (Bisaga et al.,
2010). A neutraceutical that targets the glutamate system is
N-acetyl cysteine, a natural compound used for the treatment
of acetaminophen overdose. N-acetyl cysteine’s proposed anti-
addictive effects include normalization of reduced extracellular
glutamate levels in the nucleus accumbens by stimulating the
cystine-glutamate antiporter (Baker et al., 2003). N-acetyl
cysteine has shown some positive results in small clinical trials
for cocaine and nicotine addiction and pathological gambling
(Grant et al., 2007; Knackstedt et al., 2009; Mardikian et al.,
2007). Larger studies are underway to test its efficacy in these
disorders. In addition, compounds targeting metabotropic gluta-
mate receptors have shown efficacy in blocking reinstatement of
drug use behavior in animal models for relapse. For example,
Neuron 69, February 24, 2011 ª2011 Elsevier Inc. 701

LY379268, an agonist of the group II metabotropic glutamate
receptors, reduces self-administration and reinstatement of
drug-seeking behavior for nicotine (Liechti et al., 2007), alcohol
(Sidhpura et al., 2010; Zhao et al., 2006), and cocaine (Adewale
et al., 2006; Baptista et al., 2004). Several metabotropic gluta-
mate agonists are available for human use and should be evalu-
ated for the treatment of addictive disorders.
Medications Targeting Individual Vulnerability Factors
to Addiction
Individuals vary in their vulnerability to addiction. For example,
among those who had tried cocaine, only about 17% become
addicted (Wagner and Anthony, 2002). For alcohol, about 15%
of those who drink eventually become dependent, while 30%
of those who try smoking become addicted smokers. These
proportions are similar to those observed in preclinical models
of addiction (Belin et al., 2008). The individual factors contrib-
uting to vulnerability to addiction are complex and have not yet
been fully elucidated (George and Koob, 2010; Kreek et al.,
2005; Le Moal, 2009; Sinha, 2008; Uhl et al., 2009). Comorbid
psychiatric conditions and cognitive deficits are two examples
of individual vulnerability factors that could be targeted by phar-
macotherapies.
1. Treatments targeting comorbid psychiatric conditions.
Comorbidity exists between drug addiction and primary psychi-
atric disorders including schizophrenia, mood and anxiety disor-
ders, and attention-deficit hyperactivity disorder (Hasin et al.,
2007; Kessler et al., 2005). For example, among individuals
with schizophrenia, 40% to 60% abuse drugs or alcohol and
over 90% smoke cigarettes (George et al., 2002). Addicted indi-
viduals with comorbid psychiatric disorders tend to have poorer
outcomes than those without comorbidity (Brady and Sinha,
2005; Havassy et al., 2004; Potenza, 2007). One of the possible
mechanisms underlying this high comorbidity is self-medication,
which posits that individual with primary psychiatric disorders
use drugs or alcohol to relieve specific symptoms (e.g., negative
affect) or side effects of their treatment medications (e.g., seda-
tion). Alternatively, common genetic and other neurobiolgical
factors may lead to high comorbidity between addictions and
other psychiatric disorders (Chambers et al., 2001; Potenza
et al., 2005). Common vulnerability factors may include
increased impulsivity, reward sensitivity, and cognitive deficits.
One implication of comorbidity is that effective treatment of
psychiatric disorders may also reduce substance use, although
existing clinical trials indicate mixed results in this regard (Nunes
and Levin, 2004).
2. Medications targeting cognitive deficits. A large body of
evidence has documented cognitive deficits in chronic alcohol,
cocaine, methamphetamine, and cannabis users (Ersche et al.,
2006; Ersche and Sahakian, 2007; Goldstein and Volkow,
2002). Cognitive deficits may represent a particular challenge
for treatment-seeking users who require intact cognitive func-
tioning in order to engage in treatment and learn new behavioral
strategies in order to stop their drug use. As demonstrated
previously, cognitive deficits are associated with higher rates
of attrition and poor treatment outcome (Aharonovich et al.,
2006; Bates et al., 2006). Cognitive enhancement strategies
may be especially important early in the treatment by improving
their ability to learn, remember, and implement new skills and
702 Neuron 69, February 24, 2011 ª2011 Elsevier Inc.
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coping strategies. The range of deficits that is found in addicted
individuals includes attention, working memory, and response
inhibition, functions that are attributed to the prefrontal cortex.
Cognitive functioning in the prefrontal cortex is modulated
by many neurotransmitters, including glutamate, GABA, acetyl-
choline, and monoamines: dopamine, serotonin, and norepi-
nephrine (Robbins and Arnsten, 2009). Many cognitive
enhancers targeting these neurotransmitters are in different
stages of development.
In a recent proof-of-concept study, we examined the efficacy
of galantamine, a cholinesterase inhibitor, as a cognitive
enhancer in abstinent cocaine users (M.S., J. Poling, and
K.M.C., unpublished data). Cholinesterase inhibitors, including
tacrine, rivastigmine, donepezil, and galantamine, have been
used for the treatment of dementia and other disorders charac-
terized by cognitive impairment, including Parkinson’s disease,
traumatic brain injury, and schizophrenia (Giacobini, 2004).
Cholinesterase inhibitors increase the synaptic concentrations
of acetylcholine (ACh), which lead to increased stimulation of
both nicotinic and muscarinic cholinergic receptors. Galant-
amine is also an allosteric modulator of the a7 and a4b2 nicotinic
ACh receptor (nAChR) subtypes (Schilström et al., 2007). In our
study, 10 day treatment with galantamine, compared to placebo,
improved the attention and working memory functions in absti-
nent cocaine users (M.S., J. Poling, and K.M.C., unpublished
data). These findings support the promise of galantamine as
a cognitive enhancer among cocaine users. This study did not
examine treatment effect on cocaine use because participants
had to be abstinent of drug use to allow accurate assessment
of galantamine on cognitive performance. Additional clinical
trials are underway to test the efficacy of galantamine in the
treatment of cocaine-addicted individuals.
Another promising medication for cognitive enhancement is
atomoxetine, a selective norepinephrine transporter (NET) inhib-
itor used for the treatment of attention deficit hyperactivity
disorder (ADHD). In prefrontal cortex, the NET is responsible
for the reuptake of norepinephrine as well as dopamine into
presynaptic nerve terminals (Kim et al., 2006). As a result, atom-
oxetine increases both NE and dopamine levels in the PFC, and
both actions may contribute to the cognitive-enhancing effects
of atomoxetine (Bymaster et al., 2002). Consistent with preclin-
ical studies (Jentsch et al., 2009; Seu et al., 2009), atomoxetine
improves attention and response inhibition functions in healthy
controls and patients with ADHD (Chamberlain et al., 2007,
2009; Faraone et al., 2005). Attention and response inhibition
functions are essential in optimum cognitive control needed to
prevent drug use, and atomoxetine in preclinical models dimin-
ished drug-seeking behaviors (Economidou et al., 2011). Both
attention and response inhibition are impaired in cocaine users
(Li et al., 2006; Monterosso et al., 2005). Whether these cognitive
functions can be improved and drug use curtailed with atomox-
etine remains to be determined in cocaine users.
In addition to cholinesterase inhibitors and atomoxetine, there
are many other potential cognitive enhancers include modafinil,
amphetamines, partial nAChR agonists, like varenicline, and
metabotropic glutamate agonists (Olive, 2010). The safety and
efficacy of these medications remain to be tested in clinical
studies with addicted individuals.
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Combined Behavioral and Pharmacological Treatment
Approaches
While great progress has been made in identification of effective
pharmacotherapies and behavioral therapies for the addictions,
no existing treatment, delivered alone, is completely effective
(Carroll and Onken, 2005; Vocci et al., 2005). Thus, an important
strategy to enhance the efficacy of monotherapies is to combine
them with one or more alternative treatments (National Institute
on Drug Abuse, 2007). The results of combined treatments can
be additive, interactive, nonadditive (adding a second treatment
neither adds nor subtracts), or subtractive. Strategies for
choosing treatments to combine include (1) use of complemen-
tary efficacious treatments that address weakness in either
therapy alone, (2) use of efficacious treatments that target the
same processes in different ways, and (3) use of treatments
that are not efficacious alone but catalyze each other.
Frequently, these strategies involve combining a top-down
approach with a bottom-up intervention, such as combinations
of behavioral and pharmacotherapies (Figure 1).
There are multiple examples of behavioral and pharmacolog-
ical treatments having complementary effects. A classic
example is the combination of methadone maintenance with
behavioral therapies (McLellan et al., 1993; Peirce et al., 2006).
Without behavioral treatments, provision of methadone was
associated with early treatment failure and dropout (Ball and
Ross, 1991). Another example of this strategy involves antide-
pressant medications and cognitive behavioral therapy, each
of which has been demonstrated to reduce depression in
depressed smokers (Hall et al., 2002). Antidepressants are tar-
geted at neurotransmitter systems thought to underlie depres-
sion symptoms while CBT attempts to change behaviors and
cognitions associated with maintaining depression (DeRubeis
et al., 1999; DeRubeis et al., 2008). An example of catalytic, or
synergistic, treatment effects is provided by studies that
combine contingency management with tricyclic antidepres-
sants for cocaine abuse in methadone-maintained patients (Kos-
ten et al., 2003; Poling et al., 2006). In both of these trials, neither
tricyclics nor contingency management was efficacious alone
but the combination yielded superior results compared to a stan-
dard treatment condition. Behavioral therapies may also work in
a complementary fashion, particularly in different stages of treat-
ment. For example, motivational interventions may help engage
individuals in treatment, contingency management may help
maintain individuals in treatment, and CBT may help with long-
term abstinence through relapse prevention and ‘‘sleeper
effects.’’ Although not linked to a specific therapy, there are
data to suggest that these different aspects of treatment
outcome are differentially associated with specific neural
circuits. For example, in cocaine-dependent individuals,
pretreatment fMRI measures of cognitive control were differen-
tially associated with outcome measures of retention and absti-
nence, with retention correlating with activation in the dorsolat-
eral prefrontal cortex (implicated in executive functioning) and
abstinence with activation in striatal and ventromedial prefrontal
cortical regions (implicated in reward processing and decision
making) (Brewer et al., 2008a). As this study involved a small
sample of subjects receiving combinations of behavioral and
pharmacological therapies, additional larger controlled studies
involving pre- and posttreatment imaging are needed to assess
more directly the relationships between specific treatments,
outcome measures, and neural functions.
Although it is tempting to speculate that specific combinations
of treatments (e.g., behavioral and pharmacological therapies
that theoretically engage top-down processes and bottom-up
processes, respectively; Figure 1) may have complementary
mechanisms of action, the precise mechanisms for synergism
between behavioral and pharmacotherapies are not well under-
stood and require direct investigation. Existing data offer some
insight. For example, consistent with the notion of pharmaco-
therapies working in a bottom-up fashion, bupropion treatment
of tobacco smokers was associated with less craving and dimin-
ished limbic activation to smoking cues when attempting to
resist craving, whereas placebo treatment did not demonstrate
changes in limbic activations (Culbertson et al., 2011). However,
in a study of tobacco smokers receiving treatment with bupro-
pion, practical group counseling, or pill placebo, individuals
receiving either active treatment differed from those receiving
placebo by showing greater reduction in glucose metabolism
posttreatment in the posterior cingulate cortex (Costello et al.,
2010). The decreased metabolism was not related to cigarette
use measures and appeared largely similar across the behavioral
and pharmacological therapies. As the posterior cingulate is an
integral component of the default mode network, the authors
speculated that effective treatments for nicotine dependence
may improve default mode network functioning, moving individ-
uals toward better goal-oriented states (Costello et al., 2010).
