Neuropsychopharmacology REVIEWS (2008) 33, 166–180

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Drug Addiction as a Pathology of Staged Neuroplasticity

Peter W Kalivas*,1 and Charles O’Brien2

1
Departments of Neurosciences, Medical University of South Carolina, Charleston, SC, USA; 2Department of Psychiatry,
Philadelphia VA Medical Center, University of Pennsylvania, Philadelphia, PA, USA

Using addictive drugs can evolve from controlled social use into the compulsive relapsing disorder that characterizes
addiction. This transition to addiction results from genetic, developmental, and sociological vulnerabilities, combined with
pharmacologically induced plasticity in brain circuitry that strengthens learned drug-associated behaviors at the expense of
adaptive responding for natural rewards. Advances over the last decade have identified the brain circuits most vulnerable to
drug-induced changes, as well as many associated molecular and morphological underpinnings. This growing knowledge
has contributed to an expanded understanding of how drugs usurp normal learning circuitry to create the pathology of
addiction, as evidenced by involuntary activation of reward circuits in response to drug-associated cues and simultaneous
reports of drug craving. This new understanding provides unprecedented potential opportunities for novel pharmacother-
apeutic targets in treating addiction. There appears to be plasticity associated with the addiction phenomenon in general as
well as changes produced by addiction to a specific class of addicting drugs. These findings also provide the basis for the
current understanding of addiction as a chronic, relapsing disease of the brain with changes that persist long after the last use
of the drug. Here, we describe the neuroplasticity in brain circuits and cell function induced by addictive drugs that is thought
to underlie the compulsions to resume drug-taking, and discuss how this knowledge is impelling exploration and testing of
novel addiction therapies.
Neuropsychopharmacology Reviews (2008) 33, 166–180; doi:10.1038/sj.npp.1301564; published online 5 September 2007
Keywords: addiction; neuroplasticity; motivational circuitry; glutamate; dopamine

