Glutamate systems in cocaine addiction Peter W Kalivas
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Glutamate systems in cocaine addiction
Peter W Kalivas
All addictive drugs facilitate dopamine transmission, and In contrast to dopamine, glutamate transmission appears
determining the role of dopamine has been the predominant to be a primary contributor in the majority of examples of
focus of biomedical research in addiction for 20 years. Newer enduring neuroplasticity in the brain, and the develop-
data and hypotheses have begun to shift our focus to ment and expression of cocaine addiction is no exception
involvement of cortex and corticofugal glutamate projections. [4]. For example, convincing neuropharmacological evi-
The rationale for shifting focus to glutamate ranges from dence for involvement of glutamate transmission in the
evidence showing that cortical activity is altered in addicts to development and expression of behavioral sensitization
data from animal models demonstrating drug-induced changes to repeated cocaine administration has accumulated over
in the function of proteins that regulate pre- and postsynaptic the past decade [5]. In this review, we proceed from this
glutamate neurotransmission. Recent studies have particularly neuropharmacological foundation and explore the invol-
focused on involvement of a circuit that includes glutamate vement of glutamate in the reinstatement model of
projections from the prefrontal cortex to the nucleus accumbens. relapse. Specifically, we examine recent data supporting
the hypothesis that altered glutamate transmission in the
Addresses projection from the prefrontal cortex to the nucleus
Department of Physiology & Neuroscience, Medical University of South accumbens mediates behavioral neuroplasticity asso-
Carolina, 173 Ashley Ave, BSB 403, Charleston, SC 29465, USA ciated with addiction, including relapse and sensitization
e-mail: kalivasp@musc.edu
to components of the drug experience.
Current Opinion in Pharmacology 2004, 4:23–29 Neurocircuitry in addiction
Figure 1 shows the interconnected circuit amalgamated
This review comes from a themed issue on
Neurosciences
from a 20-year research effort that is thought to be
Edited by Joseph Coyle necessary to develop addiction and to manifest addictive
behaviors, such as relapse and sensitization [6,7]. This
1471-4892/$ – see front matter
circuit is derived from studies that employ neuroimaging
ß 2003 Elsevier Ltd. All rights reserved.
in addicts [8], behavioral pharmacology in animal mod-
DOI 10.1016/j.coph.2003.11.002 els of addiction [7,9,10] and, most recently, cell phy-
siology and molecular biology [10,11,12,13]. The
Abbreviations
dopamine projection to the prefrontal cortex, nucleus
AGS3 activator of G protein signaling-3 accumbens and amygdala is a primary site of pharmaco-
GABA g-aminobutyric acid logical action by cocaine, as well as a site where addictive
mGluR metabotropic glutamate receptor behaviors such as relapse and sensitization can be
initiated [1]. The regions of the prefrontal cortex most
clearly tied to addiction in both neuroimaging studies in
Introduction addicts and lesion/pharmacological studies in animal
The most widely studied neurobiological characteristic models of addiction are the anterior cingulate/prelimbic
of cocaine addiction is the role played by dopamine cortex and the ventral orbital cortex [7,8,14]. Similarly,
transmission [1]. It is clear that enhanced dopamine neuroimaging and animal studies show that the amygdala
transmission in neurons projecting from the ventral is a primary component of the circuitry mediating cue-
mesencephalon to the limbic forebrain, including the primed relapse [8,15]. The nucleus accumbens is com-
medial prefrontal cortex and nucleus accumbens, is the posed of two compartments termed the core and the shell
pharmacological target for cocaine-induced reinforcement and, although the shell is more clearly associated with
and locomotor stimulation [2]. However, persistence of dopamine-dependent reward, the core has been linked to
the behavioral characteristics of cocaine addiction, such as the enduring cellular changes elicited by repeated use of
paranoia (sensitization) and the propensity to relapse years addictive drugs [7,16]. The projections from the amyg-
after the acute rewarding effects of the drug have dis- dala and prefrontal cortex to the nucleus accumbens are
appeared, indicates that there must also be neuronal glutamatergic, as are the reciprocal connections between
substrates undergoing long-term neuroplastic changes. the basolateral amygdala and prefrontal cortex. The
Although studies have endeavored to identify enduring prefrontal cortex also sends glutamatergic efferents to
changes in dopamine transmission that might underlie the dopamine cell body region in the ventral tegmental
behavioral sensitization and the reinstatement of drug- area. This topographically organized circuit has primary
seeking (relapse), the results have not been entirely con- output through co-localized g-amino butyric acid
sistent with an obligatory role for dopamine [3]. (GABA)ergic and peptidergic neurons in the nucleus
www.sciencedirect.com Current Opinion in Pharmacology 2004, 4:23–2924 Neurosciences
Figure 1 frontal cortex [9,11,19]. Thus, pharmacological inacti-
vation of the prefrontal cortex with voltage-dependent
sodium channel blockers or GABA receptor agonists
prevents reinstatement induced by stress, cocaine-asso-
PFC NA VP
ciated cues or administration of cocaine itself [19–22].