As children with ADHD show suppression of default mode pro-
cessing in response to stimulant treatment (Peterson et al.,
2009), the findings suggest that improved default mode process-
ing function may represent an important treatment target across
disorders characterized by impaired impulse control. Moreover,
as posterior cingulate activation during drug craving has been
associated with treatment outcome for cocaine dependence
(Kosten et al., 2006), the findings also suggest an important
role for posterior cingulate function for treatment outcome
across addictions and one that may also relate to the involve-
ment of the posterior cingulate in circuits related to emotional
and motivational processing (Sinha, 2008). Such possibilities
warrant direct examination.
Using Neuroscience to Investigate Treatment
Mechanisms
As reviewed above, traditional pharmacologic approaches to
addiction have focused on exploiting our understanding of the
specific actions of various neurotransmitters in the brain (e.g.,
dopamine for reward, opioids for pleasure, and adrenergic
neurochemicals for excitement) (Potenza, 2008). While
continuing to increase our understanding of the neurochemical
underpinnings of addictions remains important (particularly for
pharmacotherapy development), approaches to understanding
brain function related to addictions are increasingly focusing
on neural systems in the pathophysiologies of addictions.
Thus, incorporating pre- and posttreatment neuroimaging
measures into randomized clinical trials for addictions is partic-
ularly important if we are to identify neural predictors and
correlates of effective treatments for these disorders.
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There exist multiple considerations when integrating neuroi-
maging and clinical trials for addictions. While some are practical
(e.g., a relatively short time frame between evaluation/randomi-
zation and scanning requiring coordination between an interdis-
ciplinary research team, questions as to how best to manage and
consider recency of drug use—and potentially intoxication or
withdrawal—with respect to scanning), others are theoretical
(e.g., selecting measures that are theoretically related to the
therapies’ proposed mechanisms of action, a notion consistent
with selecting evaluative measures in clinical trials in general
[Walker et al., 2006]). An important advantage of fMRI in this
respect is the ability to monitor brain activity (via blood oxygen
level dependent [BOLD] signal) during task performance. As
such, specific fMRI paradigms may offer particular insights into
the mechanisms of action of particular therapies. For example,
effective contingency management, involving the delivery of
small immediate rewards based on positive short-term behav-
iors (e.g., drug abstinence) may be expected to involve changes
in reward processing that can be assessed through fMRI
paradigms like the monetary incentive delay task (Andrews
et al., 2010). Alternatively, specific aspects of CBT, such as
developing skills to cope with drug cues or triggers, might
involve changes in brain circuitry underlying regulation of craving
or cognitive control that may be assessed through different
fMRI paradigms (Brewer et al., 2008a; Janes et al., 2010;
Kober et al., 2010). Other fMRI paradigms (e.g., those probing
stress responsiveness) may be particularly well suited for
investigating mechanisms underlying mindfulness-based
therapies (Brewer et al., 2009; Sinha et al., 2005). Additionally,
advances in fMRI technology that facilitate real-time feedback
of regional brain activation may be used to investigate features
relevant to specific therapies (e.g., control of craving in
CBT and meditational states in mindfulness-based therapies)
(deCharms, 2008).
Conversely, novel methods of treatment delivery, such as
computer-assisted delivery of CBT (Carroll et al., 2008; Carroll
et al., 2009), may facilitate understanding of treatment mecha-
nisms through neuroimaging studies. Given the consistency
with which it is delivered, computerized treatment offers
a more robust and standardized form of treatment. The conse-
quent reduction in variance in the treatment variable may
increase the power of fMRI paradigms to detect processes
that are specific to this form of treatment, offering an advantage
in small-sample fMRI studies (Frewen et al., 2008). Also, compo-
nents of computer-delivered treatments could conceivably be
studied directly using fMRI.
Future Directions: Individual Differences,
Endophenotypes, and Treatment Matching
One current focus in optimizing treatment involves identifying
individual differences related to addiction treatment outcome
to guide the selection of therapies. While the consideration of
individual differences is not new (e.g., Project MATCH investi-
gated individual differences and treatment specificity with argu-
ably limited success [Cutler and Fishbein, 2005]), recent
approaches have considered individual differences from
a different perspective (e.g., as possible endophenotypes [Got-
tesman and Gould, 2003]). Some individual differences may
704 Neuron 69, February 24, 2011 ª2011 Elsevier Inc.
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represent important targets for treatment development (e.g.,
potential endophenotypes like impulsivity or compulsivity [Dalley
et al., 2011]), whereas others (e.g., developmental stages, sex
differences, stage of the addiction process) may represent
important considerations when targeting or matching specific
treatments to specific individuals.
Endophenotypes represent particularly attractive therapeutic
targets as they may associate more closely to biological mecha-
nisms than do heterogeneous psychiatric disorders like addic-
tions (Fineberg et al., 2010; Gottesman and Gould, 2003). One
potential endophenotype relevant to addiction treatment is
impulsivity (Dalley et al., 2011). Preclinical data indicate that
impulsive tendencies prior to drug exposure both are linked to
ventral striatal dopamine function and predict the development
of addictive behaviors (Belin et al., 2008; Dalley et al., 2007).
Studies also link midbrain to ventral striatal dopamine pathways
to impulsivity in people (Buckholtz et al., 2010). Clinical data
suggest that impulsivity is associated with addiction severity
and that changes in addiction severity during treatment correlate
with changes in impulsivity (Blanco et al., 2009). Thus, targeting
impulsivity through behavioral or pharmacological mechanisms
that promote self-control warrants consideration. As elevated
impulsivity may predate addictive problems, such interventions
may be considered at early points in either the addictive process
or in development. This latter point seems particularly salient as
individual differences in self-control during childhood predict
important measures of functioning during adolescence and
into adulthood (Lehrer, 2009; Mischel et al., 1989). Furthermore,
as substance exposure during adolescence may lead to greater
impulsivity in adulthood (Nasrallah et al., 2009), early intervention
appears particularly important.
Targeting of specific factors may be complicated by the
complexities of the constructs. For example, impulsivity is
a multifaceted construct that factors into two or more domains
(Meda et al., 2009; Moeller et al., 2001). Two domains repeatedly
identified include those related to choice/decision making and
response disinhibition, and each appears relevant to addiction
(de Wit, 2009; Perry and Carroll, 2008; Potenza and de Wit,
2010; Reynolds et al., 2006; Verdejo-Garcı́a et al., 2008). The
specific domains of impulsivity may relate differentially to other
relevant psychobiological processes (e.g., reward processing
and cognitive control appear theoretically and biologically linked
to choice and response impulsivity, respectively) and thus
combinations of therapies that preferentially target each domain
may be needed to optimize treatments.
As self-report and behavioral measures of impulsivity have
been found to factor separately (Meda et al., 2009) and behav-
ioral and self-reported measures of the same constructs (e.g.,
temporal discounting) may not correlate with one another and
be differentially related to treatment outcome (Krishnan-Sarin
et al., 2007), a broad range of self-report, behavioral, and biolog-
ical assessments (including neurocognitive ones) may provide
the deep phenotyping that will be vital to treatment develop-
ments for addictions. Additionally, as brain circuits underlying
motivation, reward responsiveness, decision making, and
behavioral control are undergoing significant changes during
periods of increased addiction vulnerability such as adolescence
(Casey et al., 2010; Chambers et al., 2003; Rutherford et al.,
Neuron
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2010; Somerville et al., 2010), developmental considerations are
important in this process.
Potential endophenotypes may underlie multiple kinds of
addictions (Frascella et al., 2010). However, specific drugs are
also associated with unique short- and long-term effects,
including potential neurotoxicities. Drug exposure may have
specific influences on brain structure and function, and such
changes warrant particular attention as they relate to treatment
development. For example, cocaine use has been associated
with metabolic impairments, with increasing chronicity of use
progressively influencing cortical regions from more ventral
and medial regions to more dorsal and lateral ones (Beveridge
et al., 2008). These findings are consistent with a broad range
of cognitive deficits observed in cocaine dependent individuals,
including on tasks associated with ventromedial prefrontal
cortical function (Bechara, 2003) as well as ones linked to dorso-
lateral prefrontal cortical function and associated with treatment
outcome measures of retention (Brewer et al., 2008a; Streeter
et al., 2008). Other brain differences, such as white matter integ-
rity (Lim et al., 2002, 2008; Moeller et al., 2005; Moeller et al.,
2007), have been observed in cocaine dependence and associ-
ated with disadvantageous decision making (Lane et al., 2010)
and treatment outcome (Xu et al., 2010). Both pharmacological
(Harsan et al., 2008; Schlaug et al., 2009) and behavioral (Tang
et al., 2010) approaches may alter white matter integrity. Thus,
white matter integrity may represent an underexamined thera-
peutic target in addictions. Additionally, investigating means
for altering synaptic connections, including rapid mechanisms
related to brief exposure to antiglutamatergic drugs (Li et al.,
2010), may aid addiction treatment development efforts, partic-
ularly as related to stress or other negative reinforcement
processes. These considerations underscore the promise of
developing and testing (both singly and in combination) pharma-
cological and behavioral treatments aimed at improving cogni-
tive functions such as attention, working memory, decision
making, and self-control. Relating the results of these treatments
to measures of impulsivity and brain function can provide
evidence for mechanisms of these treatments.
Endophenotypes may track closely with genetic factors, and
individual differences related to addictions and their treatments
may be influenced by genetic, environmental, or interactive influ-
ences (Goldman et al., 2005; Renthal and Nestler, 2008). As
commonly occurring allelic variants have been variably linked
to treatment outcomes for addictions (e.g., a functional variant
of the gene encoding the m opioid receptor has been associated
with opioid antagonist treatment outcome in some (Oslin et al.,
2003) but not other (Arias et al., 2008) studies of alcohol depen-
dence or heavy drinking) and specific environmental exposures
in conjunction with commonly occurring allelic variants may shift
the risk for developing and treating addictions (e.g., stress expo-
sure and serotonin-transporter-encoding genetic variants
interact to influence alcohol intake in young adults and may be
linked to ondansetron response in alcohol dependence [Johnson
et al., 2008; Laucht et al., 2009; Sinha, 2009]), it will be important
to carefully assess multiple environmental and genetic measures
as related to treatment outcome. Furthermore, as timing of envi-
ronmental exposures may differentially impact individuals (e.g.,
influences of trauma early versus later in life) and do so in
a sex- or culture-specific fashion, thorough assessments and
large samples involving targeted recruitment may be necessary
to optimize treatment strategies for individuals.
Drug-Related Brain Changes: Consideration
of Nonsubstance Addictions
Given the potential neurotoxic and neuroadaptation effects of
abused substances, understanding the neuroscience of addic-
tive processes may be enhanced by focusing on addictions
that do not necessarily involve use of psychoactive substances.
