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The Journal of Neuroscience, May 1, 2002, 22(9):3312-3320
MINI REVIEW
Psychomotor Stimulant Addiction: A Neural Systems Perspective
Barry J.
Everitt1 and
Marina E.
Wolf2
1 Department of Experimental Psychology, University of
Cambridge, Downing Street, Cambridge CB2 3EB, United Kingdom, and
2 Department of Neuroscience, Chicago Medical School, North
Chicago, Illinois 60064-3095
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ARTICLE |
The reinforcing (rewarding) effects of psychomotor stimulants
(cocaine and amphetamine) depend on the mesocorticolimbic dopamine system innervating the nucleus accumbens (Wise, 1981 ; for review, see
Koob, 1992), perhaps especially the shell subregion (Bassareo and Di
Chiara, 1997). Prominent theories of addiction are based on adaptations
associated with both sensitization to and withdrawal from repeated
exposure to psychomotor stimulants (Robinson and Berridge, 1993; Koob
and Le Moal, 2001). Great progress has been achieved toward revealing
the nature of cellular and molecular adaptations in animal models of
addiction (Hyman and Malenka, 2001; Koob and Le Moal, 2001; Nestler,
2001), many of which are similar, if not identical, to those implicated
in models of learning and memory (Hyman and Malenka, 2001; Nestler,
2001).
One challenge in addiction research is to understand how molecular and
cellular adaptations are related to altered functioning of
neural systems that underlie compulsive
drug-seeking behavior. This review highlights associative influences on
psychomotor stimulant addiction, building on the view that plasticity
in neural systems converging on the nucleus accumbens (Nac) and
dorsal striatum (DS) is usurped by chronic drug self-administration,
leading to the aberrant engagement of pavlovian and instrumental
learning processes. At a systems level, one product of the gradual
strengthening or "consolidation" of behavior arising from the
reinforcing action of drugs may be the eventual progression of
addiction to a form of habit-based learning, in which voluntary control
over drug use is lost and the propensity to relapse is high and readily precipitated by exposure to drug-associated stimuli (O'Brien and McLellan, 1996; Robbins and Everitt, 1999; Everitt et al., 2001; Hyman
and Malenka, 2001).
In human cocaine addicts, otherwise neutral environmental stimuli, such
as paraphernalia associated with drug-taking, become associated with
the effects of cocaine through pavlovian conditioning (Childress et
al., 1992). Subsequent exposure to these stimuli elicits powerful drug
craving and precipitates relapse to drug-taking despite prolonged
periods of abstinence (Childress et al., 1992; O'Brien and McLellan,
1996). Recent functional imaging studies have exploited the fact that
craving can be evoked in human subjects exposed to images and other
stimuli, including biographical scripts, associated with cocaine
taking. Consistently, the amygdala, anterior cingulate cortex (ACg),
and orbital prefrontal cortex (PFC) are activated in these studies,
along with (less consistently) the striatum and dorsolateral PFC (Grant
et al., 1996; Maas et al., 1998; Childress et al., 1999; Wang et al.,
1999). These structures have been implicated not only in conditioning
processes, but in executive functions such as inhibitory control (for
review, see Robbins and Everitt, 1999; Everitt et al., 2001), both of
which play important roles in the development of cocaine addiction.
Understanding the impact of pavlovian conditioning on drug-seeking
behavior has been achieved by combining behavioral studies with
in vivo neurochemical monitoring, cellular imaging
approaches, and intracranial injection of drugs. These complementary
approaches have revealed neuronal populations and neurotransmitters
engaged during pavlovian conditioning and retrieval in a
cocaine-seeking setting and the impact of cocaine-associated stimuli on
drug seeking and its reinstatement after abstinence.
Corticostriatopallidal systems (Fig.