Drug addiction is traditionally underappreciated as a tion of behavior towards drug-seeking and drug-taking
disease rooted in neuropathology (O’Brien, 2003). The strategies (Kalivas and Volkow, 2005). Importantly, these
perspective that drug-dependent individuals should simply changes are long-lasting and, at present, not readily
disengage from the self-destructive behaviors that are reversed (Hyman et al, 2006).
driven by addiction has distracted society from treating The modern definition of addiction was first established
drug abuse as a chronic medical disorder. The last 20 years in DSM IIIR by the American Psychiatric Association in
of research has made it clear that addiction to drugs is 1987 (APA, 1987). The clinical picture is marked by
based on pathological changes in brain function produced compulsive drug use that the individual cannot fully
by repeated pharmacological insult to the brain circuits that control. Tolerance and withdrawal symptoms may be
regulate how a person interprets and behaviorally responds present, but they do not necessarily signal addiction.
to motivationally relevant stimuli. Thus, addictive drugs Rather, the essential elements consist of persistent and
strongly interact with and change the brain circuits that recurrent drug-seeking behavior at the expense of pursuit of
permit us to learn about and behaviorally adapt to normal rewards. The definition assumed, without clear
important environmental stimuli, whether it be how to evidence in 1987, that there is a ‘core’ addiction syndrome
best approach rewards such as food or sex, or to avoid that pharmacologically diverse drugs of abuse can produce.
dangerous situations (Kelley, 2004; Everitt and Robbins, In this review, we marshal currently available evidence to
2005). By changing motivational circuitry, addictive drugs describe this core syndrome as a neuropathology in the
impair the development of behavioral strategies towards molecular and circuitry underpinnings of motivated beha-
biological stimuli in favor of progressively greater orienta- vior. From this perspective, addiction is a pathology in
mechanisms of brain neuroplasticity that are used to
establish the adaptive hierarchy of behaviors that ensure
survival. Thus, enduring drug-induced neuroplasticity
*Correspondence: Dr P Kalivas, Departments of Neurosciences, Medical establishes a maladaptive orientation to the environment
University of South Carolina, 173 Ashley Ave, BSB 410, Charleston, that manifests as the two cardinal features of addiction,
SC 29425, USA, Tel: + 1 843 792 4400, Fax: + 1 843 792 4423, (1) impaired ability to regulate the drive to obtain and use
E-mail: [email protected] drugs (ie, relapse), and (2) reduced drive to obtain natural
Received 12 July 2007; revised 8 August 2007; accepted 8 August 2007 rewards.
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NEUROPLASTICITY AND THE STAGES OF drug-seeking, and a conscious decision is never made, the
ADDICTION person automatically relapses.
Obviously, compulsive relapse is a more severe phase
For this review, neuroplasticity will be operationally parsed that, as we shall see, contains potential neuropathological
into two categories: first, relatively transient changes in targets for developing pharmacotherapeutic interventions.
neuronal function that continue for hours up to weeks of As illustrated in Figure 1, we will propose towards the
drug abstinence, and second, relatively stable changes end of this review that based on the neuropathology of
lasting from weeks to being relatively permanent changes. compulsive relapse being a form of stable neuroplasticity, a
Transient neuroplasticity corresponds to the necessary primary role of psychopharmacology in treating addiction
changes that are antecedent to developing a new behavior, is to develop drugs that promote regulated over compulsive
whereas stable neuroplasticity corresponds to the stable relapse. In other words, among the most valuable pharma-
information that is retrieved to guide the execution of cotherapies will be those that facilitate active decision-
learned behavior. For addiction, these stages are generally making, permitting the addict to choose not to take the
described as developing addiction (ie, learning to become drug. In contrast, transitioning from regulated relapse to
addicted), and a relative stable state of high vulnerability to social use or abstinence is best treated with a combination
relapse after stopping drug-taking. The development of of pharmacology and behavioral interventions that rein-
addiction is typically achieved through repeated social use force and support correct decisions (Centonze et al, 2005).
of the drug, and involves many relatively short-lived For example, behavioral interventions can range from
changes in brain chemistry and physiology based largely classic approaches such as extinction training and cognitive
on the molecular pharmacology of the drug itself (Nestler, behavioral therapy, to finding a steady job or reuniting with
2005). In Figure 1a, this stage is referred to as social use. loved ones.
The second stage is wrought by repeated drug insults and is
based on enduring changes in the synaptic physiology of
brain circuits regulating cognitive and emotional respond- Stages of Addiction and Stages of Normal
ing to important environmental stimuli. This is illustrated Reward Learning
in Figure 1a as two phases of relapse. The first phase of Figure 1b attempts to map our current understanding of
relapse is defined as regulated relapse, the second as biological reward memory and learning processes onto the
compulsive relapse. Regulated relapse refers to a relatively stages of addiction (Kelley, 2004; LaLumiere and Kalivas,
declarative decision-making process whereby the addict 2006). Thus, the acquisition of memories and developing
consciously decides to relapse. For example, the individual adaptive behavioral responses to important stimuli is
may make a choice between helping their child with referred to as acquisition and corresponds to social drug
homework or drinking a glass of wine. In this stage, the use. The counterpart to regulated relapse is the retrieval of
addict often makes the socially appropriate choice. In declarative memories, that is, memories that are verbalized
compulsive relapse, the addict is not making a conscious and are used in conscious decision-making. Finally,
choice. For example, although helping their child with compulsive relapse can be considered equivalent to habit
homework may have been an agenda item for the evening, or procedural memories. The retrieval of procedural
exposure to various environmental cues or stressors that the memories is not verbalized, and guides the unconscious
individual has associated with repeated drug use activates execution of adaptive motor behaviors. These behaviors are
well-learned and proceed most efficiently without ongoing
decision-making (eg, riding a bike, or opening the
Transition to addiction
refrigerator door when hungry).
Transient Stable
neuroplasticity neuroplasticity There have been large advances over the last decade in
our understanding of the underlying brain circuitry and
Social Regulated Compulsive neurotransmitters playing key roles in how motivational
use relapse relapse
memories are acquired, and the learned behaviors executed.
Abstinence