For example, obesity shares similarities with drug addictions
at neurobiological levels (e.g., with respect to striatal D2/D3
dopamine receptor function), and these similarities may inform
treatment and policy strategies (A.N. Gearhardt, C.M. Grilo,
R.J. DeLeone, K.D. Brownell, and M.N.P., unpublished data;
Vanbuskirk and Potenza, 2010). Pathological gambling also
demonstrates clinical and biological similarities with drug addic-
tions (Holden, 2010; Potenza, 2006, 2008). Consistently, treat-
ments, particularly those with proposed mechanisms of action
(e.g., modulation of neurotransmission in the mesolimbic dopa-
mine pathway by opioid receptor antagonists like naltrexone or
nalmefene or enhancing cognitive function via glutamatergic
agents like memantine) that target features observed across
addictions, appear efficacious for both substance and gambling
addictions (Brewer et al., 2008b; Cheon et al., 2008; Grant et al.,
2010; Potenza, 2008). Furthermore, among individuals with
pathological gambling, response to an opioid receptor antago-
nist appears strongly related to a family history of alcoholism
(Grant et al., 2008), suggesting a possible endophenotype
common to pathological gambling and alcoholism. However,
other features, such as executive processes involving dorsal
prefrontal cortical function, appear more impaired in individuals
with alcoholism than in those with gambling problems, consis-
tent with neurotoxic influences of alcohol (Lawrence et al.,
2009; Potenza, 2009b). As pathological gambling is unhindered
by drug-on-brain-substrate effects that may complicate the
treatment of substance addictions, it represents an important
disorder for better understanding substance addictions and their
treatments.
Conclusions
Although significant advances have been made over the past
several decades in the development of effective treatments for
addictions, they remain a substantial public health problem.
The development of neuroscience methodologies for assessing
brain structure and function provides an exciting opportunity for
applying these tools to understand and improve treatments.
Additional research efforts should define novel targets for treat-
ment (e.g., cognitive function, control of craving, impulsivity,
compulsivity, and/or self-control), implement tools for assessing
these targets over time (including self-report, behavioral, neuro-
cognitive/neural measures), and identify clinically relevant indi-
vidual differences that may be used to guide the selections of
therapies, including combinations of therapies that may operate
in complementary or synergistic fashions. As effects of drug use
on brain and brain function may be a major factor underlying
ability to benefit from treatment, direct investigation of drug-
related influences on brain structure and function are warranted
in translational and longitudinal studies. Concurrent investigation
Neuron 69, February 24, 2011 ª2011 Elsevier Inc. 705

of substance and nonsubstance addictions should be especially
informative.
ACKNOWLEDGMENTS
The authors report that they have no financial conflicts of interest with respect
to the content of this manuscript. Dr. Potenza has received financial support or
compensation for the following: Dr. Potenza has consulted for and advised
Boehringer Ingelheim; has consulted for and has financial interests in
Somaxon; has received research support from the National Institutes of
Health, Veteran’s Administration, Mohegan Sun Casino, the National Center
for Responsible Gaming and its affiliated Institute for Research on Gambling
Disorders, and Forest Laboratories, Ortho-McNeil, Oy-Control/Biotie and
Glaxo-SmithKline pharmaceuticals; has participated in surveys, mailings or
telephone consultations related to drug addiction, impulse control disorders
or other health topics; has consulted for law offices and the federal public
defender’s office in issues related to impulse control disorders; provides
clinical care in the Connecticut Department of Mental Health and Addiction
Services Problem Gambling Services Program; has performed grant reviews
for the National Institutes of Health and other agencies; has guest-edited jour-
nal sections; has given academic lectures in grand rounds, CME events and
other clinical or scientific venues; and has generated books or book chapters
for publishers of mental health texts. The content of this manuscript is solely
the responsibility of the authors and does not necessarily represent the official
views of the funding agencies. Support was provided by National Institute
on Drug Abuse grants P50-DA09241, P50-DA016556, P20-DA027844,
R37-DA015969, K02-DA021304, R01-DA020908, RC1-DA028279,
R01-DA018647, R21 DA029445, and R01-DA019039, the National Institute
on Alcoholism and Alcohol Abuse grant RL1-AA017539, the VISN 1 Mental
Illness Educational, Research, and Clinical Center (MIRECC), and a Center
of Excellence in Gambling Research from the National Center for Responsible
Gaming.
REFERENCES
Achat-Mendes, C., Grundt, P., Cao, J., Platt, D.M., Newman, A.H., and Speal-
man, R.D. (2010). Dopamine D3 and D2 receptor mechanisms in the abuse-
related behavioral effects of cocaine: Studies with preferential antagonists in
squirrel monkeys. J. Pharmacol. Exp. Ther. 334, 556–565.
Adewale, A.S., Platt, D.M., and Spealman, R.D. (2006). Pharmacological
stimulation of group ii metabotropic glutamate receptors reduces cocaine
self-administration and cocaine-induced reinstatement of drug seeking in
squirrel monkeys. J. Pharmacol. Exp. Ther. 318, 922–931.
Aharonovich, E., Hasin, D.S., Brooks, A.C., Liu, X., Bisaga, A., and Nunes, E.V.
(2006). Cognitive deficits predict low treatment retention in cocaine dependent
patients. Drug Alcohol Depend. 81, 313–322.
Alexander, G.E., Crutcher, M.D., and DeLong, M.R. (1990). Basal ganglia-tha-
lamocortical circuits: Parallel substrates for motor, oculomotor, ‘‘prefrontal’’
and ‘‘limbic’’ functions. Prog. Brain Res. 85, 119–146.
Alexander, G.E., DeLong, M.R., and Strick, P.L. (1986). Parallel organization of
functionally segregated circuits linking basal ganglia and cortex. Annu. Rev.
Neurosci. 9, 357–381.
Anderson, A.L., Reid, M.S., Li, S.H., Holmes, T., Shemanski, L., Slee, A., Smith,
E.V., Kahn, R., Chiang, N., Vocci, F., et al. (2009). Modafinil for the treatment of
cocaine dependence. Drug Alcohol Depend. 104, 133–139.
Andrews, M.M., Meda, S.A., Thomas, A.D., Potenza, M.N., Krystal, J.H.,
Worhunsky, P., Stevens, M.C., O’Malley, S.S., Book, G.A., and Pearlson,
G.D. (2010). Individuals family history positive for alcoholism show fMRI
abnormalities in reward sensitivity that are related to impulsivity factors.
Biol. Psychiatry, in press. Published online November 30, 2010. 10.1016/
j.biopsych.2010.09.049.
Alcoholics Anonymous. (1986). Twelve Steps and Twelve Traditions, Vol. 32nd
Printing (New York, NY: Alcoholics Anonymous World Services, Inc.).
Arias, A.J., Armeli, S., Gelernter, J., Covault, J., Kallio, A., Karhuvaara, S.,
Koivisto, T., Mäkelä, R., and Kranzler, H.R. (2008). Effects of opioid receptor
gene variation on targeted nalmefene treatment in heavy drinkers. Alcohol.
Clin. Exp. Res. 32, 1159–1166.
706 Neuron 69, February 24, 2011 ª2011 Elsevier Inc.
Neuron
Review
Baker, D.A., McFarland, K., Lake, R.W., Shen, H., Toda, S., and Kalivas, P.W.
(2003). N-acetyl cysteine-induced blockade of cocaine-induced reinstate-
ment. Ann. N. Y. Acad. Sci. 1003, 349–351.
Ball, J.C., and Ross, A. (1991). The Effectiveness of Methadone Maintenance
Treatment (New York, NY: Springer Verlag).
Balleine, B.W., Doya, K., O’Doherty, J., and Sakagami, M. (2007). Current
trends in decision making. Ann. N. Y. Acad. Sci. 1104, xi–xv.
Baptista, M.A., Martin-Fardon, R., and Weiss, F. (2004). Preferential effects of
the metabotropic glutamate 2/3 receptor agonist LY379268 on conditioned
reinstatement versus primary reinforcement: Comparison between cocaine
and a potent conventional reinforcer. J. Neurosci. 24, 4723–4727.
Bates, M.E., Pawlak, A.P., Tonigan, J.S., and Buckman, J.F. (2006). Cognitive
impairment influences drinking outcome by altering therapeutic mechanisms
of change. Psychol. Addict. Behav. 20, 241–253.
Bechara, A. (2003). Risky business: Emotion, decision-making, and addiction.
J. Gambl. Stud. 19, 23–51.
Belin, D., Mar, A.C., Dalley, J.W., Robbins, T.W., and Everitt, B.J. (2008). High
impulsivity predicts the switch to compulsive cocaine-taking. Science 320,
1352–1355.
Bell, M., Bryson, G., Greig, T., Corcoran, C., and Wexler, B.E. (2001). Neuro-
cognitive enhancement therapy with work therapy: Effects on neuropsycho-
logical test performance. Arch. Gen. Psychiatry 58, 763–768.
Berridge, K.C., Robinson, T.E., and Aldridge, J.W. (2009). Dissecting
components of reward: ‘Liking’, ‘wanting’, and learning. Curr. Opin. Pharma-
col. 9, 65–73.
Beveridge, T.J.R., Gill, K.E., Hanlon, C.A., and Porrino, L.J. (2008). Review.
Parallel studies of cocaine-related neural and cognitive impairment in humans
and monkeys. Philos. Trans. R. Soc. Lond. B Biol. Sci. 363, 3257–3266.
Bickel, W.K., and Yi, R. (2008). Temporal discounting as a measure of execu-
tive function: Insights from the competing neuro-behavioral decision system
hypothesis of addiction. Adv. Health Econ. Health Serv. Res. 20, 289–309.
Bickel, W.K., Yi, R., Landes, R.D., Hill, P.F., and Baxter, C. (2011). Remember
the future: Working memory training decreases delay discounting among stim-
ulant addicts. Biol. Psychiatry 69, 260–265.
Bisaga, A., Aharonovich, E., Cheng, W.Y., Levin, F.R., Mariani, J.J., Raby,
W.N., and Nunes, E.V. (2010). A placebo-controlled trial of memantine for
cocaine dependence with high-value voucher incentives during a pre-random-
ization lead-in period. Drug Alcohol Depend. 111, 97–104.
Blanco, C., Potenza, M.N., Kim, S.W., Ibáñez, A., Zaninelli, R., Saiz-Ruiz, J.,
and Grant, J.E. (2009). A pilot study of impulsivity and compulsivity in patho-
logical gambling. Psychiatry Res. 167, 161–168.
Blum, K., Cull, J.G., Braverman, E.R., and Comings, D.E. (1996). Reward defi-
ciency syndrome. Am. Sci. 84, 132–145.
Botvinick, M.M., Braver, T.S., Barch, D.M., Carter, C.S., and Cohen, J.D.
(2001). Conflict monitoring and cognitive control. Psychol. Rev. 108, 624–652.
Brady, K.T., and Sinha, R. (2005). Co-occurring mental and substance use
disorders: The neurobiological effects of chronic stress. Am. J. Psychiatry
162, 1483–1493.
Brauer, L.H., and De Wit, H. (1997). High dose pimozide does not block
amphetamine-induced euphoria in normal volunteers. Pharmacol. Biochem.
Behav. 56, 265–272.
Brewer, J.A., Worhunsky, P.D., Carroll, K.M., Rounsaville, B.J., and Potenza,
M.N. (2008a). Pretreatment brain activation during stroop task is associated
with outcomes in cocaine-dependent patients. Biol. Psychiatry 64, 998–1004.