1) and associative mechanisms underlying
cocaine addiction
Cue-controlled cocaine seeking
Stimuli associated with drug taking both elicit drug seeking and
reinforce instrumental acts directed toward procuring the drug (Robbins
and Everitt, 1999; Everitt et al., 2001). One model of cocaine seeking,
sensitive to the contingency between instrumental behavior and drug
administration as well as the presence of drug-associated stimuli, is
provided by a second-order schedule of reinforcement. In this
procedure, rats respond for prolonged periods of time to obtain an
infusion of cocaine; this drug seeking depends critically on the
contingent presentation of cocaine-associated cues that act as
conditioned reinforcers (Arroyo et al., 1998; Everitt and Robbins,
2000). Rats with lesions of the basolateral amygdala (BLA) were unable
to acquire such cue-controlled cocaine seeking (Whitelaw et al., 1996),
consistent with an earlier literature implicating the BLA in
conditioned reinforcement (Everitt et al., 1999). Reversible
inactivation of the caudal, but not rostral, BLA also disrupted the
maintenance of cocaine seeking under a second-order schedule (Kantak et
al., 2002), indicating that the BLA plays an important role that
endures beyond initial acquisition. Furthermore, rats with lesions of
the ACg or medial PFC (mPFC) showed persistent responding for
cocaine, but responding was no longer under the control of contingent
presentations of cocaine-associated cues (Weissenborn et al., 1997),
indicating that these cortical structures, along with the BLA,
contribute to associative mechanisms controlling cocaine seeking, as
also suggested by functional imaging studies (Grant et al., 1996;
Childress et al., 1999). Inactivation of the NAc core also impaired
acquisition of cocaine seeking under a second-order schedule (Ito et
al., 2001), further suggesting that limbic cortical structures, via
their glutamatergic projections to the NAc, subserve conditioned
influences on cocaine seeking. Supporting this view, infusions of an
AMPA, but not an NMDA, receptor antagonist into the NAc core, but not
shell, greatly attenuated cue-controlled cocaine seeking (Di Ciano and
Everitt, 2001). Additionally, systemic treatment with dopamine (DA) D3
receptor ligands also greatly reduced cue-controlled cocaine seeking
(Pilla et al., 1999; Di Ciano et al., 2001). Although the precise site
of action of these DA D3 ligands is unclear, the restricted regional
expression of D3 receptors strongly implicates targets within limbic
corticostriatal circuitry: DA D2/D3 receptors within the amygdala have
already been implicated in pavlovian conditioning (Hitchcott and
Phillips, 1998).
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Figure 1.
A highly schematic representation of limbic
cortical-ventral striatopallidal circuitry that tentatively localizes
particular functions discussed in the text: (1) sensitization ventral
tegmental area and also the nucleus accumbens, via glutamate-dopamine
interactions; (2) processing of discrete and contextual drug-associated
conditioned stimulibasolateral amygdala and hippocampal formation,
respectively; (3) goal-directed actions ("action-outcome"
associations)nucleus accumbens; (4) "habits" (stimulus-response
learning)dorsal striatum. Both 3 and 4 involve interactions between
cortical afferents and striatal processes modulated by dopamine. (5)
"Executive control"prefrontal cortical areas; (6) subjective
processes, such as craving, activate areas such as orbital and anterior
cingulate cortex, as well as temporal lobe structures including the
amygdala, in functional imaging studies; (7) "behavioral output" is
intended to subsume ventral and dorsal striatopallidal outflow via both
brainstem structures and reentrant thalamocortical loop circuitry; (8)
"spirals" refers to the serial, spiraling interactions between the
striatum and midbrain dopamine neurons that are organized in a
ventral-to-dorsal progression (Haber et al., 2000); (8) blue
arrows indicate glutamatergic pathways; orange
arrows indicate GABAergic pathways; red arrows
indicate dopaminergic pathways. The transmitter used by central
amygdala neurons is less certain but is probably glutamate and also a
neuropeptide(s). BLA, Basolateral amygdala;
CeN, central nucleus of the amygdala;
VTA, ventral tegmental area; SNc,
substantia nigra pars compacta. This diagram is modified from Altman et
al. (1996).
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Many of the same pathways, in particular glutamatergic
projections to the NAc, are implicated by studies using other models to
study cocaine-conditioned responses, consistent with the fact that the
NAc receives convergent inputs from many cortical regions activated by
cocaine-related cues. For example, intra-NAc administration of an AMPA
receptor antagonist blocked psychostimulant-induced conditioned
place preference (Layer et al., 1993; Kaddis et al., 1995). Intra-NAc
AMPA infusion produced heightened motor responses in rats that had
previously received cocaine in the test environment (Bell and Kalivas,
1996), whereas a cocaine challenge in the training environment
increased NAc glutamate levels in rats for which the environment had
previously been paired with cocaine (Bell et al., 2000). Moreover,
during a drug-free microdialysis test session, discrete
cocaine-associated stimuli increased NAc glutamate levels, and this
effect could be temporally dissociated from the locomotor response
itself (Hotsenpiller et al., 2001). A striking finding was that basal
extracellular glutamate levels in the NAc, measured before introduction
of the cocaine cue, were markedly reduced in the paired group
(Hotsenpiller et al., 2001). Because both groups had the same cocaine
history, this neurochemical change must be attributed to the fact that
one group had formed an association between cocaine and the discrete
cue during the weeks before the microdialysis experiment. Paired
subjects tested in the cocaine-paired environment also showed decreased
basal glutamate levels in the NAc compared with saline controls (Bell
et al., 2000). These findings demonstrate that conditioning processes
have marked effects on glutamate transmission, consistent with the
central role of glutamate in plasticity and learning, and suggest that
addictive behavior may involve glutamate-dependent neuroplasticity in
limbic corticostriatal systems.