Moreover, studies using the induction of immediate early
genes as an index of neuronal activity demonstrate invol-
Dopamine vement of the prefrontal cortex in reinstatement behavior
[10,14]. The basolateral amygdala appears to be critical
GABA selectively for reinstatement elicited by a drug-associated
cue [15,23,24]. As shown in Figure 1, both the amygdala
Glutamate and prefrontal cortex send glutamatergic projections to
VTA the nucleus accumbens and, through using the reinstate-
GABA peptides ment model of relapse, the nucleus accumbens has also
been shown to be critical for cocaine- and stress-primed
reinstatement [20,21]. Moreover, the administration of
AMPA glutamate receptor antagonists into the accum-
Amygdala bens prevents reinstatement elicited by cocaine adminis-
tered directly into the prefrontal cortex [25]. Using
Current Opinion in Pharmacology microdialysis, both drug- and stress-primed reinstatement
were shown to produce an increase in glutamate release
Illustration of circuitry involved in the development and expression of into the core of the accumbens, and inhibition of pre-
addiction. NA, nucleus accumbens; PFC, prefrontal cortex; VP, frontal cortical afferents blocked both reinstatement and
ventral pallidum; VTA, ventral tegmental area. the increase in accumbens glutamate [11,20].
Glutamatergic neuroadaptations in the
ventral tegmental area
accumbens that project to the ventral pallidum and A critical role for glutamatergic projections from the
ventral tegmental area [17]. prefrontal cortex and amygdala to the nucleus accumbens
in the expression of addictive behaviors is consistent with
Focus on glutamatergic projections a well-developed literature showing long-term changes in
Recent data indicate that activation of glutamatergic gene expression and protein function in the nucleus
efferents from the amygdala and prefrontal cortex is accumbens induced by chronic administration of addic-
critical in the expression of addictive behaviors. The tive drugs [13]. As with circuitry, the historic focus by
importance of these projections can be seen superficially neurochemists and molecular biologists has been the
in neuroimaging studies where blood flow to the anterior sequence of intracellular events precipitated by stimula-
cingulate cortex, ventral orbital cortex and amygdala is tion of dopamine receptors as a result of repeated use of
increased during craving for a variety of addictive drugs, cocaine. This research effort has identified molecular
including alcohol, cocaine, methamphetamine, heroin candidates related to dopamine transmission as important
and nicotine [8,18]. More invasive and quantitative mediators of establishing sensitization and reinstatement
techniques applicable in animal studies clearly reveal behaviors. For example, dopamine D1 receptor stimula-
the importance of these cortical and allocortical glutama- tion of cAMP-dependent protein kinase (or PKA) and
tergic structures. The most common animal model subsequent changes in protein function and gene expres-
employed for these studies is the reinstatement model, sion in the nucleus accumbens and ventral tegmental area
in which animals are trained to self-administer cocaine appear critical to establishing sensitization [13]. The most
and are then provided with a stimulus that will cause the well-characterized effect of increased cAMP-dependent
animal to perform an operant task (e.g. lever pressing or protein kinase activity is the induction of cAMP response
nose poke) to obtain only saline [7,9]. The number of element and the subsequent change in deltaFosB and
operant responses for saline is used as a measure of drug- cyclin-dependent kinase 5 [26,27]. Furthermore, manip-
seeking behavior (e.g. relapse). This reinstatement beha- ulating dopamine D2 receptor signaling by regulating the
vior is typically engendered by exposing the animal to in vivo level of the regulator-of-G-protein-signaling 9-2
one of three stimuli: a single administration of cocaine, (RGS9-2) was found to alter the rewarding effects of
a cue that was previously associated with cocaine self- cocaine [28]. In addition to the immediate consequences
administration, or an experimental stressor such as mild of dopamine receptor signaling, calcium/calmodulin and
footshock. Using the reinstatement model of relapse, it ras/mitogen-activated protein kinase activity in the ven-
has been shown that, regardless of the stimulus modality, tral tegmental area are critical to the development of
there is a dependence on neurotransmission in the pre- sensitization [29].