Brewer, J.A., Grant, J.E., and Potenza, M.N. (2008b). The treatment of patho-
logic gambling. Addict. Disorders Treatment 7, 1–14.
Brewer, J.A., and Potenza, M.N. (2008). The neurobiology and genetics of
impulse control disorders: Relationships to drug addictions. Biochem. Phar-
macol. 75, 63–75.
Brewer, J.A., Sinha, R., Chen, J.A., Michalsen, R.N., Babuscio, T.A., Nich, C.,
Grier, A., Bergquist, K.L., Reis, D.L., Potenza, M.N., et al. (2009). Mindfulness
Neuron
Review
training reduces stress reactivity and relapse in substance abuse: Results from
a randomized, controlled pilot study. Subst. Abus. 30, 306–317.
Brewer, J.A., Bowen, S., Smith, J.T., Marlatt, G.A., and Potenza, M.N. (2010).
Mindfulness-based treatments for co-occurring depression and substance
use disorders: What can we learn from the brain? Addiction 105, 1698–1706.
Buckholtz, J.W., Treadway, M.T., Cowan, R.L., Woodward, N.D., Li, R., Ansari,
M.S., Baldwin, R.M., Schwartzman, A.N., Shelby, E.S., Smith, C.E., et al.
(2010). Dopaminergic network differences in human impulsivity. Science
329, 532.
Burke, B.L., Arkowitz, H., and Menchola, M. (2003). The efficacy of motiva-
tional interviewing: A meta-analysis of controlled clinical trials. J. Consult.
Clin. Psychol. 71, 843–861.
Bush, G., Luu, P., and Posner, M.I. (2000). Cognitive and emotional influences
in anterior cingulate cortex. Trends Cogn. Sci. (Regul. Ed.) 4, 215–222.
Bush, G., Vogt, B.A., Holmes, J., Dale, A.M., Greve, D., Jenike, M.A., and
Rosen, B.R. (2002). Dorsal anterior cingulate cortex: A role in reward-based
decision making. Proc. Natl. Acad. Sci. USA 99, 523–528.
Bymaster, F.P., Katner, J.S., Nelson, D.L., Hemrick-Luecke, S.K., Threlkeld,
P.G., Heiligenstein, J.H., Morin, S.M., Gehlert, D.R., and Perry, K.W. (2002).
Atomoxetine increases extracellular levels of norepinephrine and dopamine
in prefrontal cortex of rat: A potential mechanism for efficacy in attention
deficit/hyperactivity disorder. Neuropsychopharmacology 27, 699–711.
Cahill, K.M., Stead, L.F., and Lancaster, T. (2010). Nicotine receptor partial
agonists for smoking cessation. Cochrane Database Syst. Rev. 12, CD006103.
Carroll, K.M., Connors, G.J., Cooney, N.L., DiClemente, C.C., Donovan, D.M.,
Kadden, R.R., Longabaugh, R.L., Rounsaville, B.J., Wirtz, P.W., and Zweben,
A. (1998). A Cognitive Behavioral Approach: Treating Cocaine Addiction
(Rockville, MD: NIDA).
Carroll, K.M., Kosten, T.R., and Rounsaville, B.J. (2004). Choosing a behavioral
therapy platform for pharmacotherapy of substance users. Drug Alcohol
Depend. 75, 123–134.
Carroll, K.M., Ball, S.A., Martino, S., Nich, C., Babuscio, T.A., Nuro, K.F.,
Gordon, M.A., Portnoy, G.A., and Rounsaville, B.J. (2008). Computer-assisted
delivery of cognitive-behavioral therapy for addiction: A randomized trial of
CBT4CBT. Am. J. Psychiatry 165, 881–888.
Carroll, K.M., Ball, S.A., Martino, S., Nich, C., Babuscio, T.A., and Rounsaville,
B.J. (2009). Enduring effects of a computer-assisted training program for
cognitive behavioral therapy: A 6-month follow-up of CBT4CBT. Drug Alcohol
Depend. 100, 178–181.
Carroll, K.M., and Onken, L.S. (2005). Behavioral therapies for drug abuse. Am.
J. Psychiatry 162, 1452–1460.
Carroll, K.M., Rounsaville, B.J., Nich, C., Gordon, L.T., Wirtz, P.W., and Gawin,
F.H. (1994). One-year follow-up of psychotherapy and pharmacotherapy for
cocaine dependence. Delayed emergence of psychotherapy effects. Arch.
Gen. Psychiatry 51, 989–997.
Casey, B.J., Duhoux, S., and Malter Cohen, M. (2010). Adolescence: What
do transmission, transition, and translation have to do with it? Neuron 67,
749–760.
Chamberlain, S.R., Del Campo, N., Dowson, J., Müller, U., Clark, L., Robbins,
T.W., and Sahakian, B.J. (2007). Atomoxetine improved response inhibition
in adults with attention deficit/hyperactivity disorder. Biol. Psychiatry 62,
977–984.
Chamberlain, S.R., Hampshire, A., Müller, U., Rubia, K., Del Campo, N., Craig,
K., Regenthal, R., Suckling, J., Roiser, J.P., Grant, J.E., et al. (2009).
Atomoxetine modulates right inferior frontal activation during inhibitory
control: A pharmacological functional magnetic resonance imaging study.
Biol. Psychiatry 65, 550–555.
Chambers, R.A., Krystal, J.H., and Self, D.W. (2001). A neurobiological basis
for substance abuse comorbidity in schizophrenia. Biol. Psychiatry 50, 71–83.
Chambers, R.A., Bickel, W.K., and Potenza, M.N. (2007). A scale-free systems
theory of motivation and addiction. Neurosci. Biobehav. Rev. 31, 1017–1045.
Chambers, R.A., Taylor, J.R., and Potenza, M.N. (2003). Developmental
neurocircuitry of motivation in adolescence: A critical period of addiction
vulnerability. Am. J. Psychiatry 160, 1041–1052.
Chen, B.T., Hopf, F.W., and Bonci, A. (2010). Synaptic plasticity in the meso-
limbic system: Therapeutic implications for substance abuse. Ann. N Y Acad.
Sci. 1187, 129–139.
Cheon, Y., Park, J., Joe, K.-H., and Kim, D.-J. (2008). The effect of 12-week
open-label memantine treatment on cognitive function improvement in
patients with alcohol-related dementia. Int. J. Neuropsychopharmacol. 11,
971–983.
Childress, A.R., Mozley, P.D., McElgin, W., Fitzgerald, J., Reivich, M., and
O’Brien, C.P. (1999). Limbic activation during cue-induced cocaine craving.
Am. J. Psychiatry 156, 11–18.
Costello, M.R., Mandelkern, M.A., Shoptaw, S., Shulenberger, S., Baker, S.K.,
Abrams, A.L., Xia, C., London, E.D., and Brody, A.L. (2010). Effects of treat-
ment for tobacco dependence on resting cerebral glucose metabolism.
Neuropsychopharmacology 35, 605–612.
Culbertson, C.S., Bramen, J., Cohen, M.S., London, E.D., Olmstead, R.E.,
Gan, J.J., Costello, M.R., Shulenberger, S., Mandelkern, M.A., and Brody,
A.L. (2011). Effect of bupropion treatment on brain activation induced by ciga-
rette-related cues in smokers. Arch. Gen. Psychiatry, in press. Published
online January 3, 2011. 10.1001/archgenpsychiatry.2010.193.
Cutler, R.B., and Fishbein, D.A. (2005). Are alcoholism treatments effective?
The Project MATCH data. BMC Public Health 5, 75.
Dackis, C.A., Kampman, K.M., Lynch, K.G., Pettinati, H.M., and O’Brien, C.P.
(2005). A double-blind, placebo-controlled trial of modafinil for cocaine depen-
dence. Neuropsychopharmacology 30, 205–211.
Dalley, J.W., and Everitt, B.J. (2009). Dopamine receptors in the learning,
memory and drug reward circuitry. Semin. Cell Dev. Biol. 20, 403–410.
Dalley, J.W., Everitt, B.J., and Robbins, T.W. (2011). Impulsivity, compulsivity,
and top-down cognitive control. Neuron 69, this issue, 680–694.
Dalley, J.W., Fryer, T.D., Brichard, L., Robinson, E.S.J., Theobald, D.E.H.,
Lääne, K., Peña, Y., Murphy, E.R., Shah, Y., Probst, K., et al. (2007). Nucleus
accumbens D2/3 receptors predict trait impulsivity and cocaine reinforce-
ment. Science 315, 1267–1270.
Danaei, G., Ding, E.L., Mozaffarian, D., Taylor, B., Rehm, J., Murray, C.J.L.,
and Ezzati, M. (2009). The preventable causes of death in the United States:
Comparative risk assessment of dietary, lifestyle, and metabolic risk factors.
PLoS Med. 6, e1000058.
de Wit, H. (2009). Impulsivity as a determinant and consequence of drug use:
A review of underlying processes. Addict. Biol. 14, 22–31.
deCharms, R.C. (2008). Applications of real-time fMRI. Nat. Rev. Neurosci. 9,
720–729.
DeRubeis, R.J., Gelfand, L.A., Tang, T.Z., and Simons, A.D. (1999). Medica-
tions versus cognitive behavior therapy for severely depressed outpatients:
Mega-analysis of four randomized comparisons. Am. J. Psychiatry 156,
1007–1013.
DeRubeis, R.J., Siegle, G.J., and Hollon, S.D. (2008). Cognitive therapy versus
medication for depression: Treatment outcomes and neural mechanisms.
Nat. Rev. Neurosci. 9, 788–796.
Dutra, L., Stathopoulou, G., Basden, S.L., Leyro, T.M., Powers, M.B., and Otto,
M.W. (2008). A meta-analytic review of psychosocial interventions for
substance use disorders. Am. J. Psychiatry 165, 179–187.
Economidou, D., Dalley, J.W., and Everitt, B.J. (2011). Selective norepineph-
rine reuptake inhibition by atomoxetine prevents cue-induced heroin and
cocaine seeking. Biol. Psychiatry 69, 266–274.
Edwards, S., and Koob, G.F. (2010). Neurobiology of dysregulated motiva-
tional systems in drug addiction. Future Neurol. 5, 393–401.
Eisenberg, M.J., Filion, K.B., Yavin, D., Bélisle, P., Mottillo, S., Joseph, L.,
Gervais, A., O’Loughlin, J., Paradis, G., Rinfret, S., and Pilote, L. (2008).
Pharmacotherapies for smoking cessation: A meta-analysis of randomized
controlled trials. CMAJ 179, 135–144.
Neuron 69, February 24, 2011 ª2011 Elsevier Inc. 707

Ersche, K.D., Fletcher, P.C., Roiser, J.P., Fryer, T.D., London, M., Robbins,
T.W., and Sahakian, B.J. (2006). Differences in orbitofrontal activation during
decision-making between methadone-maintained opiate users, heroin users
and healthy volunteers. Psychopharmacology (Berl.) 188, 364–373.
Ersche, K.D., and Sahakian, B.J. (2007). The neuropsychology of amphet-
amine and opiate dependence: Implications for treatment. Neuropsychol.
Rev. 17, 317–336.
Evans, S.M., Levin, F.R., Brooks, D.J., and Garawi, F. (2007). A pilot double-
blind treatment trial of memantine for alcohol dependence. Alcohol. Clin.
Exp. Res. 31, 775–782.