Immediate-early gene expression has also been used to map neuronal
circuits underlying drug-conditioned behaviors. Pairing an environment
or discrete stimulus with experimenter-administered cocaine or
amphetamine results in a conditioned locomotor response to the stimulus
alone that is accompanied by increased expression of
c-fos in limbic cortical regions that
varied somewhat among studies but included the PFC, ACg, BLA, and NAc
(Brown et al., 1992; Mead et al., 1999; Franklin and Druhan, 2000a;
Hotsenpiller et al., 2002). Moreover, this conditioned locomotion was
disrupted by infusion of GABA agonists into the PFC or the NAc, but not into the BLA (Franklin and Druhan, 2000b). Psychomotor stimulants also
induced quantitatively and qualitatively different patterns of Fos
expression when administered in a novel environment, a finding relevant
to the ability of novelty to enhance locomotor sensitization and
emphasizing the importance of environmental stimuli in determining some
stimulant drug effects (Badiani et al., 1998, 1999; Day et al., 2001;
Uslaner et al., 2001). Exposure to a discrete stimulus associated with
self-administered cocaine also increased expression of the
plasticity-associated gene  protein kinase C in the amygdala, medial
PFC, ACg cortex, and NAc, although the regional pattern of expression
depended on whether the stimulus was presented unexpectedly or
contingent on instrumental responses (Thomas and Everitt, 2001), an
issue that we return to below.
Reinstatement of cocaine seeking by cocaine-associated stimuli
After extinction of drug self-administration, exposure to
drug-associated stimuli, experimenter-administered drug, or stress reinstates drug-seeking behavior, i.e., responding in extinction on a
lever that previously resulted in drug infusions. This procedure was introduced, refined, and detailed by Stewart and colleagues (de Wit
and Stewart, 1981; Shaham et al., 1994) and has led to many
investigations of psychological and neurobiological mechanisms of
relapse. We focus here on cue-induced reinstatement of cocaine seeking,
because this not only models key aspects of relapse in human
addicts, but also reveals the involvement of limbic cortical-ventral striatopallidal systems (Fig. 1) in cocaine addiction. A basic feature
of this procedure is that established drug taking is first extinguished
and then its reinstatement is subsequently studied. Although an
effective and fruitful model of relapse, extinction of drug
self-administration is not a means by which human addicts achieve
abstinence, which is more likely to arise through an active decision to
abstain or through forced abstinence. Moreover, because the
extinguished response is so readily reinstated, it is unlikely that
extinction training will provide an effective clinical approach to
treatment. On the other hand, non-reinforced exposure to
cocaine-associated stimuli, and thereby extinction of their
motivational effects, might be a useful therapeutic strategy (O'Brien
et al., 1990, 1992; Robbins et al., 1992), although cue exposure in the
clinic is unlikely to be sufficient because the cues may remain potent elicitors of craving in the original drug-associated environment.
The BLA is critical for reinstatement of cocaine seeking after
extinction after exposure to cocaine cues. Bilateral excitotoxic lesions of the BLA (Meil and See, 1997) or its inactivation by infusion
of tetrodotoxin (TTX) (Grimm and See, 2000) or lidocaine (Kantak et
al., 2002) all prevent reinstatement of cocaine seeking after
extinction, the latter study using a second-order schedule procedure.
In addition, although the BLA is important in both the acquisition and
expression of conditioned relapse to cocaine seeking, inactivation of
the central amygdala (CeN) prevented only the expression of conditioned
relapse (Kruzich and See, 2001), suggesting the existence of
dissociable processes within the amygdala [see below and Everitt et
al. (2000)]. Although antagonism of NMDA or AMPA receptors in the BLA
failed to prevent cued reinstatement of cocaine seeking, infusion of a
D1, but not a D2, DA receptor antagonist did (See et al., 2001). These
results suggest a role for DA in the amygdala in conditioned influences
on cocaine seeking, but they also need to be reconciled with earlier
findings suggesting involvement of amygdala D2/D3 receptors in
conditioning (Hitchcott and Phillips, 1998).