Behavioral intervention and pharmacology
Interestingly, much of this knowledge has come through an
iterative discovery process between researchers studying
Normal motivated learning mechanisms of normal motivated learning and those
Consolidation Retrieval and reconsolidation studying drug-addiction as a pathology in normal learning.
Figure 1b illustrates how key brain circuits and correspond-
Declarative Working or
Acquisition
memory habit memory ing neurotransmitters map onto stages of addiction. Thus,
learning to become addicted through social drug use
critically involves dopamine cells in the ventral tegmental
Mesocorticolimbic Prefrontal Cortico-striatal
dopamine glutamate glutamate area (VTA) that release dopamine into the prefrontal cortex
(PFC), amygdala, and nucleus accumbens (NA) (Berridge
Figure 1 Illustration of the relationship between neuroplasticity, and Robinson, 1998; Kelley, 2004; Schultz, 2004; Wise, 2004;
motivated learning, brain circuitry, and the stages of addiction. (a) The Jones and Bonci, 2005). One reasonable sequence supported
phases of addiction from the development of addiction (social use) to by animal models is that as drug-seeking becomes well-
vulnerability to relapse (transitioning from regulated to compulsive). Also
shown is the proposed use of pharmacotherapeutics and pharmacology
learned, a reliance of the behavior on glutamatergic
and behavioral interventions. (b) Mapping normal motivated learning projections from PFC to the NA emerges (Pierce and
processes and the relevant dopaminergic and glutamatergic circuitry onto Kalivas, 1997; Cardinal and Everitt, 2004; Wolf et al, 2004).
the stages of addiction. Thus, regulated relapse strongly depends on the retrieval of
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drug-associated memories and the integration of these Figure 2b illustrates two major distinctions between
declarative memories through glutamatergic projections dopamine release following motivational biological stimuli
from the PFC to the NA. While glutamate continues to play vs following exposure to an addictive drug. First, the release
a dominant role in compulsive relapse in this model, the of dopamine by addictive drugs is of greater amplitude and
glutamatergic circuit transitions from more declarative, duration than can be achieved through physiological
executive prefrontal circuitry to habit circuitry involving mechanisms. Simply put, drug pharmacology drives dopa-
classic cortico-striato-thalamic motor pattern generators, mine release beyond physiological limits by overcoming
and the procedural memories that drive the unconscious normal homeostatic mechanisms for controlling dopamine
engagement of well-learned behaviors (Barnes et al, 2005; release. For example, amphetamine-like psychostimulants
Everitt and Robbins, 2005). inhibit the elimination of dopamine from synapses, and in
The remainder of this review involves a deeper dissection some cases promote presynaptic dopamine release (Seiden
of the neuroplasticity underlying the stages of addiction, et al, 1993), whereas other drugs such as nicotine or opioids
and an integration of this neuroplasticity into prospects for act to alter feedback regulation of dopamine cells, causing
new drug development for transitioning addicts from an increase in dopamine cell activity. Thus, nicotine
compulsive to regulated relapse. promotes excitatory glutamate transmission in the VTA,
whereas opioids reduce the inhibitory GABA release on
dopamine neurons (Nader and van der Kooy, 1997;
THE ACQUISITION OF ADDICTION THROUGH Laviolette and van der Kooy, 2004; Pierce and Kumaresan,
REPEATED DRUG EXPOSURE 2006). The second major difference shown in Figure 2b
between drug-induced dopamine release and that produced
As outlined in Figure 1, repeated drug intake (social drug by biological stimuli, is that tolerance develops to the
use) involves the repeated release of dopamine from cells in release of dopamine by biological stimuli, whereas addictive
the VTA into the PFC, striatal complex (including the NA), drugs release dopamine every time the drug is taken. In
and amygdala. This circuit is illustrated in Figure 2a. Akin chronic users, increased dosing is required due to tolerance,
with motivationally relevant biological stimuli, all addictive but with sufficient dose, a dopamine increase reliably
drugs increase dopamine release within this circuit, albeit occurs. An exception to this includes binges with amphe-
by different molecular mechanisms of action (Jay, 2003; tamine-like psychostimulants, which can cause short-term
Kelley, 2004; Nestler, 2005). This association between depletions of dopamine and chronic stimulant users who
increased dopamine transmission and learning behaviors have reported extreme insensitivity or tolerance to the
to obtain reward has led to an understanding that dopamine activating effects of the drug through as yet unknown
release is a key event to facilitate learning. Thus, many mechanisms (Martinez et al, 2007). Thus, for biological
studies show that inhibiting dopamine transmission de- rewards, once the person has learned the most efficient
creases motivation and learning, whereas stimulating behavior to obtain a reward, dopamine release to facilitate
dopamine typically promotes the acquisition of learned further learning is not necessary and does not occur
behaviors. The release of dopamine has been purported to (Deutch and Roth, 1990; Schultz, 2004). However, it is
imbue an event with salience, creating an internal sense that important to note that dopamine continues to signal the
this is a relatively important event requiring the develop- arrival of a reward by conditioned stimuli (Schultz, 1998).
ment of a behavioral response (Berridge and Robinson, For example, whereas delivery of food reward in response to
1998). Important distinctions exist between dopamine a conditioned cue may no longer activate dopamine
released by addictive drugs vs motivationally relevant transmission in a trained animal, the appearance of a cue
environmental stimuli, and these distinctions are thought previously associated with food delivery will increase
to be critical for the development of regulated and dopamine cell firing, presumably preparing the animal to
compulsive drug-seeking. initiate the adaptive food-seeking response. Thus, within

Biological Addictive
motivational drug
stimulus administration
Hypothetical change (%)

PFC NA VP
300
Dopamine release

BLA
Dopamine
200
Glutamate

VTA GABA/peptide

100
Time

Figure 2 Corticolimbic dopaminergic pathways and a hypothetical comparison between dopamine release induced by motivationally important biological
stimuli and addictive drugs. (a) Corticolimbic circuit regulating drug-seeking, including dopaminergic innervation from the VTA, to the PFC, basolateral
amygdala (BLA), and NA; glutamatergic projections from the PFC and BLA to the nucleus accumbens; GABAergic/peptidergic projection from the NA to
the VP. (b) Based primarily on the microdialysis literature, hypothetical changes in dopamine release in response to important biological stimuli (rewarding or
aversive stimuli) vs the administration of addictive drugs. Note that drugs elicit more dopamine release for greater duration, and upon repeated
administration (green arrows) tolerance does not develop to drug-induced dopamine release.