Everitt, B.J., and Robbins, T.W. (2005). Neural systems of reinforcement for
drug addiction: From actions to habits to compulsion. Nat. Neurosci. 8,
1481–1489.
Faraone, S.V., Biederman, J., Spencer, T., Michelson, D., Adler, L., Reimherr,
F., and Seidman, L. (2005). Atomoxetine and stroop task performance in adult
attention-deficit/hyperactivity disorder. J. Child Adolesc. Psychopharmacol.
15, 664–670.
Fineberg, N.A., Potenza, M.N., Chamberlain, S.R., Berlin, H.A., Menzies, L.,
Bechara, A., Sahakian, B.J., Robbins, T.W., Bullmore, E.T., and Hollander,
E. (2010). Probing compulsive and impulsive behaviors, from animal models
to endophenotypes: A narrative review. Neuropsychopharmacology 35,
591–604.
Fiore, M.C., Jaen, C.R., Baker, T.B., Bailey, W.C., Benowitz, N.L., Curry, S.J.,
Dorfman, S.F., Froelicher, E.S., Goldstein, M.G., Healton, C.G., et al. (2008).
Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice
Guidelines (Rockville, MD: U.S. Department of Health and Human Services.
Public Health Service).
Fong, T., Kalechstein, A., Bernhard, B., Rosenthal, R., and Rugle, L. (2008). A
double-blind, placebo-controlled trial of olanzapine for the treatment of video
poker pathological gamblers. Pharmacol. Biochem. Behav. 89, 298–303.
Frascella, J., Potenza, M.N., Brown, L.L., and Childress, A.R. (2010). Shared
brain vulnerabilities open the way for nonsubstance addictions: Carving addic-
tion at a new joint? Ann. N. Y. Acad. Sci. 1187, 294–315.
Frewen, P.A., Dozois, D.J., and Lanius, R.A. (2008). Neuroimaging studies of
psychological interventions for mood and anxiety disorders: Empirical and
methodological review. Clin. Psychol. Rev. 28, 228–246.
George, O., and Koob, G.F. (2010). Individual differences in prefrontal cortex
function and the transition from drug use to drug dependence. Neurosci.
Biobehav. Rev. 35, 232–247.
George, T.P., Vessicchio, J.C., Termine, A., Bregartner, T.A., Feingold, A.,
Rounsaville, B.J., and Kosten, T.R. (2002). A placebo controlled trial of bupro-
pion for smoking cessation in schizophrenia. Biol. Psychiatry 52, 53–61.
Ghahremani, D.G., Tabibnia, G., Monterosso, J., Hellemann, G., Poldrack,
R.A., and London, E.D. (2011). Effect of modafinil on learning and task-related
brain activity in methamphetamine-dependent and healthy individuals.
Neuropsychopharmacology, in press. Published online February 2, 2011.
10.1038/npp.2010.233.
Giacobini, E. (2004). Cholinesterase inhibitors: New roles and therapeutic
alternatives. Pharmacol. Res. 50, 433–440.
Glimcher, P.W., and Rustichini, A. (2004). Neuroeconomics: The consilience of
brain and decision. Science 306, 447–452.
Goldapple, K., Segal, Z., Garson, C., Lau, M., Bieling, P., Kennedy, S., and
Mayberg, H. (2004). Modulation of cortical-limbic pathways in major depres-
sion: Treatment specific effects of cognitive behavioral therapy compared to
paroxetine. Arch. Gen. Psychiatry 61, 34–41.
Goldman, D., Oroszi, G., and Ducci, F. (2005). The genetics of addictions:
Uncovering the genes. Nat. Rev. Genet. 6, 521–532.
Goldstein, R.Z., and Volkow, N.D. (2002). Drug addiction and its underlying
neurobiological basis: Neuroimaging evidence for the involvement of the
frontal cortex. Am. J. Psychiatry 159, 1642–1652.
Gottesman, I.I., and Gould, T.D. (2003). The endophenotype concept
in psychiatry: Etymology and strategic intentions. Am. J. Psychiatry 160,
636–645.
708 Neuron 69, February 24, 2011 ª2011 Elsevier Inc.
Neuron
Review
Grabowski, J., Rhoades, H., Stotts, A., Cowan, K., Kopecky, C., Dougherty, A.,
Moeller, F.G., Hassan, S., and Schmitz, J. (2004). Agonist-like or antagonist-
like treatment for cocaine dependence with methadone for heroin depen-
dence: Two double-blind randomized clinical trials. Neuropsychopharmacol-
ogy 29, 969–981.
Grant, J.E., Kim, S.W., Hollander, E., and Potenza, M.N. (2008). Predicting
response to opiate antagonists and placebo in the treatment of pathological
gambling. Psychopharmacology (Berl.) 200, 521–527.
Grant, J.E., Donahue, C.B., Odlaug, B.L., Kim, S.W., Miller, M.J., and Petry,
N.M. (2009). Imaginal desensitisation plus motivational interviewing for patho-
logical gambling: A randomised controlled trial. Br. J. Psychol. 195, 266–267.
Grant, J.E., Kim, S.W., and Odlaug, B.L. (2007). N-acetyl cysteine, a gluta-
mate-modulating agent, in the treatment of pathological gambling: A pilot
study. Biol. Psychiatry 62, 652–657.
Grant, J.E., Chamberlain, S.R., Odlaug, B.L., Potenza, M.N., and Kim, S.W.
(2010). Memantine shows promise in reducing gambling severity and cognitive
inflexibility in pathological gambling: A pilot study. Psychopharmacology
(Berl.) 212, 603–612.
Grant, J.E., Potenza, M.N., Weinstein, A., and Gorelick, D.A. (2010b). Introduc-
tion to behavioral addictions. Am. J. Drug Alcohol Abuse 36, 233–241.
Grohman, K., Fals-Stewart, W., and Donnelly, K. (2006). Improving treatment
response of cognitively impaired veterans with neuropsychological rehabilita-
tion. Brain Cogn. 60, 203–204.
Gual, A., and Lehert, P. (2001). Acamprosate during and after acute alcohol
withdrawal: A double-blind placebo-controlled study in Spain. Alcohol
Alcohol. 36, 413–418.
Haber, S.N., and Knutson, B. (2010). The reward circuit: Linking primate
anatomy and human imaging. Neuropsychopharmacology 35, 4–26.
Hall, S.M., Humfleet, G.L., Reus, V.I., Muñoz, R.F., Hartz, D.T., and Maude-
Griffin, R. (2002). Psychological intervention and antidepressant treatment in
smoking cessation. Arch. Gen. Psychiatry 59, 930–936.
Haney, M., Gunderson, E.W., Jiang, H., Collins, E.D., and Foltin, R.W. (2010).
Cocaine-specific antibodies blunt the subjective effects of smoked cocaine in
humans. Biol. Psychiatry 67, 59–65.
Haney, M., Ward, A.S., Foltin, R.W., and Fischman, M.W. (2001). Effects of
ecopipam, a selective dopamine D1 antagonist, on smoked cocaine self-
administration by humans. Psychopharmacology (Berl.) 155, 330–337.
Harsan, L.A., Steibel, J., Zaremba, A., Agin, A., Sapin, R., Poulet, P., Guignard,
B., Parizel, N., Grucker, D., Boehm, N., et al. (2008). Recovery from chronic
demyelination by thyroid hormone therapy: Myelinogenesis induction and
assessment by diffusion tensor magnetic resonance imaging. J. Neurosci.
28, 14189–14201.
Hasin, D.S., Stinson, F.S., Ogburn, E., and Grant, B.F. (2007). Prevalence,
correlates, disability, and comorbidity of DSM-IV alcohol abuse and depen-
dence in the United States: Results from the National Epidemiologic Survey
on Alcohol and Related Conditions. Arch. Gen. Psychiatry 64, 830–842.
Havassy, B.E., Alvidrez, J., and Owen, K.K. (2004). Comparisons of patients
with comorbid psychiatric and substance use disorders: Implications for treat-
ment and service delivery. Am. J. Psychiatry 161, 139–145.
Heidbreder, C.A., and Newman, A.H. (2010). Current perspectives on selective
dopamine D(3) receptor antagonists as pharmacotherapeutics for addictions
and related disorders. Ann. N. Y. Acad. Sci. 1187, 4–34.
Herin, D.V., Rush, C.R., and Grabowski, J. (2010). Agonist-like pharmaco-
therapy for stimulant dependence: Preclinical, human laboratory, and clinical
studies. Ann. N. Y. Acad. Sci. 1187, 76–100.
Higgins, S.T., Delaney, D.D., Budney, A.J., Bickel, W.K., Hughes, J.R., Foerg,
F., and Fenwick, J.W. (1991). A behavioral approach to achieving initial
cocaine abstinence. Am. J. Psychiatry 148, 1218–1224.
Highfield, D., Yap, J., Grimm, J.W., Shalev, U., and Shaham, Y. (2001).
Repeated lofexidine treatment attenuates stress-induced, but not drug
cues-induced reinstatement of a heroin-cocaine mixture (speedball) seeking
in rats. Neuropsychopharmacology 25, 320–331.
Neuron
Review
Hogarty, G.E., Flesher, S., Ulrich, R., Carter, M., Greenwald, D., Pogue-Geile,
M., Kechavan, M., Cooley, S., DiBarry, A.L., Garrett, A., et al. (2004). Cognitive
enhancement therapy for schizophrenia: Effects of a 2-year randomized trial
on cognition and behavior. Arch. Gen. Psychiatry 61, 866–876.
Holden, C. (2001). ‘Behavioral’ addictions: Do they exist? Science 294,
980–982.
Holden, C. (2010). Psychiatry. Behavioral addictions debut in proposed
DSM-V. Science 327, 935.
Horder, J., Harmer, C.J., Cowen, P.J., and McCabe, C. (2010). Reduced neural
response to reward following 7 days treatment with the cannabinoid CB(1)
antagonist rimonabant in healthy volunteers. Int. J. Neuropsychopharmacol.
13, 1103–1113.
Hu, J., Henry, S., Gallezot, J.-D., Ropchan, J., Neumaier, J.F., Potenza, M.N.,
Sinha, R., Krystal, J.H., Huang, Y., Ding, Y.-S., et al. (2010). Serotonin 1B
receptor imaging in alcohol dependence. Biol. Psychiatry 67, 800–803.
Irvin, J.E., Bowers, C.A., Dunn, M.E., and Wang, M.C. (1999). Efficacy of
relapse prevention: A meta-analytic review. J. Consult. Clin. Psychol. 67,
563–570.
Janes, A.C., Pizzagalli, D.A., Richardt, S., deB Frederick, B., Chuzi, S., Pachas,
G., Culhane, M.A., Holmes, A.J., Fava, M., Evins, A.E., and Kaufman, M.J.
(2010). Brain reactivity to smoking cues prior to smoking cessation predicts
ability to maintain tobacco abstinence. Biol. Psychiatry 67, 722–729.
Jentsch, J.D., Aarde, S.M., and Seu, E. (2009). Effects of atomoxetine and
methylphenidate on performance of a lateralized reaction time task in rats.
Psychopharmacology (Berl.) 202, 497–504.
Johansson, B.A., Berglund, M., and Lindgren, A. (2006). Efficacy of mainte-
nance treatment with naltrexone for opioid dependence: A meta-analytical
review. Addiction 101, 491–503.