Given that exposure to cocaine cues increases both DA (Di Ciano et al.,
1998; Ito et al., 2000) and glutamate (Hotsenpiller et al., 2001)
release in the NAc, it is perhaps surprising that inactivation of the
NAc by TTX did not affect conditioned reinstatement of cocaine seeking
but instead prevented reinstatement induced by a priming injection of
cocaine (Grimm and See, 2000). Indeed, the importance of the NAc in
drug-primed reinstatement has been confirmed and shown to depend on
glutamate transmission there (Cornish et al., 1999; Cornish and
Kalivas, 2000). However, systemic psychopharmacological studies have
shown that D2, but not D1, DA receptor agonists can precipitate
reinstatement of cocaine seeking (Self et al., 1996) and that both D1
and D2/D3 DA receptor antagonists can prevent conditioned reinstatement
(Weiss et al., 2001). Determining the central sites of action of these
DAergic effects on reinstatement of cocaine seeking remains an
important goal. These effects might depend principally on DA receptors
in the NAc, which mediate not only the reinforcing effects of cocaine (Koob, 1992) but also the potentiation of conditioned reinforcement (Taylor and Robbins, 1986; Wolterink et al., 1993). However, the amygdala is clearly an important locus of DA effects on pavlovian conditioning and conditioned reinstatement, indicating that DAergic processes in limbic cortical sites, rather than at the striatal termination of the projections from these cortical areas, may contribute significantly to conditioned influences on cocaine seeking.
In a study of cocaine-primed (rather than conditioned) reinstatement,
the importance of a medial PFC-ventral striatopallidal system (Fig. 1)
was established, and the medial PFC, not the striatum, was identified
as the primary site at which DA receptor blockade prevented the
relapse-inducing effects of cocaine (McFarland and Kalivas, 2001).
Distinct pathways are apparently involved, therefore, in reinstatement
produced by conditioned cues and cocaine priming injections; notably,
the BLA is implicated only in the former (Grimm and See, 2000). Using
microinjections of GABA agonists to selectively inactivate brain
regions or combinations of regions, McFarland and Kalivas (2001) showed
that cocaine-induced reinstatement depended on sequential information
flow between the ventral tegmental area (VTA), dorsal PFC, NAc core,
and ventral pallidum and suggested that cue-induced reinstatement
depends on similar circuitry, but through a different point of entry
involving the BLA (McFarland and Kalivas, 2001) (Fig. 1). Studies in
which Fos expression was used to map neuronal circuits involved in
drug-seeking behavior triggered by cocaine-paired environmental stimuli
versus cocaine priming injections further support the idea that
overlapping, but distinct, structures are involved in these responses,
although the ACg cortex may be common to both (Neisewander et al.,
2000).
The vigor or degree of conditioned reinstatement of cocaine seeking
increases with increasing duration of withdrawal from cocaine (Grimm et
al., 2001), suggesting that neuroadaptations to chronic cocaine
self-administration and withdrawal interact with the motivation to seek
cocaine, especially, but not exclusively, when cocaine cues are
present. These findings may provide insight into the possible
mechanisms that underlie the persistence or "incubation" of cocaine
seeking in abstinent cocaine addicts when exposed to similar stimuli.
Although limbic cortical-ventral striatopallidal systems are
implicated in the conditioned control of drug seeking and reinstatement after extinction, much remains to be established in terms of the processes occurring in cortical and subcortical structures and the ways
in which different subsystems interact, for example, those involving
the amygdala, the hippocampal formation, and the medial or orbital PFC.
Although the BLA mediates reinstatement after exposure to discrete,
cocaine-associated stimuli, the hippocampus may underlie the
motivational impact of contextual stimuli. Interestingly, theta burst
stimulation of the hippocampus has been shown to reinstate extinguished
cocaine seeking in a manner that depended on glutamate transmission in
the VTA, and this was suggested to mimic the process by which
reinstatement occurs when animals are placed in a context associated
with drug taking rather than in response to discrete cocaine cues
(Vorel et al., 2001). This view accords with data suggesting
differential involvement of the amygdala in conditioning to discrete
stimuli and the hippocampal formation in conditioning to contextual (or
spatial) stimuli (Selden et al., 1991; McDonald and White, 1993).
Moreover, electrophysiological and in vivo neurochemical studies have demonstrated that hippocampal, amygdala, and PFC projections interact in the NAc in a way that is modulated by mesolimbic DA and that, in turn, can modulate the release of DA (O'Donnell and Grace, 1995; Di Ciano et al., 1998; Floresco et al.,
2001). Thus, hippocampal, amygdala, and PFC mechanisms may influence
cocaine seeking through their convergent projections to the NAc,
perhaps competing for access to response strategies subserved by
different cortical-striatopallidothalamocortical reentrant loops (Fig.
1).