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physiological parameters, dopamine serves two functions, D1 dopamine receptor

(1) to facilitate initial learning of adaptive responding to
important stimuli, and (2) to cue the retrieval of the
information needed to execute the adaptive behavioral Gs
response when environmental circumstances predict that
food is imminent. In contrast, every administration of an
cAMP Dynorphin
addictive drug reward is associated with a large release of Arc, NAC-1
dopamine that can be expected to promote new learning c-Fos, Homer Cdk5
∆FosB GluR2
(ie, new associations between the drug and environment) or Narp
PKA
reinforce prior learning, as well as to cue the addict to
execute a drug-seeking behavior (ie relapse). In animal
models, cues may also augment the response to stimulants CREB
thus producing a sensitized response to a given dose of the
stimulant. In this way, repeated use of addictive drugs
promotes increasing associations between the drug and life
events, whereas biologically important stimuli do not. This
Figure 3 Dopamine D1 receptor-dependent signaling in spiny cells of
may account for why repeated use of a drug causes drug- the nucleus accumbens hypothesized to underlie the transition from social
seeking behaviors to encroach upon all facets of daily life as use to enduring vulnerability to relapse. By stimulating cAMP synthesis and
the person becomes more dependent. ultimately phosphoryating and activating the transcriptional regulator CREB,
As indicated above, different drugs of abuse release a cascade of changes in protein synthesis occurs through the induction of
dopamine via different molecular mechanisms. One of the additional transcriptional regulators (eg, c-Fos and DFosB). Also, the
actions of ethanol is activation of the endogenous opioid synthesis of proteins is induced that are important compensatory regulators
system so that if opiate receptors are blocked by an of cellular functions and contribute to long-term drug-induced neuroplas-
ticity (see text for discussions of specific proteins).
antagonist such as naltrexone, the alcohol-induced dopa-
mine increase does not occur and the reward is blocked
(Gonzales and Weiss, 1998). Thus, the behavioral manifes-
tations of plasticity in human addicts may differ according and chromatin remodeling which are thought to underlie
to the drug. In heroin addicts, for example, repeated drug the transition from social use to regulated and compulsive
use produces marked tolerance with conditioned cues relapse. Thus, stimulation of D1 receptors in the striatum
producing drug-opposite or withdrawal-like responses and cortex increases cAMP, cAMP-dependent protein
(O’Brien, 1975; O’Brien et al, 1977). Drug cues in cocaine kinase (PKA), and cAMP response element-binding protein
addicts produce cocaine craving and limbic activation (CREB) that promotes the transcription of many genes
(Childress et al, 1999) with associated conditioned dopa- implicated in addiction, such as cfos, deltaFosB, Homer,
mine release (Volkow et al, 2006). Overall, in human and preprodynorphin (Hurd and Herkenham, 1993; Nestler
addicts, tolerance is the neuroadaptation most often et al, 2001; McClung and Nestler, 2003; Benavides and Bibb,
observed even in cocaine addicts (O’Brien et al, 2006). This 2004). Importantly, the rise of CREB in the NA and, to a
results in increasing doses of self-administered drugs to lesser extent, the VTA has been linked to reduced drug-
achieve the drug effects originally obtained. induced reinforcement (Carlezon et al, 1998; Nestler, 2005).
Although not all addictive drugs appear to increase CREB
Dopamine-Induced Neuroplasticity Underlying in the accumbens (Pandey et al, 2004), overexpression of
Development of Regulated and Compulsive CREB in the accumbens inhibits the rewarding effects of
Relapse psychostimulants, mu opioids, and biological rewards,
whereas overexpression of a dominant-negative CREB
The D1 and delta-FosB signaling cascade. The release of mutant promotes drug reward (Barrot et al, 2002; Lu
dopamine by important stimuli or addictive drugs produces et al, 2003; McClung and Nestler, 2003). Interestingly, some
changes in how neurons integrate excitatory and inhibitory studies show that CREB is necessary for the rewarding
neurotransmission. The effects of dopamine receptor effects of addictive drugs and biological reinforcement (Jin
activation are complex and distinctions exist between et al, 2005; Walters et al, 2005; Choi et al, 2006), posing the
activation of D1-like vs D2-like receptors depending on possibility that whereas acute regulation of CREB is
the presence of pre- and postsynaptic localizations within required for motivated behaviors, repeated upregulation
the local circuitry of a given nucleus. There are a number of of CREB induces tolerance to the reinforcing effects of
excellent reviews describing the current state of knowledge rewarding stimuli. Certain CREB-regulated genes, such as
regarding dopamine signaling as it pertains to addiction preprodynorphin, NAC-1, and Homer, undoubtedly con-
and motivated learning (Berke and Hyman, 2000; Nicola tribute to the compensatory effect increasing CREB to
et al, 2000; El-Ghundi, 2007). For our purposes, Figure 3 reduce the value of drug reward. For example, increased
illustrates some key events precipitated directly by D1 dynorphin inhibits the activity of dopamine cells and
receptor activation that are thought to be important presynaptic dopamine release (Carlezon et al, 1998; Chefer
antecedents for developing the enduring changes in et al, 2000; Hyman et al, 2006), and viral overexpression of
neuronal physiology that underlie the establishment of NAC-1 or Homer1c in the accumbens inhibits the develop-
adaptive behaviors to motivationally relevant events, as well ment of sensitized motor behaviors by repeated cocaine
as maladaptive drug-seeking behaviors. Importantly, this (Mackler et al, 2000; Szumlinski et al, 2006). Importantly,
signaling cascade involves changes in gene transcription two of these proteins, preprodynorphin and NAC-1 show an
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enduring upregulation in abstinence, indicating a long- or in the vulnerability to relapse is complex. For example,
lasting compensatory inhibition of drug reward (Hurd the short-term and enduring neuroplasticity induced by
and Herkenham, 1993; Cha et al, 1997). Unfortunately, as activation of CREB is most often shown to serve a
discussed in detail below, the devaluing of drug reward may compensatory function to reduce dopamine or glutamate
also extend to biological rewards. transmission in the accumbens, whereas increased delta-
Of the CREB-regulated genes, the increase in the FosB regulates gene expression in a manner that is both
transcriptional regulator, deltaFosB, has proven particularly compensatory (increased Cdk5) and supportive of drug