Current Opinion in Pharmacology 2004, 4:23–29 www.sciencedirect.comGlutamate systems in cocaine addiction Kalivas 25
Although these dopamine-dependent changes have been normalized extracellular glutamate levels and prevented
linked to the development of cocaine-induced behavior cocaine-primed reinstatement [38]. In the brain, it
and neuroplasticity, it is generally thought that the tran- appears that the majority of cystine-glutamate exchange
sient molecular adaptations in the ventral tegmental area occurs in glia [40], and recent studies have identified
are most critical to the development of addictive beha- enduring changes in other glial proteins following
viors, and glutamate transmission in the ventral tegmental repeated cocaine administration [41]. The reduction in
area has been shown to regulate dopamine-dependent cystine-glutamate exchange might be related to the
alterations. For example, acute cocaine sensitizes the reported reduction in group I metabotropic glutamate
glutamatergic input from the prefrontal cortex and receptor (mGluR1/5) regulation of extracellular gluta-
enhances the induction of long-term potentiation in mate, which results in part from a cocaine-induced reduc-
dopamine cells [30,31,32]. In addition, cocaine induces tion in Homer proteins that scaffold mGluR1/5 to inositol
a transient increase in glutamate receptor-1 (GluR1), trisphosphate-sensitive intracellular calcium pools [42,43].
which is linked to more enduring cellular changes in The importance of the reduction of Homer proteins in
the nucleus accumbens and the development of sensiti- the accumbens in addiction is indicated by findings
zation [33], and blocking ionotropic glutamate receptors that antisense oligonucleotide reductions in Homer1 or
in the ventral tegmental area prevents the development deletion of the Homer2 gene produces a behavioral
of conditioned place preference to cocaine [34]. Finally, phenotype resembling cocaine addiction, including sen-
following a cocaine overdose, addicts demonstrate ele- sitization of cocaine-induced locomotion and reward [44].
vated levels of several ionotropic glutamate receptor In apparent contradiction to the effects of reduced
subunits in the ventral tegmental area [35]. Taken mGluR1/5 signaling through Homer proteins, which
together, these newer studies are consistent with the idea causes enhanced responsiveness to cocaine, deletion of
that the ventral tegmental area is a site of action for the mGluR5 gene or administration of mGluR5 antago-
cocaine, where increasing dopamine release produces a nists inhibits the behavioral response to cocaine [45,46].
cascade of events that facilitates enduring cellular This contradiction is readily explained by the fact that
changes elsewhere in the brain; this cascade includes a enhanced release of glutamate through the cystine-
transient increase in pre- and postsynaptic glutamate glutamate exchanger, caused by mGluR1/5 stimulation,
transmission. is mediated by mGluR1, not mGluR5 [42]. Another ada-
ptation in presynaptic glutamate is the apparent desensi-
Glutamatergic neuroadaptations in the tization of group II mGluRs (mGluR2/3) following
nucleus accumbens withdrawal from cocaine. Signaling through mGluR2/3
Although neuroadaptations related directly to dopamine and the ability of mGluR2/3 to inhibit glutamate release is
receptor stimulation appear critical for the development blunted, and this arises in part from an increased phos-
of addiction, once addiction is established a variety of phorylation of the receptor, as well as a rise in activator of
emerging data indicates that changes in proteins regulat- G protein signaling-3 (AGS3), which selectively binds to
ing glutamate transmission are critical for the expression Gia [47,48].
of behaviors that characterize addiction, such as sensitiza-
tion and relapse. Thus, a sequence of neuroadaptations The way in which this sequence of adaptations could
produced by repeated cocaine might first involve adapta- synergize to dysregulate presynaptic glutamate transmis-
tions in signaling pathways related directly to dopamine sion in cocaine addiction is illustrated in Figure 2. This
transmission that become more permanently manifested hypothetical model describes how reduced Homer1bc
by changes in glutamate transmission [36]. For example, could account for reduced activity of the cystine-gluta-
it has been known for some time that acute cocaine mate exchanger and the accompanying reduced basal
administration does not alter glutamate release in the levels of extracellular glutamate. The reduced levels
accumbens of naı̈ve animals, but produces marked gluta- of glutamate, combined with desensitization of the
mate release in animals previously treated with repeated mGluR2/3 receptor, results in a loss of regulatory feed-
cocaine, especially when cocaine is associated with envir- back on synaptic glutamate release. Thus, lower basal
onmental cues [11,37]. The enhanced release of gluta- levels of glutamate, combined with increased release of
mate occurs against a background of significantly reduced synaptic glutamate in response to activation of prefrontal
basal levels of glutamate in the extracellular space and cortical afferents to the nucleus accumbens, results in an
inside presynaptic terminals [38,39]. It has been specul- amplified signal and behavioral drive to engage drug-
ated that the reduced glutamate background may accent- seeking (e.g. to relapse).