One feature of conditioned drug seeking and reinstatement is that
pavlovian associations between discrete stimuli or contexts and the
effects of cocaine can be established in different ways, and equally
important, the particular manner of presentation of these stimuli
subsequently determines the behavioral response. Different kinds of
associations are formed during pavlovian conditioning, and pavlovian
conditioned stimuli can elicit or support instrumental behavior, such
as drug-seeking, in ways that depend on the engagement of dissociable
neural systems (for review, see Everitt et al., 1999; Holland and
Gallagher, 1999; Parkinson et al., 2000a). Discrete stimuli (light,
tone) can be paired with each dose of self-administered cocaine (Meil
and See, 1996; Arroyo et al., 1998; Self and Nestler, 1998),
with noncontingent cocaine injections (Kruzich et al., 2001), or can
serve as a discriminative stimulus (DS+)
that signals the availability of cocaine (Weiss et al., 2001). The
effects of subsequent presentation of these stimuli vary considerably. Thus, contingent presentations of a cocaine-associated stimulus (acting as a conditioned reinforcer) support cocaine seeking and reinstatement (Meil and See, 1997; Arroyo et al., 1998; Kruzich et al.,
2001), whereas noncontingent presentations of the same stimulus, or of
a classically conditioned stimulus, do not precipitate reinstatement
(Kruzich et al., 2001). However, noncontingent presentation of a
cocaine DS+ that previously signaled cocaine availability (rather than
a cocaine infusion) caused long-lasting reinstatement of cocaine
seeking (Weiss et al., 2001) that was associated with both increased DA
release in amygdala and NAc (Weiss et al., 2000) and c-fos
expression in BLA and ACg that was itself blocked by a DA D1 receptor
antagonist (Ciccocioppo et al., 2001).
Parallel studies of pavlovian conditioning have shed light on these
intriguing differences. Conditioned reinforcement depends critically on
the BLA (Cador et al., 1989; Burns et al., 1993) and its interactions
with the NAc (Everitt et al., 2000). This accords well with the effects
of amygdala manipulations on cue-controlled cocaine seeking and
reinstatement. But discriminated approach to appetitive pavlovian
stimuli depends on the CeN of the amygdala, not the BLA, and also on an
ACg-NAc system and its DA innervation (Parkinson et al., 2000a,b).
Furthermore, the ability of noncontingent presentations of pavlovian
stimuli to potentiate instrumental behavior (pavlovian-instrumental
transfer) also depends on the CeN and NAc, but not the BLA (Corbit et
al., 2001; Hall et al., 2001). This potentiation of instrumental
behavior by pavlovian stimuli is amplified by increased DA in the NAc
shell in a way that is itself subject to sensitization (Wyvell and
Berridge, 2000, 2001), perhaps representing the sensitized conditioned
incentive salience that underlies drug "wanting," the process at
the heart of the incentive salience theory of addiction (Robinson and
Berridge, 1993). However, the process of pavlovian-instrumental
transfer has not been studied directly in the context of drug seeking
and its reinstatement, although the dramatic and persistent elevation of cocaine seeking in the presence of a DS+ previously paired with
cocaine (Weiss et al., 2001) might reflect the impact of this process
on relapse, a key element of addiction. This convergence of experiments
investigating the neural basis of pavlovian conditioning underpinned by
learning theory, together with those investigating associative
mechanisms in addiction, offers promise for understanding the
complexities of cocaine seeking and its relapse (Everitt et al.,
2000).
Addiction: the transition to compulsive drug seeking
From the above review, it might be suggested that psychostimulant
(and other drug) addiction can be understood in terms of the aberrant
engagement of pavlovian and instrumental learning processes.
Goal-directed actions by which animals and humans seek and take drugs
may become firmly established high in the response repertoire through
the impact of self-administered drugs on instrumental learning. In
addition, stimuli consistently present in the environment gain
motivational power through their predictive association with drugs and
thereby elicit and support drug seeking and precipitate relapse.
This view is consistent with the role of midbrain DA neurons in
functions more complicated than simple "reward." Midbrain DA
neurons respond to unpredicted rewards, and with training this response
transfers to stimuli predictive of rewards (Schultz et al., 1997;
Schultz and Dickinson, 2000). By signaling reward prediction errors, DA
may act as a teaching signal for striatal learning (Schultz and
Dickinson, 2000). DA-dependent processes are involved in the
development of stimulus-response (S-R) habits (Robbins et al., 1990;
Packard and McGaugh, 1996) and the consolidation of habit learning
(Packard and White, 1989, 1991). Midbrain DA neurons innervate
the striatal, cortical, and limbic regions implicated in addiction, so
drug effects on DA neuronal activity may be important for synaptic
"learning" throughout limbic-cortical circuitry.