Johnson, B.A., Javors, M.A., Roache, J.D., Seneviratne, C., Bergeson, S.E.,
Ait-Daoud, N., Dawes, M.A., and Ma, J.Z. (2008). Can serotonin transporter
genotype predict serotonergic function, chronicity, and severity of drinking?
Prog. Neuropsychopharmacol. Biol. Psychiatry 32, 209–216.
Johnson, M.W., Bickel, W.K., and Baker, F. (2007). Moderate drug use and
delay discounting: A comparison of heavy, light, and never smokers. Exp.
Clin. Psychopharmacol. 15, 187–194.
Johnson, M.W., Bickel, W.K., Baker, F., Moore, B.A., Badger, G.J., and Bud-
ney, A.J. (2010). Delay discounting in current and former marijuana-dependent
individuals. Exp. Clin. Psychopharmacol. 18, 99–107.
Kable, J.W., and Glimcher, P.W. (2007). The neural correlates of subjective
value during intertemporal choice. Nat. Neurosci. 10, 1625–1633.
Kampman, K.M., Dackis, C., Lynch, K.G., Pettinati, H., Tirado, C., Gariti, P.,
Sparkman, T., Atzram, M., and O’Brien, C.P. (2006). A double-blind,
placebo-controlled trial of amantadine, propranolol, and their combination
for the treatment of cocaine dependence in patients with severe cocaine with-
drawal symptoms. Drug Alcohol Depend. 85, 129–137.
Kenny, P.J. (2011). Reward mechanisms in obesity: New insights and future
directions. Neuron 69, this issue, 664–679.
Kessler, R.C., Chiu, W.T., Demler, O., Merikangas, K.R., and Walters, E.E.
(2005). Prevalence, severity, and comorbidity of 12-month DSM-IV disorders
in the National Comorbidity Survey Replication. Arch. Gen. Psychiatry 62,
617–627.
Kim, C.H., Hahn, M.K., Joung, Y., Anderson, S.L., Steele, A.H., Mazei-Robin-
son, M.S., Gizer, I., Teicher, M.H., Cohen, B.M., Robertson, D., et al. (2006). A
polymorphism in the norepinephrine transporter gene alters promoter activity
and is associated with attention-deficit hyperactivity disorder. Proc. Natl.
Acad. Sci. USA 103, 19164–19169.
Knackstedt, L.A., LaRowe, S., Mardikian, P., Malcolm, R., Upadhyaya, H.,
Hedden, S., Markou, A., and Kalivas, P.W. (2009). The role of cystine-gluta-
mate exchange in nicotine dependence in rats and humans. Biol. Psychiatry
65, 841–845.
Knutson, B., and Greer, S.M. (2008). Anticipatory affect: Neural correlates
and consequences for choice. Philos. Trans. R. Soc. Lond. B Biol. Sci. 363,
3771–3786.
Kober, H., Mende-Siedlecki, P., Kross, E.F., Weber, J., Mischel, W., Hart, C.L.,
and Ochsner, K.N. (2010). Prefrontal-striatal pathway underlies cognitive regu-
lation of craving. Proc. Natl. Acad. Sci. USA 107, 14811–14816.
Koob, G.F., and Le Moal, M. (2001). Drug addiction, dysregulation of reward,
and allostasis. Neuropsychopharmacology 24, 97–129.
Koob, G.F., and Le Moal, M. (2005). Plasticity of reward neurocircuitry and the
‘dark side’ of drug addiction. Nat. Neurosci. 8, 1442–1444.
Koob, G.F., and Volkow, N.D. (2010). Neurocircuitry of addiction. Neuropsy-
chopharmacology 35, 217–238.
Koob, G.F., and Zorrilla, E.P. (2010). Neurobiological mechanisms of addic-
tion: Focus on corticotropin-releasing factor. Curr. Opin. Investig. Drugs 11,
63–71.
Kosten, T., Oliveto, A., Feingold, A., Poling, J., Sevarino, K., McCance-Katz, E.,
Stine, S., Gonzalez, G., and Gonsai, K. (2003). Desipramine and contingency
management for cocaine and opiate dependence in buprenorphine main-
tained patients. Drug Alcohol Depend. 70, 315–325.
Kosten, T.R., Scanley, B.E., Tucker, K.A., Oliveto, A., Prince, C., Sinha, R.,
Potenza, M.N., Skudlarski, P., and Wexler, B.E. (2006). Cue-induced brain
activity changes and relapse in cocaine-dependent patients. Neuropsycho-
pharmacology 31, 644–650.
Kreek, M.J., Nielsen, D.A., Butelman, E.R., and LaForge, K.S. (2005). Genetic
influences on impulsivity, risk taking, stress responsivity and vulnerability to
drug abuse and addiction. Nat. Neurosci. 8, 1450–1457.
Krishnan-Sarin, S., Reynolds, B., Duhig, A.M., Smith, A., Liss, T., McFetridge,
A., Cavallo, D.A., Carroll, K.M., and Potenza, M.N. (2007). Behavioral impul-
sivity predicts treatment outcome in a smoking cessation program for adoles-
cent smokers. Drug Alcohol Depend. 88, 79–82.
Krupitsky, E.M., Neznanova, O., Masalov, D., Burakov, A.M., Didenko, T.,
Romanova, T., Tsoy, M., Bespalov, A., Slavina, T.Y., Grinenko, A.A., et al.
(2007). Effect of memantine on cue-induced alcohol craving in recovering
alcohol-dependent patients. Am. J. Psychiatry 164, 519–523.
Lajtha, A., and Sershen, H. (2010). Heterogeneity of reward mechanisms.
Neurochem. Res. 35, 851–867.
Lane, S.D., Steinberg, J.L., Ma, L., Hasan, K.M., Kramer, L.A., Zuniga, E.A.,
Narayana, P.A., and Moeller, F.G. (2010). Diffusion tensor imaging and deci-
sion making in cocaine dependence. PLoS ONE 5, e11591.
Laucht, M., Treutlein, J., Schmid, B., Blomeyer, D., Becker, K., Buchmann,
A.F., Schmidt, M.H., Esser, G., Jennen-Steinmetz, C., Rietschel, M., et al.
(2009). Impact of psychosocial adversity on alcohol intake in young adults:
Moderation by the LL genotype of the serotonin transporter polymorphism.
Biol. Psychiatry 66, 102–109.
Lawrence, A.J., Luty, J., Bogdan, N.A., Sahakian, B.J., and Clark, L. (2009).
Problem gamblers share deficits in impulsive decision-making with alcohol-
dependent individuals. Addiction 104, 1006–1015.
Le Moal, M. (2009). Drug abuse: Vulnerability and transition to addiction. Phar-
macopsychiatry 42 (Suppl 1 ), S42–S55.
Lehrer, J. (2009). DON’T! The secret of self-control. The New Yorker, pp. 26-
32. http://www.newyorker.com/reporting/2009/05/18/090518fa_fact_lehrer.
LeSage, M.G., Keyler, D.E., and Pentel, P.R. (2006). Current status of immuno-
logic approaches to treating tobacco dependence: Vaccines and nicotine-
specific antibodies. AAPS J. 8, E65–E75.
Lewis, C.M., Baldassarre, A., Committeri, G., Romani, G.L., and Corbetta, M.
(2009). Learning sculpts the spontaneous activity of the resting human brain.
Proc. Natl. Acad. Sci. USA 106, 17558–17563.
Leyton, M., Boileau, I., Benkelfat, C., Diksic, M., Baker, G., and Dagher, A.
(2002). Amphetamine-induced increases in extracellular dopamine, drug
wanting, and novelty seeking: A PET/[11C]raclopride study in healthy men.
Neuropsychopharmacology 27, 1027–1035.
Leyton, M., Casey, K.F., Delaney, J.S., Kolivakis, T., and Benkelfat, C. (2005).
Cocaine craving, euphoria, and self-administration: A preliminary study of
the effect of catecholamine precursor depletion. Behav. Neurosci. 119,
1619–1627.
Neuron 69, February 24, 2011 ª2011 Elsevier Inc. 709

Li, C.S.R., Milivojevic, V., Kemp, K.A., Hong, K., and Sinha, R. (2006).
Performance monitoring and stop signal inhibition in abstinent patients with
cocaine dependence. Drug Alcohol Depend. 85, 205–212.
Li, N., Lee, B., Liu, R.J., Banasr, M., Dwyer, J.M., Iwata, M., Li, X.Y., Aghaja-
nian, G., and Duman, R.S. (2010). mTOR-dependent synapse formation
underlies the rapid antidepressant effects of NMDA antagonists. Science
329, 959–964.
Liechti, M.E., Lhuillier, L., Kaupmann, K., and Markou, A. (2007). Metabotropic
glutamate 2/3 receptors in the ventral tegmental area and the nucleus
accumbens shell are involved in behaviors relating to nicotine dependence.
J. Neurosci. 27, 9077–9085.
Lim, K.O., Choi, S.J., Pomara, N., Wolkin, A., and Rotrosen, J.P. (2002).
Reduced frontal white matter integrity in cocaine dependence: A controlled
diffusion tensor imaging study. Biol. Psychiatry 51, 890–895.
Lim, K.O., Wozniak, J.R., Mueller, B.A., Franc, D.T., Specker, S.M., Rodriguez,
C.P., Silverman, A.B., and Rotrosen, J.P. (2008). Brain macrostructural and
microstructural abnormalities in cocaine dependence. Drug Alcohol Depend.
92, 164–172.
Longo, M., Wickes, W., Smout, M., Harrison, S., Cahill, S., and White, J.M.
(2010). Randomized controlled trial of dexamphetamine maintenance for the
treatment of methamphetamine dependence. Addiction 105, 146–154.
Lussier, J.P., Heil, S.H., Mongeon, J.A., Badger, G.J., and Higgins, S.T. (2006).
A meta-analysis of voucher-based reinforcement therapy for substance use
disorders. Addiction 101, 192–203.
Maddux, J.F., and Desmond, D.P. (2000). Addiction or dependence? Addic-
tion 95, 661–665.
Magill, M., and Ray, L.A. (2009). Cognitive-behavioral treatment with adult
alcohol and illicit drug users: A meta-analysis of randomized controlled trials.
J. Stud. Alcohol Drugs 70, 516–527.
Mann, K. (2004). Pharmacotherapy of alcohol dependence: A review of the
clinical data. CNS Drugs 18, 485–504.
Mardikian, P.N., LaRowe, S.D., Hedden, S., Kalivas, P.W., and Malcolm, R.J.
(2007). An open-label trial of N-acetylcysteine for the treatment of cocaine
dependence: A pilot study. Prog. Neuropsychopharmacol. Biol. Psychiatry
31, 389–394.
Martell, B.A., Mitchell, E., Poling, J., Gonsai, K., and Kosten, T.R. (2005).
Vaccine pharmacotherapy for the treatment of cocaine dependence. Biol.
Psychiatry 58, 158–164.
Martell, B.A., Orson, F.M., Poling, J., Mitchell, E., Rossen, R.D., Gardner, T.,
and Kosten, T.R. (2009). Cocaine vaccine for the treatment of cocaine depen-
dence in methadone-maintained patients: A randomized, double-blind,
placebo-controlled efficacy trial. Arch. Gen. Psychiatry 66, 1116–1123.