uate the synaptic signal delivered by glutamate released
in the projection from the prefrontal cortex to nucleus In addition to adaptations in presynaptic and possibly
accumbens [11,38]. Recently, it was discovered that glial release of glutamate that regulate the expression of
the reduced basal level of extracellular glutamate results sensitization and/or reinstatement, a variety of changes in
from diminished activity of the cystine-glutamate postsynaptic glutamate transmission have been docu-
exchanger, and restoration of cystine-glutamate exchange mented in the nucleus accumbens. Interestingly, although
www.sciencedirect.com Current Opinion in Pharmacology 2004, 4:23–2926 Neurosciences
Figure 2
Synaptic terminal
PKA Glu
Glu
Glu
Glu
Glu
3 4
mGluR2/3
G G
Cys/Glu GG C
mGluR1 C
Exchange CC C
C
G G
GGG 2
G
Homer GG
1
C
C
IP3 C
Ca C
Ca
Ca
Ca Ca Ca
Glia
Current Opinion in Pharmacology
The potential mechanisms regulating glutamatergic transmission in the nucleus accumbens that are involved in the reinstatement of drug-seeking
behavior. The cocaine-induced changes in extrasynaptic glutamate release outlined below are postulated to increase the signal-to-noise ratio of
synaptically released glutamate, thereby facilitating drug-seeking. 1 ¼ Homer1bc protein is reduced in the nucleus accumbens, causing a reduction
in signaling via mGluR1 receptors through inositol trisphosphate (IP3) receptor regulation of internal calcium (Ca) stores. 2 ¼ Because glutamate
release stimulated by mGluR1 receptors results from activation of the cystine/glutamate exchanger, it is proposed that downregulated mGluR1
signaling may mediate the reduced activity of the cystine/glutamate exchanger produced by chronic cocaine admnistration. 3 ¼ The reduced
heteroexchange of extracellular cystine (C) for intracellular glutamate (G) in glia results in reduced basal extracellular glutamate and reduced tone on
mGluR2/3 presynaptic autoreceptors. 4 ¼ This reduced tone, accompanied by mGluR2/3 residing in a more phosphorylated (desensitized) state,
results in reduced inhibitory regulation of synaptically released glutamate (Glu).
presynaptic release of glutamate was augmented by glutamate transmission are suppressed after withdrawal
withdrawal from repeated cocaine, most data indicate a from chronic cocaine. Against this suppressed background,
reduction in postsynaptic responses to glutamate. Elec- the enhanced release of glutamate from prefrontal glu-
trophysiological responses to iontophoretic or stimulated tamatergic afferents (as occurs during reinstatement of
glutamate release are blunted [49,50]. This blunting drug-seeking; see above) will be more easily detected as a
might be associated with changes in iontotropic glutamate biologically relevant signal. This would especially be true
receptor subunits, although these data are variable, with if the reinstatement stimulus promotes postsynaptic as
the direction of change depending on the laboratory and well as presynaptic transmission. For example, if the
withdrawal time [27,51–54]. A clear reconciliation of stimulus (e.g. a cocaine injection or stressor) increases
how augmented presynaptic glutamate transmission dopamine release simultaneously with glutamate in the
and reduced postsynaptic glutamate transmission might nucleus accumbens, it would be expected to rapidly
mediate the expression of addictive behaviors is not yet increase surface expression of GluR1 [36].
available. However, one consideration is that reduced
electrophysiological estimates of postsynaptic glutamate Glutamatergic neuroadaptations in the
transmission are made in tissue slices or anesthetized prefrontal cortex
animals, and the activity of accumbens spiny cells is Enduring cellular changes in the prefrontal cortex pro-
state-dependent [55]. Thus, the effects of glutamate will duced by withdrawal from repeated cocaine are not as
depend on tonic activity of afferents to spiny cells and, in well characterized as in the nucleus accumbens. How-
both the slice and anesthetized preparations, tonic activ- ever, in vivo intracellular recording of pyramidal cells in
ity of afferents is suppressed. Another consideration is the prefrontal cortex projecting to the nucleus accumbens
that, in the basal state, both presynaptic and postsynaptic or ventral tegmental area reveals a loss in membrane
Current Opinion in Pharmacology 2004, 4:23–29 www.sciencedirect.comGlutamate systems in cocaine addiction Kalivas 27
bistability [12]. The membrane potential of pyramidal Acknowledgements
cells normally fluctuates between relatively depolarized This work was supported in part by USPHS grants DA12513,
DA03906 and DA05369.
and hyperpolarized potentials. This fluctuation is reg-
ulated by both dopaminergic and glutamatergic afferents,
References and recommended reading
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chronic cocaine reflects changes within the pyramidal cells of special interest
or changes in dopaminergic and/or glutamatergic afferents. of outstanding interest
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elicited by a cocaine-priming injection.
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