Clues about circuitry from studies of behavioral sensitization
Another important source of information about systems involved in
addiction arises from studies of behavioral sensitization, which refers
to the progressive enhancement of species-specific behavioral responses
to drugs of abuse that develops over the course of repeated drug
exposure and persists after long periods of withdrawal. As mentioned
above, sensitization occurs not only to the locomotor activating
effects of psychostimulants but perhaps also to the incentive
motivational effects of drugs of abuse, i.e., wanting (Robinson and
Berridge, 1993; Deroche et al., 1999). Previous exposure to cocaine or
amphetamine, resulting in locomotor sensitization, promotes drug
self-administration (Horger et al., 1990; Mendrek et al., 1998; Lorrain
et al., 2000) and enhances stimulus-reward learning and responding for
conditioned reward (Taylor and Horger, 1999; Taylor and Jentsch, 2001).
The expression of sensitization is also associated with the
reinstatement of self-administration after long-term extinction (De
Vries et al., 1998), whereas environmental stimuli and conditioning
strongly modulate sensitization in rats, as well as drug craving in
humans (Robinson et al., 1998).
The development of sensitization requires a transient increase in the
activity of glutamate transmission between PFC and VTA DA neurons (Fig.
1), leading to an activation of DA cell firing that somehow transfers
sensitization to forebrain sites (NAc) that are important for its
maintenance and expression. Sensitization is initiated by stimulant
actions in the VTA, and its development is blocked by intra-VTA
administration of glutamate receptor antagonists or by ibotenic acid
lesions of the PFC. A transient increase in excitatory drive to VTA DA
neurons occurs shortly after discontinuing stimulant administration
(for review, see Wolf, 1998), suggesting that plasticity at synapses
between glutamatergic afferents and VTA DA neurons is responsible for
driving downstream changes related to sensitization, an idea directly
supported by evidence that cocaine sensitization is accompanied by
long-term potentiation (LTP) in VTA DA neurons (Ungless et al.,
2001). Although it was originally imagined that such plasticity
occurred between glutamate terminals originating in PFC and midbrain DA
neurons, anatomical studies have shown that PFC afferents to the VTA
synapse on mesoaccumbens GABA, rather than DA, neurons (Carr and
Sesack, 2000). So the route of communication between PFC and VTA may be
indirect, perhaps involving PFC projections to the laterodorsal
tegmentum and neighboring mesopontine nuclei, which in turn send
excitatory glutamatergic and cholinergic projections to the VTA
(Forster and Blaha, 2000). The VTA also receives excitatory drive from
the bed nucleus of the stria terminalis (George and Aston-Jones, 2001).
Adding to the potential complexity of circuitries involved in induction mechanisms, the BLA also participates in the development of behavioral sensitization (Kalivas and Alesdatter, 1993; Wolf et al.,
1995), and the NAc, traditionally associated with expression
mechanisms, may also participate under some conditions (Khan and
Shoaib, 1996). Thus, several components of limbic-corticostriatal
circuits may contribute to sensitization, perhaps explaining the
ability of very different previous experiences to lead to a similar
outcome, i.e., enhanced responsiveness to psychostimulants.
The circuitry involved in expression of sensitization is less well
established. Some studies indicate that it requires activation of
glutamatergic projections from dorsal PFC to the NAc core (Pierce et
al., 1998), whereas others indicate that PFC lesions that prevent development of sensitization do not alter its expression (Li et al.,
1999). Yet there is an emerging consensus that the maintenance of
sensitization may be associated with loss of inhibitory DA tone in the
PFC, leading to a loss of inhibitory control over PFC projections to
the NAc and other targets (Karler et al., 1998; Prasad et al., 1999).
How might this contribute to sensitization of incentive-motivational
processes related to drug seeking? Acutely increased DA release in the
PFC may send PFC neurons into a depolarized "up-state" and thus
increase corticofugal excitatory transmission (Lewis and O'Donnell,
2000). Stimulation of the PFC usually suppresses the activity of BLA
projection neurons via inhibitory interneurons that suppress sensory
cortical inputs to BLA, whereas BLA DA release may augment activation
of BLA by sensory cortical inputs and dampen PFC regulation of BLA
outflow (Rosenkranz and Grace, 2001). If, in the sensitized state,
there is loss of inhibitory tone in the PFC, this would impair
PFC-induced inhibitory regulation of BLA neurons, and the enhancing
effects of DA release on BLA outflow would be unopposed. The resulting
enhancement of excitatory drive from BLA to NAc could contribute to
many glutamate-dependent mechanisms implicated in drug and conditioning
effects in the NAc (Rosenkranz and Grace, 2001). This is consistent
with theories of addiction that combine augmented conditioned reward
with loss of inhibitory control mechanisms and the development of
impulsivity (Jentsch and Taylor, 1999; Robbins and Everitt 1999).