Martelle, J.L., Claytor, R., Ross, J.T., Reboussin, B.A., Newman, A.H., and
Nader, M.A. (2007). Effects of two novel D3-selective compounds,
NGB 2904 [N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-9H-fluorene-2-
carboxamide] and CJB 090 [N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)
butyl)-4-(pyridin-2-yl)benzamide], on the reinforcing and discriminative stim-
ulus effects of cocaine in rhesus monkeys. J. Pharmacol. Exp. Ther. 321,
573–582.
Martı́nez-Raga, J., Knecht, C., and Cepeda, S. (2008). Modafinil: A useful
medication for cocaine addiction? Review of the evidence from neuropharma-
cological, experimental and clinical studies. Curr Drug Abuse Rev 1, 213–221.
Mason, B.J., and Heyser, C.J. (2010). The neurobiology, clinical efficacy and
safety of acamprosate in the treatment of alcohol dependence. Expert Opin.
Drug Saf. 9, 177–188.
Mattick, R.P., Breen, C., Kimber, J., and Davoli, M. (2003). Methadone main-
tenance therapy versus no opioid replacement therapy for opioid dependence.
Cochrane Database Syst. Rev., CD002209.
Mattick, R.P., Kimber, J., Breen, C., and Davoli, M. (2004). Buprenorphine
maintenance versus placebo or methadone maintenance for opioid depen-
dence. Cochrane Database Syst. Rev., CD002207.
710 Neuron 69, February 24, 2011 ª2011 Elsevier Inc.
Neuron
Review
McClure, S.M., Laibson, D.I., Loewenstein, G., and Cohen, J.D. (2004).
Separate neural systems value immediate and delayed monetary rewards.
Science 306, 503–507.
McLellan, A.T., Arndt, I.O., Metzger, D.S., Woody, G.E., and O’Brien, C.P.
(1993). The effects of psychosocial services in substance abuse treatment.
JAMA 269, 1953–1959.
Meda, S.A., Stevens, M.C., Potenza, M.N., Pittman, B., Gueorguieva, R.,
Andrews, M.M., Thomas, A.D., Muska, C., Hylton, J.L., and Pearlson, G.D.
(2009). Investigating the behavioral and self-report constructs of impulsivity
domains using principal component analysis. Behav. Pharmacol. 20, 390–399.
Miller, W.R., and Rollnick, S. (2002). Motivational Interviewing: Preparing
People for Change, Second Edition (New York, NY: Guilford Press).
Mischel, W., Shoda, Y., and Rodriguez, M.I. (1989). Delay of gratification in
children. Science 244, 933–938.
Moeller, F.G., Barratt, E.S., Dougherty, D.M., Schmitz, J.M., and Swann, A.C.
(2001). Psychiatric aspects of impulsivity. Am. J. Psychiatry 158, 1783–1793.
Moeller, F.G., Hasan, K.M., Steinberg, J.L., Kramer, L.A., Dougherty, D.M.,
Santos, R.M., Valdes, I., Swann, A.C., Barratt, E.S., and Narayana, P.A.
(2005). Reduced anterior corpus callosum white matter integrity is related to
increased impulsivity and reduced discriminability in cocaine-dependent
subjects: Diffusion tensor imaging. Neuropsychopharmacology 30, 610–617.
Moeller, F.G., Hasan, K.M., Steinberg, J.L., Kramer, L.A., Valdes, I., Lai, L.Y.,
Swann, A.C., and Narayana, P.A. (2007). Diffusion tensor imaging eigenvalues:
Preliminary evidence for altered myelin in cocaine dependence. Psychiatry
Res. 154, 253–258.
Moll, J., Zahn, R., de Oliveira-Souza, R., Krueger, F., and Grafman, J. (2005).
Opinion: The neural basis of human moral cognition. Nat. Rev. Neurosci. 6,
799–809.
Monterosso, J.R., Aron, A.R., Cordova, X., Xu, J., and London, E.D. (2005).
Deficits in response inhibition associated with chronic methamphetamine
abuse. Drug Alcohol Depend. 79, 273–277.
Naqvi, N.H., and Bechara, A. (2009). The hidden island of addiction: The insula.
Trends Neurosci. 32, 56–67.
Nasrallah, N.A., Yang, T.W.H., and Bernstein, I.L. (2009). Long-term risk pref-
erence and suboptimal decision making following adolescent alcohol use.
Proc. Natl. Acad. Sci. USA 106, 17600–17604.
National Institute on Drug Abuse. (2007). Principles of Drug Addiction Treat-
ment: A Research Based Guide (Bethesda, MD: NIDA).
Nunes, E.V., and Levin, F.R. (2004). Treatment of depression in patients with
alcohol or other drug dependence: A meta-analysis. JAMA 291, 1887–1896.
O’Brien, C.P., Volkow, N., and Li, T.K. (2006). What’s in a word? Addiction
versus dependence in DSM-V. Am. J. Psychiatry 163, 764–765.
Olive, M.F. (2010). Cognitive effects of Group I metabotropic glutamate
receptor ligands in the context of drug addiction. Eur. J. Pharmacol. 639,
47–58.
Orson, F.M., Kinsey, B.M., Singh, R.A., Wu, Y., Gardner, T., and Kosten, T.R.
(2008). Substance abuse vaccines. Ann. N Y Acad. Sci. 1141, 257–269.
Oslin, D.W., Berrettini, W., Kranzler, H.R., Pettinati, H., Gelernter, J., Volpicelli,
J.R., and O’Brien, C.P. (2003). A functional polymorphism of the mu-opioid
receptor gene is associated with naltrexone response in alcohol-dependent
patients. Neuropsychopharmacology 28, 1546–1552.
Partilla, J.S., Dempsey, A.G., Nagpal, A.S., Blough, B.E., Baumann, M.H., and
Rothman, R.B. (2006). Interaction of amphetamines and related compounds at
the vesicular monoamine transporter. J. Pharmacol. Exp. Ther. 319, 237–246.
Patterson, F., Jepson, C., Strasser, A.A., Loughead, J., Perkins, K.A., Gur,
R.C., Frey, J.M., Siegel, S., and Lerman, C. (2009). Varenicline improves
mood and cognition during smoking abstinence. Biol. Psychiatry 65, 144–149.
Peirce, J.M., Petry, N.M., Stitzer, M.L., Blaine, J.D., Kellogg, S., Satterfield, F.,
Schwartz, M., Krasnansky, J., Pencer, E., Silva-Vazquez, L., et al. (2006).
Effects of lower-cost incentives on stimulant abstinence in methadone main-
tenance treatment: A National Drug Abuse Treatment Clinical Trials Network
study. Arch. Gen. Psychiatry 63, 201–208.
Neuron
Review
Perry, J.L., and Carroll, M.E. (2008). The role of impulsive behavior in drug
abuse. Psychopharmacology (Berl.) 200, 1–26.
Peterson, B.S., Potenza, M.N., Wang, Z., Zhu, H., Martin, A., Marsh, R., Ples-
sen, K.J., and Yu, S. (2009). An FMRI study of the effects of psychostimulants
on default-mode processing during Stroop task performance in youths with
ADHD. Am. J. Psychiatry 166, 1286–1294.
Petry, N.M. (2001a). Delay discounting of money and alcohol in actively using
alcoholics, currently abstinent alcoholics, and controls. Psychopharmacology
(Berl.) 154, 243–250.
Petry, N.M. (2001b). Pathological gamblers, with and without substance use
disorders, discount delayed rewards at high rates. J. Abnorm. Psychol. 110,
482–487.
Petry, N.M. (2005). Pathological Gambling: Etiology, Comorbidity and Treat-
ment (Washington, DC: American Psychological Association).
Poling, J., Oliveto, A., Petry, N.M., Sofuoglu, M., Gonsai, K., Gonzalez, G.,
Martell, B., and Kosten, T.R. (2006). Six-month trial of bupropion with contin-
gency management for cocaine dependence in a methadone-maintained
population. Arch. Gen. Psychiatry 63, 219–228.
Potenza, M.N., and de Wit, H. (2010). Control yourself: Alcohol and impulsivity.
Alcohol. Clin. Exp. Res. 34, 1303–1305.
Potenza, M.N. (2006). Should addictive disorders include non-substance-
related conditions? Addiction 101 (Suppl 1 ), 142–151.
Potenza, M.N. (2007). Impulse control disorders and co-occurring disorders:
Dual diagnosis considerations. J. Dual Diagn. 3, 47–57.
Potenza, M.N. (2008). Review. The neurobiology of pathological gambling and
drug addiction: An overview and new findings. Philos. Trans. R. Soc. Lond. B
Biol. Sci. 363, 3181–3189.
Potenza, M.N. (2009a). Gambling and morality: A neuropsychiatric perspec-
tive. In Gambling: Mapping the American Moral Landscape, A. Wolfe and
E.C. Owens, eds. (Waco, TX: Baylor University Press), pp. 175–192.
Potenza, M.N. (2009b). Non-substance and substance addictions. Addiction
104, 1016–1017.
Potenza, M.N., Bergquist, K.L., Milovojevic, V., Lacadie, C.M., Rajeevan, N.,
Li, C.S.R., and Sinha, R. (2007). Sex differences in the neural correlates of
stress and craving in cocaine dependence. J. Womens Health (Larchmt) 16,
1108.
Potenza, M.N., Xian, H., Shah, K., Scherrer, J.F., and Eisen, S.A. (2005).
Shared genetic contributions to pathological gambling and major depression
in men. Arch. Gen. Psychiatry 62, 1015–1021.
Ray, L.A., Hutchison, K.E., MacKillop, J., Miranda, R., Jr., Audette, A., Swift,
R., and Monti, P.M. (2008). Effects of naltrexone during the descending limb
of the blood alcohol curve. Am. J. Addict. 17, 257–264.
Reissner, K.J., and Kalivas, P.W. (2010). Using glutamate homeostasis as
a target for treating addictive disorders. Behav. Pharmacol. 21, 514–522.
Renthal, W., and Nestler, E.J. (2008). Epigenetic mechanisms in drug addic-
tion. Trends Mol. Med. 14, 341–350.
Reynolds, B., Ortengren, A., Richards, J.B., and de Wit, H. (2006). Dimensions
of impulsive behavior: Personality and behavioral measures. Personality and
Individual Differences 40, 305–315.
Ritchey, M., Dolcos, F., Eddington, K.M., Strauman, T.J., and Cabeza, R.
(2010). Neural correlates of emotional processing in depression: Changes
with cognitive behavioral therapy and predictors of treatment response.
J. Psychiatr. Res.
Robbins, T.W., and Arnsten, A.F. (2009). The neuropsychopharmacology of
fronto-executive function: Monoaminergic modulation. Annu. Rev. Neurosci.
32, 267–287.
Robinson, T.E., and Berridge, K.C. (1993). The neural basis of drug craving:
An incentive-sensitization theory of addiction. Brain Res. Brain Res. Rev. 18,
247–291.
Robinson, T.E., and Berridge, K.C. (2001). Incentive-sensitization and addic-
tion. Addiction 96, 103–114.
Ross D., Kincaid H., Spurrett D., and Collins P., eds. (2009). What is addiction?
(Cambridge, MA: MIT Press).
Rutherford, H.J.V., Mayes, L.C., and Potenza, M.N. (2010). Neurobiology of
adolescent substance use disorders: Implications for prevention and treat-
ment. Child Adolesc. Psychiatr. Clin. N. Am. 19, 479–492.