interesting (Nestler et al, 2001). The increase in many reward (increased GluR2; decreased dynorphin). These
transcriptional regulators and immediate early genes by adaptations in general would reduce the relative value of
addictive drugs or biological motivational stimuli, such as motivational biological stimuli, and this could indirectly
cfos, Arc, Homer1a, and narp, diminishes after repeated contribute to the enduring vulnerability to relapse to drug-
exposure. In contrast, deltaFosB accumulates in dopamine- seeking. Thus, by functioning in a compensatory fashion to
terminal fields in the cortex and striatum (Nestler et al, devalue all rewards, the enduring molecular consequences
2001; McClung and Nestler, 2003). This accumulation of transitory potentiation of the D1-CREB signaling cascade
occurs in response to chronic administration of all drugs (eg, increased dynorphin, NAC1, and Homer1c) are
of abuse tested to date, as well as in response to repeated promoting drug-seeking in favor of obtaining biological
biologically motivating stimuli. Thus, the accumulation of rewards.
deltaFosB is likely critical for learning and developing
motivated behaviors in general. In the case of addictive
Brain-Derived Neurotrophic Factor Regulation of
drugs, pharmacological or genetic disruption of this cascade
Synaptic Plasticity in Addiction
inhibits the development of certain forms of addiction-
associated behavioral plasticity, such as sensitized motor Another dopamine-dependent change in protein synthesis
behaviors (Nestler et al, 2001; McClung and Nestler, 2003). that appears particularly important in establishing physio-
Akin to genes regulated by CREB, some of the genes directly logical as well as drug-induced neuroplasticity is a rise in
regulated by deltaFosB may be compensatory and serve brain-derived neurotrophic factor (BDNF). BDNF is in the
to limit drug reinforcement, and perhaps drug-seeking class of psychostimulant-regulated immediate early genes,
(Nestler, 2005). Thus, the induction of Cdk5 phsophorylates including Arc, c-fos, and zif/268 (Dunais and McGinty,
the dopamine-regulated phosphatase DARPP-32, thereby 1994; Moratalla et al, 1996). However, BDNF and Arc appear
preventing its phosphorylation and activation by PKA unique because their mRNA is strongly induced and
(Benavides and Bibb, 2004). However, the induction of transported into dendrites by cellular activity (Steward
other genes by deltaFosB likely promotes drug reward and and Worley, 2001). Of particular interest, and apparently
the majority of studies indicates that overexpression of distinct from genes regulated by deltaFosB, as well as other
deltaFosB increases drug reward (Kelz et al, 1999; Colby activity-dependent genes upregulated by psychostimulants,
et al, 2003; Zachariou et al, 2006). Examples of deltaFosB the enduring changes in BDNF accumulate with increasing
gene regulation that would promote drug reward include periods of abstinence (Grimm et al, 2003; Lu et al, 2004a;
the induction of GluR2 in the shell of the accumbens Filip et al, 2006). Also, stimulating BDNF receptors in the
(Todtenkopf et al, 2006), and suppression of dynorphin amygdala, NA, or VTA promotes (Horger et al, 1999; Lu
expression (Zachariou et al, 2006). Importantly, the et al, 2004b; Graham et al, 2007; Pu et al, 2006), whereas
induction of deltaFosB and the gene products it regulates microinjection of BDNF into the PFC inhibits drug-seeking
appears to be relatively transient and normalizes during (Berglind et al, 2007), indicating that akin to activation of
abstinence. Therefore, although important for the acquisi- deltaFosB, BDNF serves a general physiological role in
tion of drug-seeking behaviors, deltaFosB itself is not an supporting neuroplasticity that is usurped by addictive
example of stable drug-induced neuroplasticity directly drugs to ultimately establish regulated and compulsive
mediating the execution of regulated or compulsive relapse. relapse.
Indeed, it is the transient nature of deltaFosB expression BDNF is well known to promote forms of excitatory
that makes it an ideal candidate for a protein mediating the synaptic plasticity, such as early- and late-phase long-term
transition from social use to relapsing drug use (Nestler potentiation (LTP), and also promote dendritic spine
et al, 2001). Accordingly, whereas deltaFosB regulated gene formation (Bramham and Messaoudi, 2005). The mechan-
expression itself is transient, neuroplasticity regulated by isms underlying what is in general an enhancement in
these genes may be extremely stable during abstinence. For excitatory transmission are varied, and include increasing
example, an enduring increase in dendritic spine density synaptic vesicle docking, increasing glutamate release, and
has been reported in accumbens spiny cells during extended promoting postsynaptic NMDA signaling. Given these
abstinence from chronic psychostimulant administration cellular mechanisms, it is not surprising that BDNF has
(Robinson and Kolb, 2004), and this increase is mediated in been implicated in the neuroplasticity underlying normal
part by deltaFosB stimulation of Cdk5 (Norrholm et al, learning and memory processes. Regarding drug addiction,
2003). BDNF mediates the enduring potentiation of excitatory
In summary, activation of the D1, CREB, and deltaFosB transmission onto dopamine cells in the VTA elicited by
signaling cascade is clearly necessary for driving the repeated cocaine administration (Pu et al, 2006), and along
neuroplasticity underlying both biological motivated learn- with orexin release (Borgland et al, 2006), could contribute
ing and developing drug-seeking behaviors (Nestler, 2001; to the exciting series of observations of potentiated LTP in
Hyman et al, 2006). However, the roles for drug-induced VTA dopamine cells following a single administration of an
adaptations in this cascade in the execution of drug-seeking addictive drug (for review of these findings and how they
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may contribute to the induction of enduring forms of Rapid response and tolerance
neuroplasticity that underlie relapse, see Jones and Bonci,

(function or content)
2005). Importantly, the level of BDNF in the VTA, as well as

Change in protein
NA and amygdala, progressively increases during absti-
nence (Grimm et al, 2003). This progressive increase has
been hypothesized to underlie the progressive increase in
drug-seeking that occurs during cocaine withdrawal, which
may occur, in part, by increasing dopamine D3 receptor
expression (Guillin et al, 2001; Le Foll et al, 2005). The fact
that BDNF is elevated by acute drug administration and also Time
remains elevated in certain brain areas after extended
abstinence marks this protein as a stable neuroplasticity Accumulating and temporary abstinence
candidate that may contribute to both the acquisition of
drug-seeking, and the execution of drug-seeking after

(function or content)
Change in protein
extended periods of abstinence.