Transitional mechanisms related to corticostriatal plasticity
As reviewed elsewhere, the striatum might be a critical site at
which cellular and molecular adaptations to chronically administered drugs affect learning (Hyman and Malenka, 2001; Nestler, 2001). Behaviorally, the NAc core and its DA innervation are involved in the
acquisition of pavlovian approach (Kelley et al., 1997; Parkinson et
al., 2000b) and instrumental learning (Smith-Roe and Kelley,
2000), whereas the DS is implicated in habit learning (Mishkin et al.,
1984). Both DA and glutamate receptors are implicated in learning
processes in striatal and limbic cortical structures (Baldwin et al.,
2000; Berke and Hyman, 2000). Although NAc DA may be especially
responsive to many drugs of abuse initially (Di Chiara and Imperato,
1988), the fact that DA transmission is increased in both the NAc and
DS when drugs are self-administered over extended periods of time may
contribute powerfully to aberrant learning involving both structures.
Moreover, adaptations to chronic drug exposure are often seen in both
NAc and DS (Letchworth et al., 2001; Nestler, 2001).
Compulsive drug use is characterized by behavior that is inflexible,
because it persists despite considerable cost to the addict, may become
dissociated from subjective measures of drug value (Robinson and
Berridge, 1993), and is elicited by specific environmental stimuli
(Childress et al., 1992), and yet, at least initially, it involves
complex, goal-directed behaviors for procuring and taking a drug. One
hypothesis is that limbic cortical-ventral striatopallidal circuits
that underlie goal-directed drug seeking eventually consolidate
habitual, S-R drug seeking through engagement of corticostriatal loops
operating through the dorsal striatum (Robbins and Everitt, 1999;
Everitt et al., 2001). This hypothesized progression from action to
habit, the putative "switch" from drug abuse to addiction (Leshner,
1997), may have its neural basis within the recently described
"spiraling" loop circuitry of the striatum (Fig. 1), by which each
striatal domain regulates its own DA innervation and that of its
adjacent domain in a ventral-to-dorsal, NAc-to-DS progression (Haber et
al., 2000). Chronically self-administered drugs, through their ability
to increase striatal DA, may consolidate this ventral-to-dorsal
striatal progression of control over drug seeking as a habitual form of
responding. There is little direct evidence of this from studies of
addiction in animals, but a progressive spread from NAc to DS in DA
transporter binding has been reported in the transition from acute to
chronic cocaine self-administration in monkeys (Letchworth et al.,
2001). Moreover, in well established cocaine seeking under a
second-order schedule, elevated DA release is seen in the DS and not
the NAc, although DA release in the NAc remains responsive to pavlovian
presentations of cocaine-associated stimuli at this time (R. Ito, J. W. Dalley, T. W. Robbins, and B. J. Everitt, unpublished observations).
The transition from voluntary drug seeking to a compulsive habit may
also depend on the disruption of executive control provided by
descending influences on striatal mechanisms from the PFC (Shallice, 1996; Robbins and Everitt, 1999). Jentsch and Taylor (1999) have also
proposed that impulsivity, resulting from frontostriatal dysfunction,
plays an important role in addiction that acts synergistically with
sensitization of S-R mechanisms to produce compulsive drug-seeking behavior. Recent evidence indicates that repeated drug exposure alters
cortical cognitive function and leads to loss of inhibitory control
mechanisms, including previously conditioned responses (Jentsch et al.,
2002). Such changes may reflect disruption of orbital PFC efferents to
the striatum as a result of chronic drug exposure; e.g., there are
major decreases in the functional activation of the orbital PFC in
human cocaine and methamphetamine addicts (Volkow and Fowler, 2000;
Goldstein et al., 2001). This "tuning out" of the PFC might promote
habitual drug-seeking/taking behavior (Volkow and Fowler, 2000) as well
as impair cognitive decision making, as has been reported in long-term
amphetamine abusers (Rogers et al., 1999). There have been no direct
tests of this hypothesis, but excitotoxic lesions of the mPFC
facilitate the acquisition of drug-seeking but not food-seeking
behavior (Weissenborn et al., 1997). Furthermore, this hypothesis is in
general accord with the idea that a loss of PFC inhibitory control
contributes importantly to behavioral sensitization. Experimental
procedures that are able to probe the underlying structure of drug
seeking to reveal whether it is under action-outcome or
stimulus-response (habit) control are an important goal for future research.