Saxena, S., Gorbis, E., O’Neill, J., Baker, S.K., Mandelkern, M.A., Maidment,
K.M., Chang, S., Salamon, N., Brody, A.L., Schwartz, J.M., and London,
E.D. (2009). Rapid effects of brief intensive cognitive-behavioral therapy on
brain glucose metabolism in obsessive-compulsive disorder. Mol. Psychiatry
14, 197–205.
Schilström, B., Ivanov, V.B., Wiker, C., and Svensson, T.H. (2007). Galant-
amine enhances dopaminergic neurotransmission in vivo via allosteric poten-
tiation of nicotinic acetylcholine receptors. Neuropsychopharmacology 32,
43–53.
Schlaug, G., Marchina, S., and Norton, A. (2009). Evidence for plasticity in
white-matter tracts of patients with chronic Broca’s aphasia undergoing
intense intonation-based speech therapy. Ann. N. Y. Acad. Sci. 1169, 385–394.
Schmidt, H.D., and Pierce, R.C. (2010). Cocaine-induced neuroadaptations in
glutamate transmission: Potential therapeutic targets for craving and addic-
tion. Ann. N. Y. Acad. Sci. 1187, 35–75.
Schultz, W. (2010). Dopamine signals for reward value and risk: Basic and
recent data. Behav. Brain Funct. 6, 24.
Schultz, W. (2011). Potential effects of addictive drugs on neuronal reward, risk
and decision mechanisms. Neuron 69, this issue, 603–617.
Seu, E., Lang, A., Rivera, R.J., and Jentsch, J.D. (2009). Inhibition of the norepi-
nephrine transporter improves behavioral flexibility in rats and monkeys.
Psychopharmacology (Berl.) 202, 505–519.
Shaffer, H.J. (1999). Strange bedfellows: A critical view of pathological
gambling and addiction. Addiction 94, 1445–1448.
Shearer, J., Wodak, A., Mattick, R.P., Van Beek, I., Lewis, J., Hall, W., and
Dolan, K. (2001). Pilot randomized controlled study of dexamphetamine
substitution for amphetamine dependence. Addiction 96, 1289–1296.
Shearer, J., Wodak, A., van Beek, I., Mattick, R.P., and Lewis, J. (2003). Pilot
randomized double blind placebo-controlled study of dexamphetamine for
cocaine dependence. Addiction 98, 1137–1141.
Sidhpura, N., Weiss, F., and Martin-Fardon, R. (2010). Effects of the mGlu2/3
agonist LY379268 and the mGlu5 antagonist MTEP on ethanol seeking and
reinforcement are differentially altered in rats with a history of ethanol depen-
dence. Biol. Psychiatry 67, 804–811.
Siegle, G.J., Carter, C.S., and Thase, M.E. (2006). Use of FMRI to predict
recovery from unipolar depression with cognitive behavior therapy. Am.
J. Psychiatry 163, 735–738.
Sinha, R. (2008). Chronic stress, drug use, and vulnerability to addiction. Ann.
N. Y. Acad. Sci. 1141, 105–130.
Sinha, R. (2009). Stress and addiction: A dynamic interplay of genes, environ-
ment, and drug intake. Biol. Psychiatry 66, 100–101.
Sinha, R., Garcia, M., Paliwal, P., Kreek, M.J., and Rounsaville, B.J. (2006).
Stress-induced cocaine craving and hypothalamic-pituitary-adrenal
responses are predictive of cocaine relapse outcomes. Arch. Gen. Psychiatry
63, 324–331.
Sinha, R., Kimmerling, A., Doebrick, C., and Kosten, T.R. (2007). Effects of
lofexidine on stress-induced and cue-induced opioid craving and opioid absti-
nence rates: Preliminary findings. Psychopharmacology (Berl.) 190, 569–574.
Sinha, R., Lacadie, C., Skudlarski, P., Fulbright, R.K., Rounsaville, B.J., Kos-
ten, T.R., and Wexler, B.E. (2005). Neural activity associated with stress-
induced cocaine craving: A functional magnetic resonance imaging study.
Psychopharmacology (Berl.) 183, 171–180.
Sofuoglu, M., Herman, A.I., Mooney, M., and Waters, A.J. (2009). Varenicline
attenuates some of the subjective and physiological effects of intravenous
nicotine in humans. Psychopharmacology (Berl.) 207, 153–162.
Neuron 69, February 24, 2011 ª2011 Elsevier Inc. 711

Somerville, L.H., Jones, R.M., and Casey, B.J. (2010). A time of change:
Behavioral and neural correlates of adolescent sensitivity to appetitive and
aversive environmental cues. Brain Cogn. 72, 124–133.
Srisurapanont, M., and Jarusuraisin, N. (2005). Naltrexone for the treatment of
alcoholism: A meta-analysis of randomized controlled trials. Int. J. Neuropsy-
chopharmacol. 8, 267–280.
Steeves, T.D.L., Miyasaki, J., Zurowski, M., Lang, A.E., Pellecchia, G.,
Van Eimeren, T., Rusjan, P., Houle, S., and Strafella, A.P. (2009). Increased
striatal dopamine release in Parkinsonian patients with pathological gambling:
A [11C] raclopride PET study. Brain 132, 1376–1385.
Streeter, C.C., Terhune, D.B., Whitfield, T.H., Gruber, S., Sarid-Segal, O.,
Silveri, M.M., Tzilos, G., Afshar, M., Rouse, E.D., Tian, H., et al. (2008). Perfor-
mance on the Stroop predicts treatment compliance in cocaine-dependent
individuals. Neuropsychopharmacology 33, 827–836.
Sulzer, D. (2011). How addictive drugs disrupt dopamine neurotransmission.
Neuron 69, this issue, 628–649.
Tanabe, J., Thompson, L., Claus, E., Dalwani, M., Hutchison, K., and Banich,
M.T. (2007). Prefrontal cortex activity is reduced in gambling and nongambling
substance users during decision-making. Hum. Brain Mapp. 28, 1276–1286.
Tang, Y.Y., Lu, Q., Geng, X., Stein, E.A., Yang, Y., and Posner, M.I. (2010).
Short-term meditation induces white matter changes in the anterior cingulate.
Proc. Natl. Acad. Sci. USA 107, 15649–15652.
Tolin, D.F. (2010). Is cognitive-behavioral therapy more effective than other
therapies? A meta-analytic review. Clin. Psychol. Rev. 30, 710–720.
Treadway, M.T., and Zald, D.H. (2011). Reconsidering anhedonia in depres-
sion: Lessons from translational neuroscience. Neurosci. Biobehav. Rev. 35,
537–555.
Uhl, G.R., Drgon, T., Johnson, C., and Liu, Q.R. (2009). Addiction genetics and
pleiotropic effects of common haplotypes that make polygenic contributions
to vulnerability to substance dependence. J. Neurogenet. 23, 272–282.
Uhl, G.R., and Grow, R.W. (2004). The burden of complex genetics in brain
disorders. Arch. Gen. Psychiatry 61, 223–229.
Vanbuskirk, K.A., and Potenza, M.N. (2010). The treatment of obesity and its
co-occurrence with substance use disorders. J. Addict. Med. 4, 1–10.
Verdejo-Garcı́a, A., Lawrence, A.J., and Clark, L. (2008). Impulsivity as a vulner-
ability marker for substance-use disorders: Review of findings from high-risk
research, problem gamblers and genetic association studies. Neurosci. Bio-
behav. Rev. 32, 777–810.
Vocci, F.J., Acri, J., and Elkashef, A. (2005). Medication development
for addictive disorders: The state of the science. Am. J. Psychiatry 162,
1432–1440.
Volkow, N.D., and Li, T.K. (2004). Drug addiction: The neurobiology of behav-
iour gone awry. Nat. Rev. Neurosci. 5, 963–970.
712 Neuron 69, February 24, 2011 ª2011 Elsevier Inc.
Neuron
Review
Volkow, N.D., Baler, R.D., and Goldstein, R.Z. (2011). Addiction: Pulling at the
neural threads of society. Neuron 69, this issue, 599–602.
Volkow, N.D., Fowler, J.S., Logan, J., Alexoff, D., Zhu, W., Telang, F., Wang,
G.J., Jayne, M., Hooker, J.M., Wong, C., et al. (2009). Effects of modafinil on
dopamine and dopamine transporters in the male human brain: Clinical impli-
cations. JAMA 301, 1148–1154.
Wagner, F.A., and Anthony, J.C. (2002). From first drug use to drug depen-
dence; developmental periods of risk for dependence upon marijuana,
cocaine, and alcohol. Neuropsychopharmacology 26, 479–488.
Walker, M., Toneatto, T., Potenza, M.N., Petry, N., Ladouceur, R., Hodgins,
D.C., el-Guebaly, N., Echeburua, E., and Blaszczynski, A. (2006). A framework
for reporting outcomes in problem gambling treatment research: The Banff,
Alberta Consensus. Addiction 101, 504–511.
Wang, G.J., Volkow, N.D., Thanos, P.K., and Fowler, J.S. (2009). Imaging of
brain dopamine pathways: Implications for understanding obesity. J. Addict.
Med. 3, 8–18.
Weintraub, D., Koester, J., Potenza, M.N., Siderowf, A.D., Stacy, M.A., Voon,
V., Whetteckey, J., Wunderlich, G.R., and Lang, A.E. (2010). Impulse control
disorders in Parkinson disease: A cross-sectional study of 3090 patients.
Arch. Neurol. 67, 589–595.
West, R., Baker, C.L., Cappelleri, J.C., and Bushmakin, A.G. (2008). Effect of
varenicline and bupropion SR on craving, nicotine withdrawal symptoms,
and rewarding effects of smoking during a quit attempt. Psychopharmacology
(Berl.) 197, 371–377.
Wexler, B.E., Gottschalk, C.H., Fulbright, R.F., Prohovnik, I., Lacadie, C.M.,
Rounsaville, B.J., and Gore, J.C. (2001). Functional magnetic resonance
imaging of cocaine craving. Am. J. Psychiatry 158, 86–95.
Wexler, B.E. (2011). Computerized cognitive remediation treatment for
substance abuse disorders. Biol. Psychiatry 69, 197–198.
Wrase, J., Schlagenhauf, F., Kienast, T., Wüstenberg, T., Bermpohl, F., Kahnt,
T., Beck, A., Ströhle, A., Juckel, G., Knutson, B., and Heinz, A. (2007). Dysfunc-
tion of reward processing correlates with alcohol craving in detoxified alco-
holics. Neuroimage 35, 787–794.
Xu, J., DeVito, E.E., Worhunsky, P.D., Carroll, K.M., Rounsaville, B.J., and
Potenza, M.N. (2010). White matter integrity is associated with treatment
outcome measures in cocaine dependence. Neuropsychopharmacology 35,
1541–1549.
Zack, M., and Poulos, C.X. (2007). A D2 antagonist enhances the rewarding
and priming effects of a gambling episode in pathological gamblers. Neuro-
psychopharmacology 32, 1678–1686.
Zhao, Y., Dayas, C.V., Aujla, H., Baptista, M.A., Martin-Fardon, R., and Weiss,
F. (2006). Activation of group II metabotropic glutamate receptors attenuates
both stress and cue-induced ethanol-seeking and modulates c-fos expression
in the hippocampus and amygdala. J. Neurosci. 26, 9967–9974.