Transitory Neuroplasticity Associated with the

Molecular Site of Drug Action
Other relatively transitional forms of neuroplasticity
induced by addictive drugs have also been described. Time
However, in contrast to the D1-CREB-deltaFosB signaling
pathway, these signaling events are more specific to Enduring in abstinence
individual drugs. For example, changes in dopamine (function or content)
Change in protein

transporters are associated with amphetamine-like psy-

chostimulants (Daws et al, 2002), GABA-A receptor changes
have been noted after chronic alcohol (Charlton et al, 1997),
and nicotine desensitizes nicotinic receptors (Mansvelder
and McGehee, 2000). These drug-specific changes contri-
bute important nuances of addiction to each drug, in
particular, withdrawal syndromes contain characteristics
unique for each drug class. Also, drug-specific changes Time
influence the circuitry critical for normal reward and drug
Figure 4 Stages of neuroplasticity in addiction. (a) Transient forms of
learning. In general, the drug-specific effects are beyond the neuroplasticity, typically involving the development of tolerance with
scope of the present review which is focused on what appear repeated administration; potentially important in promoting social drug use.
to be common features of brain plasticity shared by most or (b) Forms of plasticity that augment with repeated drug administration that
all drugs of abuse and in general principle, are also shared diminish within hours to weeks after discontinuing drug administration;
with motivational biological stimuli. thought to be important in the transition from social to relapsing drug use.
(c) Stable forms of plasticity emerging either during repeated drug use or
during abstinence. In some instances, protein changes in this category
progressively increase during abstinence, and are thought to contribute to
Summary of Neuroplasticity Underlying the the enduring vulnerability to relapse that is a cardinal feature drug addiction.
Acquisition of Drug Use and the Transition from Small arrows indicate repeated drug administration.
Social Drug Use to Regulated and Compulsive
Relapse
behaviors, as well as reconsolidate learned behaviors,
Figure 4 illustrates different temporal categories of neuro- including drug-seeking.
plasticity associated with the repeated use of addictive drugs The second category is characterized by proteins whose
and subsequent abstinence. It is important to note that expression gradually increases or decreases with repeated
experiments conducted with repeated psychostimulant drug exposure, and endures for various periods of
administration, and to a lesser extent opioids, provide the abstinence. Two subcategories are shown in Figure 4b.
majority of information underlying the patterns shown in The first includes protein changes that endure for hours to
Figure 4a. Three general categories are proposed. The first days into abstinence and typically correspond to changes
category includes the induction of activity-dependent genes closely associated with the drug’s molecular site of action.
by acute administration, and the development of tolerance The other subcategory is typified by the accumulation of
to this induction following repeated administration. Pro- deltaFosB, where elevated levels can endure for days or
teins in this category include c-fos, Arc, Homer1a, narp, and weeks. This latter subcategory is thought to contribute to
zif/268. Importantly, following a period of abstinence, the acquisition of motivated learning, but importantly, in
tolerance subsides and these proteins can again be induced response to repeated drug use, deltaFosB has been
by acute psychostimulant treatment, often at levels or with hypothesized to mediate the transition for social drug use
patterns of expression different from that induced by the to relapsing use (Nestler, 2005).
first drug exposure. These proteins are thought to be critical The third category contains proteins that are elevated or
for initiating the neuroplasticity necessary to acquire new reduced after prolonged abstinence. Two subcategories are
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considered in Figure 4c. The first is typified by BDNF that Enduring Neuroplasticity in Cortical Glutamate
accumulates in certain brain regions after repeated psy- Circuitry: Human Neuroimaging
chostimulant administration and this accumulation pro-
gresses with increasing duration of abstinence (Grimm et al, Much of the neuroplasticity in cortical circuits has been
2003; Lu et al, 2004a). The second subcategory will be visualized directly in addicts using various neuroimaging
considered in more detail below, and contains proteins that approaches. Thus, there is a general reduction in prefrontal
do not change markedly during drug administration, but cortical measures of cellular metabolism and blood flow in
are elevated or reduced during abstinence. It is hypothe- individuals addicted to a variety of different drugs, ranging
sized that this category contains neuroplastic events that are from cocaine to opioids to alcohol (Goldstein and Volkow,
likely responsible for the state of vulnerability to relapse. 2002). This includes regions such as the anterior cingulate
Most of these enduring changes have not been shown to and ventral orbital cortex. Given the association between
occur in response to repeated exposure to motivational activation of the anterior cingulate and engaging biologi-
biological stimuli and may be biomarkers for the neuro- cally relevant motivated behaviors (Rilling et al, 2002), and
pathology of addiction. between activation of the ventral orbital cortex and the
ability to switch a well-learned behavior to a new adaptive
behavior (Kolb et al, 2004), this hypofrontality has been
characterized as a strong indicator of reduced ability to
ENDURING NEUROPLASTICITY THAT MAY regulate drug-seeking. A reduction in frontal cortical
PROMOTE THE VULNERABILITY TO neurons has also been reported in drug-free cocaine addicts
RELAPSE (Franklin et al, 2002), but it is unknown whether these
functional and anatomical indications of hypofrontality
As described above, once a behavior designed to obtain a were vulnerability factors present before cocaine use or the
reward or avoid a negative consequence has been learned, effects of chronic stimulant use. Interestingly, when exposed
the role for dopamine changes from one of promoting new to a cue previously associated with drug use that
learning to one of enabling the use of learned information to precipitates the desire for drug, there is marked activation
efficiently execute the adaptive behavioral response in the PFC, including anterior cingulate and ventral orbital
(Schultz, 2004). In contrast, glutamate transmission from cortices (Goldstein and Volkow, 2002; Wilson et al, 2004;
cortex and allocortex (eg, amygdala and hippocampus) into Kalivas and Volkow, 2005). In many studies, increased
the striatal motor circuit (including the NA) emerges as activity in the PFC has been positively correlated with the
critical for executing a learned behavior (Kalivas and intensity of cue-induced desire for the drug. Thus, the
Volkow, 2005). Furthermore, it is thought that as a behavior differential in prefrontal activity between baseline and levels
is repeatedly executed, the role of corticofugal glutamate stimulated by drug cues is larger than what occurs in a
projecting from PFC and amygdala into the NA, becomes control subject in response to cues associated with
less important in favor of glutamate projecting from sensory biological reward, such as a sexually evocative visual
motor cortical areas to the dorsal striatum (Everitt and stimuli. Moreover, consistent with addiction being char-
Robbins, 2005). In this way, behavior evolves from being a acterized in part by reduced response to biological rewards,
declarative process involving prefrontal executive functions when cocaine addicts were presented with a sexual stimulus,
into a habitual behavior utilizing working memory circuitry prefrontal activation was significantly impaired compared
(Barnes et al, 2005). Physiologically, this transition from to controls (Garavan et al, 2000). Efforts to resist craving in
declarative to automatic behaviors can be adaptive by response to cocaine cues have also been reported to increase
permitting well-learned behaviors to proceed efficiently frontal lobe activity (Childress et al, 2007), suggesting that
without conscious involvement, and if the motivationally impaired frontal function could be implicated in inability to
important stimulus or context changes, executive functions resist relapse.
intrude to disrupt the habit as part of developing a new Another striking finding from neuroimaging studies
adaptive behavior appropriate to the environmental change. indicating reduced response to biological reward in addicts
In the case of drug-seeking, this transition from prefrontal is a reduction in dopamine receptor activation in response
circuitry to habit motor circuitry signifies loss of control to low doses of psychostimulants (Volkow et al, 2004, 2005).
and compulsive relapse. Important for the pathology of Thus, methylphenidate-induced dopamine release into the
addiction, the capacity of prefrontal, declarative circuitry to striatum is impaired in cocaine addicts relative to control
intrude and disrupt the drug-seeking habit is impaired, subjects. Also, regardless of the predominant drug being
making it more difficult for executive decision to intrude in abused, addicts show reduced levels of D2 receptors in the
drug-seeking (Everitt and Robbins, 2005; Kalivas and striatum (Volkow et al, 2004). In as much as reduced D2
Volkow, 2005). Understanding the neurophysiology that receptors indicates blunting of dopamine transmission, it is
reinforces this maladaptive transition from regulated to not surprising that addicts report reductions in high or
compulsive drug-seeking, and the impairment in reinvigor- pleasure in response to methylphenidate relative to control
ating prefrontal control over drug-seeking requires under- subjects. In contrast, whereas the methylphenidate induces
standing the enduring cellular neuroplasticity wrought by strong cravings in the addicts, there is no craving in
repeated drug use. In particular, this involves identifying comparison subjects. However, non-drug using control
changes in glutamate transmission and the emergence of subjects vary according to their striatal D2 receptor density.
the hypofrontality that permits drug-seeking to proceed Those with low D2 density report positive, pleasurable