We now have several clues about how repeated drug exposure may
influence the activity of corticostriatal pathways. In naïve rats, excitatory synapses in DS and NAc exhibit both long-term depression (LTD) and LTP, although underlying mechanisms may differ between the two regions (Hyman and Malenka, 2001; Wolf, 2002). Striatal
and NAc neurons are normally quiescent, and their activation requires
synchronous activation of multiple excitatory inputs (O'Donnell and
Grace, 1995). Thus, LTP or LTD in excitatory pathways impinging on
these neurons would have profound effects on their output, because
these processes influence synchronized activation. Several studies have
found alterations in LTD and LTP in these pathways after chronic drug
treatment (Wolf, 2002). Cocaine sensitization is accompanied by a
reduction in the magnitude of AMPA receptor-mediated quantal events
specifically at synapses in the NAc shell (but not core) that are
activated by cortical afferents. Furthermore, the magnitude of LTD was
reduced by repeated cocaine treatment, suggesting that long-lasting
depression of excitatory synaptic transmission shares expression
mechanisms with LTD (Thomas et al., 2001). Presynaptic mechanisms may
also be involved, because repeated cocaine administration decreases
glutamate immunolabeling in nerve terminals of the NAc shell (Meshul et
al., 1998), an effect that appears more persistent when cocaine is
self-administered (Keys et al., 1998). These findings are in accord
with others suggesting that the NAc is more quiescent after long-term
withdrawal from repeated stimulant administration, perhaps reflecting a
combination of depressed excitatory transmission (White et al., 1995;
Bibb et al., 2001; Thomas et al., 2001), decreased AMPA receptor
subunit expression (Lu and Wolf, 1999), and changes in
voltage-dependent conductances (Zhang et al., 1998). Decreased
excitability of the NAc could be specifically related to withdrawal
phenomena, such as elevated reward thresholds (Markou and Koob, 1991)
and anhedonia or dysphoria (Koob and Le Moal, 2001), that may also
contribute to persistent cocaine seeking and relapse.
Psychostimulants therefore may influence LTP and LTD in corticostriatal
and other pathways by acting at a systems level to alter neuronal
activity in excitatory pathways. Repeated drug exposure produces early
adaptations in glutamate receptor expression and DA and glutamate
receptor responsiveness in the PFC (Li et al., 1999; Peterson et al.,
2000), which might be responsible for triggering alterations in
corticostriatal plasticity. Stimulants may also act directly on the
mechanisms that enable synaptic plasticity, perhaps by influencing AMPA
receptor phosphorylation or membrane trafficking (Bibb et al., 2001;
Chao et al., 2002). Through such mechanisms, drugs may alter activity
in neural systems underlying motivation and reward, leading to abnormal
LTP or LTD, or directly modify the ability of neuronal activity to
elicit appropriate forms of LTP and LTD. On the basis of studies in the
hippocampus, a model has been proposed to explain the sequential
changes that may lead from LTP and LTD to alterations in the
biochemical composition of the postsynaptic membrane and ultimately to
changes in the structure of dendritic spines (Lüscher et al.,
2000). By tapping into LTP and LTD, psychostimulants could influence
these fundamental processes, perhaps explaining the ability of repeated
stimulant administration to produce changes in dendritic branching and
spine density in the NAc and PFC, similar to those in other forms of experience-dependent plasticity (Robinson and Kolb, 1997, 1999; Robinson et al., 2001). Morphological changes are also implied by the
demonstration of increased gap junction communication in the NAc and
PFC after withdrawal from repeated amphetamine (Onn and Grace, 2000).
Both types of morphological changes persist for at least 1 month and
therefore are good candidates for mediating persistent alterations in
the activity of systems that may underlie compulsive drug seeking.
Summary
There has been recent, substantial progress in understanding
psychomotor stimulant, especially cocaine, addiction on two fronts: (1)
characterization of the molecular basis of neuroadaptations induced by
drugs of abuse and (2) identification of limbic cortical-ventral striatopallidal systems that underlie associative influences on cocaine-seeking behavior and relapse. A future challenge is to determine how particular neuroadaptations lead to plasticity in these
systems, whether such changes are reversible, and how pharmacological treatments may be used to modify these processes and thereby reduce compulsive drug seeking and the propensity for relapse in human addicts.
| |
FOOTNOTES |
B.J.E. was supported by a Medical Research Council (MRC)
program grant (G9537855) and an MRC Cooperative in Brain, Behaviour and
Neuropsychiatry. M.E.W. was supported by United States Public Health
Service Grants DA09621, DA13006, and Independent Scientist Award
DA00453 and a National Alliance for Research on Schizophrenia and
Depression Independent Investigator Award. We thank Francis White for
his encouragement and editorial expertise.
Correspondence should be addressed to Barry J. Everitt, Department of
Experimental Psychology, University of Cambridge, Downing Street,
Cambridge CB2 3EB, UK, E-mail: bje10{at}cus.cam.ac.uk, or Marina E. Wolf,
Department of Neuroscience, Chicago Medical School, 3333 Green Bay
Road, North Chicago, IL 60064-3095, E-mail:
marina.wolf{at}finchcms.edu.
| |
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