without conscious interventions (Jentsch and Taylor, 1999; effects from methylphenidate, whereas those with higher D2
Goldstein and Volkow, 2002). density do not like the effects of the stimulant (Volkow et al,
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2002). This finding in normal human subjects is paralleled dorsolateral striatum is the brain region that has been
by a similar finding in nonhuman primates (Nader and shown to be obligatory regardless of the modality for
Czoty, 2005). inducing drug-seeking, or the presence or absence of
Taken together, these neuroimaging studies point to extinction training. This identifies the involvement of habit
enduring changes in mesocorticolimbic circuitry. Thus, in motor circuitry in a well-trained behavior such as drug-
the baseline state, the addict is relatively hyporesponsive seeking. Surprisingly, unless animals undergo extinction
to biological motivational stimuli, as evidenced by two training, the drug-seeking induced by placing the animals
neuroadaptations, (1) reduced activity in PFC, and (2) back in the drug context is not affected by inhibiting any
reduced striatal levels of dopamine D2 receptors. Perhaps other brain structure classically associated with motivated
even more critical to the pathology of addiction, the learning or cue-induced craving in neuroimaging studies of
capacity for biologically relevant stimuli to activate PFC is addicts (eg, areas of PFC, amygdala, or NA) (Fuchs et al,
impaired. Similarly, pharmacologically induced release of 2006). However, if the animal undergoes extinction training,
dopamine in the striatum and the corresponding subjective drug-seeking induced by cues, stress, or the drug itself
sensation of high or pleasure is impaired. However, drug- engages a much more enriched circuit, containing the
associated stimuli markedly activate PFC in addicts in a circuitry identified in human imaging of addicts. For
manner correlated with drug desire. Taken together, these example, if an experimenter locally inhibits any of the
neuroimaging data provide a neurocircuitry template for nuclei in the series circuit containing the dopamine
the prime features of addiction; excessive, uncontrolled projection from the VTA to the dorsal PFC, the glutamate
responding for drug, and poor or inappropriate responding projection from the PFC to the NA or the GABA/peptide
for biologically important stimuli. projection from the accumbens to the ventral pallidum
(VP), drug-seeking in an extinguished animal is blocked.
Enduring Neuroplasticity in Cortical Glutamate Thus, extinction training engages brain regions involved in
Circuitry: Animal Models more declarative and emotional processing in drug-seeking
behavior (McFarland and Kalivas, 2001; See, 2002; McFar-
To understand the cellular basis for how these changes in land et al, 2004), implying the assertion of executive
corticolimbic circuitry occur and hopefully identify me- behavioral modulation. Corresponding to extinction train-
chanisms for reversing or countering the changes, it is ing bringing behavioral control, the amount of drug-seeking
necessary to use animal models, which permit a more (eg, lever pressing) induced by the drug context in abstinent
mechanistic analysis. Importantly, animals self-administer animals is higher than drug-seeking induced in extin-
drugs that are addictive in humans, and the circuitry-based guished animals (Fuchs et al, 2006). Together, the circuitry
transition from the dopamine-dependent acquisition of and behavioral data indicate that the more enriched circuit
drug-seeking to the glutamate-dependent execution of associated with drug-seeking in extinguished subjects serves
drug-seeking is evident in animals studies. to regulate drug-seeking. Supporting this possibility,
The most widely employed model of relapse involves extinction training induces GluR1 and GluR2 glutamate
training rats to self-administer a drug, placing the animal in receptor subunits in the NA of cocaine-trained rats (Sutton
forced abstinence either with or without extinction training, et al, 2003). Similarly, extinction training in fear-condi-
then re-exposing the animals to the drug context, cues tioned animals involves activation of the infralimbic cortex
specifically paired with drug delivery, stress or the drug that projects to the NA (Sierra-Mercado et al, 2006). Thus,
itself (Epstein et al, 2006). In response to these stimuli, the just as psychosocial interventions in human addicts
drug-trained animal will engage in drug-seeking even in the endeavor to restore executive control over drug-seeking
absence of obtaining drug. habits, extinction training in animals engages a more
Early studies of relapse in animals involved the use of enriched prefrontal circuit that modulates the drug-seeking
opiate-dependent rats treated with naloxone or naltrexone. in response to cues, stress, or the drug itself.
Opiate reward was blocked and after initial increased The similarities in prefrontal circuitry between drug-
responding, rapid decrements occurred (Davis and Smith, trained animals and human addicts is further reflected by a
1974). More recently, alcohol self-administration was found dramatic elevation in glutamate transmission during
to activate the endogenous opioid system producing extinguished drug-seeking. Thus, rats trained to self-
dopamine release in the NA and alcohol seeking in the administer cocaine or heroin show a marked increase in
animal (Gonzales and Weiss, 1998). Rats trained to self- synaptic glutamate release in the NA in response to drug- or
administer alcohol and then given naltrexone will show a stress-induced drug-seeking (McFarland et al, 2003, 2004).
cessation of dopamine increase in the NA and cessation of Moreover, this rise is abolished by inhibition of the dorsal
alcohol self-administration. This straightforward extinction PFC, and does not occur in either yoked saline or yoked
model is mirrored in human alcoholics who report cocaine or heroin control groups. In other words, regardless
decreased or absent alcohol reward when treated with of repeated drug administration, if the animals do not
naltrexone (Volpicelli et al, 1995). engage in drug-seeking behavior there is not dysregulated
More recently, inactivation of various brain nuclei with release of synaptic glutamate. Accordingly, acute drug
GABA agonists or compounds inhibiting action potentials, administration alone is not sufficient to activate the
the brain nuclei necessary to execute drug-seeking have prefrontal accumbens glutamate pathway, rather this path-
been mapped (McFarland and Kalivas, 2001; See, 2002; way is recruited by animals learning a drug-seeking task.
McFarland et al, 2004). The results of these studies Importantly, no increase in glutamate was observed during
conducted over the last decade are remarkably parallel food-seeking in animals trained to self-administer food,
with the afore-mentioned human imaging studies. The indicating that this neuroplasticity is not induced by
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learning to seek biological rewards (McFarland et al, (Xi et al, 2002), and the induction of a protein called
2003). Supporting the importance of the dysregulation in activator of G-protein signaling 3 (AGS3), which serves to
glutamate release in driving drug-seeking behavior, intra- limit receptor signaling through the Gia class of G proteins
accumbens administration of glutamate antagonists (Blumer and Lanier, 2003; Bowers et al, 2004; Yao et al,
prevents drug seeking, as does inactivation of the PFC 2005). This relationship is illustrated in Figure 5.
(Cornish and Kalivas, 2000; Di Ciano and Everitt, 2001). The repeated dysregulated release of synaptic glutamate
Recently, some of the molecular neuroplasticity mediating during repeated drug-seeking episodes is thought to
the dysregulation of the prefrontal glutamate projection to contribute to a number of enduring postsynaptic changes.
the NA has been studied. In addition, some enduring Primary among these is the well-established changes in
consequences of repeated release of glutamate during drug- dendritic spine density seen in the NA and prefrontal
seeking have been investigated. cortical areas after repeated administration of addictive
drugs (Robinson and Kolb, 2004). It is well established that
applying glutamate to neurons in culture changes spine
Neuroplasticity Contributing to Dysregulated
density, either increasing or decreasing depending on the
Glutamate Transmission
amount of glutamate receptor stimulation and perhaps the
As the augmented release of glutamate is enduring, the subtypes stimulated (Lippman and Dunaevsky, 2005;
corresponding molecular plasticity is also enduring. Key Richards et al, 2005). Thus, it is perhaps not surprising
among these molecular adaptations is downregulation of that depending on which drug is chronically administered,
cystine–glutamate exchange (xc ) (Baker et al, 2003). xc there is an increase (psychostimulants) or decrease
is the rate-limiting step whereby cells acquire cystine to (opioids) in spine density (Robinson and Kolb, 1999,
make the intracellular antioxidant glutathione, and occurs 2004; Jedynak et al, 2007). The underlying cellular
by exchanging the uptake of one cystine in exchange for the mechanisms of neuroplasticity regulating spine morphology
release of one molecule of intracellular glutamate into the is an emerging area of extremely intense research activity.
extracellular space (McBean, 2002). Normally, this non- However, the regulation of the actin cytoskeleton that can
synaptic glutamate release results in levels in the extra- both stabilize or change spine morphology is a prime
cellular space sufficient to stimulate inhibitory presynaptic candidate for a process that may underlie changes in spine
metabotropic glutamate autoreceptors (mGluR), and there- density (Rao and Craig, 2000; Lisman, 2003; Blanpied and
by dampen synaptic glutamate release (Moran et al, 2005). Ehlers, 2004; Matus, 2005). Accordingly, there is an
However, reduced xc in the NA after chronic cocaine enduring increase in actin cycling after withdrawal from
removes this tonic inhibition, increasing synaptic glutamate chronic psychostimulant administration (Toda et al, 2006).
release probability. This reduction in tone is combined with The increase in actin cycling occurs, at least in part, from a
reduced signaling through the presynaptic mGluRs, that is reduction in Lim kinase, which critically regulates F-actin
thought to result from increased receptor phosphorylation depolymerization, as well as spine maturation (Meng et al,

Cued natural reward Cued drug reward (relapse)

PFC PFC

Glia

Cys/Glu
exchange

mGluR2/3
autoreceptor

Synaptic
Glutamate glutamate
uptake release

Spiny cell
dendritic spine

Figure 5 Molecular neuroplasticity associated with excitatory synapses in the NA hypothesized to underlie the vulnerability to relapse to cocaine and
perhaps other addictive drugs. Stimuli eliciting a learned behavior to approach a natural award result in glutamate release in the prefrontal to accumbens
pathway that is well regulated. A stimulus eliciting cocaine-seeking results in massive release of glutamate that can be measured as overflow in the
extracellular fluid. Dysregulated release results in part from downregulated xc and reduced activation of inhibitory mGluR presynaptic receptors. The
repeated massive release of glutamate also promotes dendritic dysmorphisms, including increased spine density as a result of increased actin cycling.
Increasing intensity of the red coloring in the extracellular space denotes increasing concentration of glutamate, and the green circles correspond to cystine.

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2002; Soosairajah et al, 2005). In addition to alterations in insertion into the membrane (Sun et al, 2005). The fact that
spine morphology another consequence of increased actin D1 receptor stimulation in the PFC is required for
cycling would be alterations in the trafficking of proteins reinstating drug-seeking is consistent with this possibility
into the postsynaptic membrane (Kasai et al, 2003). (Capriles et al, 2003; Sun and Rebec, 2005).
Although not necessarily the result of increased actin
cycling, a potentially critical change in postsynaptic
receptor trafficking is an enduring increase in membrane Summary of Neuroplasticity Underlying the
insertion of AMPA glutamate receptors (Mangiavacchi and Execution of Regulated and Compulsive Relapse
Wolf, 2004; Sun et al, 2005; Boudreau and Wolf, 2005).
Surprisingly, however, the increase in AMPA receptors is As shown in Figure 4c, forms of neuroplasticity that endure
associated with an inability to induce long-term depression during abstinence provide the neuroplastic substrates
(which is generally associated with reduced AMPA recep- underlying the enduring vulnerability to relapse in addic-
tors) (Martin et al, 2006). Although this finding has recently tion. A variety of studies support increased prefrontal
been contested in a study showing that after withdrawal glutamate release into the NA as a critical mediator of drug-
from cocaine there is a marked increase in AMPA current in seeking. Similarly, marked alterations in postsynaptic
accumbens spiny cells (Kourrich et al, 2007). In general, the glutamate signaling, including morphological changes in
electrophysiological correlates of addiction in accumbens striatal neurons likely contribute to the changes. The
spiny cells is currently an area of some confusion in the cellular plasticity underlying both the hypofrontality
literature (Kalivas and Hu, 2006). apparent during baseline and the strong response of PFC
Interestingly, stimulating BDNF receptors promotes actin and outputs to the NA during drug-seeking or drug desire is
cycling and modulates spine density (Bramham and beginning to be elucidated and, as outlined below,
Messaoudi, 2005), indicating that the afore-mentioned constitute new potential sites of action for developing
progressive elevation of BDNF during withdrawal may pharmacotherapies for treating addiction.
contribute directly to the enduring adaptations in excitatory
transmission. In apparent contradiction to this hypothesis,
stimulating BDNF receptors in the accumbens promotes FUTURE DIRECTIONS AND CLINICAL
cocaine-seeking (Graham et al, 2007), an effect also elicited
by inhibiting actin cycling in the NA (Toda et al, 2006). IMPLICATIONS
However, a recent study revealed that the release of BDNF As we increase our understanding of the circuitry and
into the accumbens after administration into the PFC cellular mechanisms by which repeated drug exposure
prevented both cocaine-induced drug seeking and the increases the vulnerability to relapse, new potential drug
release of glutamate associated with cocaine-seeking (Ber- targets become apparent. How this vulnerability transitions
glind et al, 2007). It was speculated that the BDNF between regulated and compulsive relapse affords rationales
administered into the PFC was anterogradely transported for the development of new medications, as well as
and release into the NA to produce this behavioral increased understanding of ways that medications might
effect (Altar et al, 1997). Thus, the endogenous release improve the results of psychosocial therapies.
of BDNF from prefrontal afferents into the NA may produce
a different effect than microinjecting pharmacological
quantities. Converting Compulsive to Regulated Relapse
Although enduring neuroplasticity in the NA and
striatum may reflect the hypofrontality observed in Using pharmacotherapies to facilitate the capacity of
neuroimaging addicts, it is assumed that enduring neuro- addicts to involve more declarative, decision-making
plasticity is also occurring directly in the PFC. Indeed, processes in relapse is critical to decreasing compulsive
repeated psychostimulant administration increases dendri- relapse. As outlined above, the transition to relapse
tic spine density on prefrontal pyramidal cells (Robinson becoming a habit based on unconscious working memory
and Kolb, 2004). In contrast to spiny cells in the accumbens circuitry involves a loss of prefrontal regulation. With some
where increased spine density is associated with less drugs of abuse this is manifested by cognitive deficits in
intrinsic membrane excitability (Zhang et al, 1998), functions related to attention, impulsivity and the ability to
prefrontal pyramidal cells appear to be more easily alter behavior based on new information. Based on these
stimulated (Dong et al, 2005). This is commensurate with findings, pharmacologically normalizing or countering
the large increase in synaptically released glutamate in the neuroplasticity produced in the PFC to regulate striatal
NA produced during drug-seeking, and may, in part, be habit circuitry would seem a valuable approach. As outlined
related to cellular neuroadaptations such as reduced above, the molecular changes involve an apparent down-
signaling through Gi-coupled receptors due to elevated grading of biological reward through reduced dopamine
AGS3 (Kalivas et al, 2005). Accordingly, while D2 receptor- transmission, and augmented prefrontal to accumbens
mediated changes in prefrontal cell firing appear blunted glutamate transmission to drive forward drug-seeking.
after withdrawal from chronic cocaine, the effects of Thus, drugs that alter dopamine transmission, glutamate
activating Gs-coupled D1 receptors are augmented (No- transmission or GABA transmission are potential candi-
gueira et al, 2006). This may contribute to the increased dates. Moreover, the GABA projection from the NA is
excitability and loss of membrane bistability reported in colocalized with a variety of neuropeptides (McGinty, 2007),
prefrontal neurons after chronic cocaine (Trantham et al, and these peptides, as well as others in corticolimibic are
2002), as D1 receptor stimulation promotes AMPA receptor also candidates for drug development.
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Dopaminergics. Dopamine transmission undergoes differ- opment of addiction and the enduring vulnerability to
ential changes depending on the receptor subtype. Thus, there relapse, we are at a very nascent stage in being able to apply
is a reduction in D2 receptor signaling (Volkow et al, 2004), a this new knowledge to treat addicts. Although we have some
potential increase in D1 signaling (Kalivas et al, 2005), and a established pharmacological candidates for regulating
marked elevation in D3 receptors as a result of enduring neurotransmission between neurons in the circuitry shown
increases in BDNF (Neisewander et al, 2004). This makes it to be important, it is difficult to manipulate the neuroplas-
difficult to predict how to best target dopamine transmission. ticity produced in intracellular signaling that is so critical to
However, there is excellent preclinical data supporting use of addiction. Using this new information awaits the develop-
D3 antagonists to inhibit drug-seeking (Xi et al, 2006). ment of compounds selective for targeted proteins in the
signaling pathways, and more importantly, means to deliver
Glutamatergics. Based on the neuroplasticity outlined the compounds. Nonetheless, the forms of neuroplasticity
above, blocking the release of synaptic glutamate associated identified to date point the way towards future therapies
with drug-seeking would seem to be an excellent approach that will become available as the delivery technology
to diminish the motivation to relapse. However, it is not evolves.
possible to use full antagonists of ionotropic glutamate
receptors due to unacceptable side effects. Accordingly, a
variety of pharmacological mechanisms are emerging for ACKNOWLEDGEMENTS
modulating rather than blocking glutamate transmission. This work was supported in part by USPHS Center Grants
Some of these compounds have already entered clinical P50 DA015369 and P60 DA01586.
trials and show modest efficacy. For example, acamprosate
and topiramate have weak actions as AMPA receptor
antagonists (Myrick and Anton, 2004; Cubells, 2006). DISCLOSURE
Topiramate has been reported to reduce relapse in cocaine
addicts (Kampman et al, 2004). Also, modafinil and N- Dr O’Brien has served as a consultant in the past three years
acetylcysteine acting to increase extracellular glutamate and to Alkermes, Cephalon, Forest and McNeil Laboratories.
thereby stimulating mGluR-induced inhibition of synaptic Dr Kalivas has nothing to disclose.
glutamate release have shown efficacy in cocaine relapse or
cue-induced craving, respectively (Dackis et al, 2005;
LaRowe et al, 2007). Three independent labs have reported
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