Phil. Trans. R. Soc.

B (2008) 363, 3147–3158

doi:10.1098/rstb.2008.0084
Published online 18 July 2008

Review

Psychological and neural mechanisms of relapse

Jane Stewart*
Center for Studies in Behavioral Neurobiology/Groupe de Recherche en Neurobiologie Comportementale,
Department of Psychology, Concordia University, 7141 Sherbrooke Street West,
Montreal, Quebec, Canada H4B 1R6
Relapse, the resumption of drug taking after periods of abstinence, remains the major problem for the
treatment of addiction. Even when drugs are unavailable for long periods or when users are successful
in curbing their drug use for extended periods, individuals remain vulnerable to events that
precipitate relapse. Behavioural studies in humans and laboratory animals show that drug-related
stimuli, drugs themselves and stressors are powerful events for the precipitation of relapse.
Molecular, neurochemical and anatomical studies have identified lasting neural changes that arise
from mere exposure to drugs and other enduring changes that arise from learning about the
relationship between drug-related stimuli and drug effects. Chronic drug exposure increases
sensitivity of some systems of the brain to the effects of drugs and stressful events. These changes,
combined with those underlying conditioning and learning, perpetuate vulnerability to drug-related
stimuli. Circuits of the brain involved are those of the mesocorticolimbic dopaminergic system and its
glutamatergic connections, and the corticotropin-releasing factor and noradrenergic systems of the
limbic brain. This paper reviews advances in our understanding of how these systems mediate the
effects of events that precipitate relapse and of how lasting changes in these systems can perpetuate
vulnerability to relapse.
Keywords: relapse to drug seeking; drug-related stimuli; stress; dopamine (DA); glutamate;
corticotropin-releasing factor

1. INTRODUCTION rapidly become associated with stimuli and events in

In the context of drug addiction, relapse refers to the the environment where they are experienced, and drug
reinitiation of drug seeking and drug taking after effects can be different in different individuals and
abstinence. The central questions that are being differentially experienced by them.
addressed by researchers in the field of drug addiction
are: what are the primary triggers for relapse; which
systems of the brain mediate the effects of these 2. PRIMARY TRIGGERS FOR RELAPSE
triggers; and what maintains the vulnerability to these Studies carried out in humans and laboratory animals
triggers in individuals even after drugs have been have demonstrated that craving (Wikler 1973; Jaffe
unavailable for long periods of time or when users are et al. 1989; Childress et al. 1992; de Wit 1996; Leyton
successful in curbing their own drug use for extended et al. 2002, 2005; Sinha et al. 2000; Duncan et al. 2007)
periods? Is it a set of physiological changes brought and the reinitiation of drug seeking (See 2002; Shalev
about by being exposed to the effects of drugs, per se? Is et al. 2002; Spealman et al. 2004; Stewart 2004; Weiss
it drug-related memories that can be reactivated by 2005) can be induced by re-exposure to cues previ-
drug-related cues and thoughts? Does it arise from ously associated with drug exposure, by acute exposure
something within individuals that makes them initially to stressors and by re-exposure to the drug itself. In
vulnerable to the effects of drugs of abuse and which experimental studies in humans, various means are
simply remains or is exaggerated after the termination used to present to drug users events that are suspected
of drug taking? No doubt, factors such as these all of triggering relapse and subjective ratings are used to
contribute. In fact, exposure to a drug can initiate assess drug craving or wanting. Such methods are
neurochemical changes with enduring molecular and now being complemented by brain-imaging techniques
anatomical consequences that affect subsequent to assess regions of the brain that are differentially
responses to events that induce relapse; drugs that are activated by these triggering events. In laboratory
abused activate appetitive motivational systems of the animals trained to self-administer drugs such as
brain, inducing behaviours and emotions that very cocaine or heroin (when drug cues or responding are
associated with obtaining the drug) and then subjected
to a period of extinction training, or simply to the
*[email protected] passage of time, the presentation of cues that have been
One contribution of 17 to a Discussion Meeting Issue ‘The explicitly paired with drug delivery, brief exposure to a
neurobiology of addiction: new vistas’. stressor or an experimenter delivered injection of the

3147 This journal is q 2008 The Royal Society

3148 J. Stewart Review. Neurobiology of relapse

drug all result in an increase in increased drug-seeking extinction, a priming injection of the previously self-
behaviour. Clearly, under non-laboratory conditions, administered drug (and presumably exposure to stress)
the reinitiation of drug seeking after abstinence occurs acts to renew the salience of the drug-associated lever
before exposure to the drug itself, and is instigated by and the surrounding stimuli. We have used the
environmental cues, thoughts or stressors. It is well conditioned place preference (CPP) procedure to
recognized, however, that re-exposure to the drug explore this hypothesis directly.
spurs on further drug seeking; thus, it is important to In this procedure, a particular stimulus environment
study in an experimental setting how the action of is paired with the effects of the drug, without the
the drug itself, increases subsequent drug seeking. animal having to learn to make a response to obtain the
In the reinstatement model of relapse (de Wit & drug, and a second environment is explicitly paired
Stewart 1981; Spealman et al. 2004; Stewart 2004; with the absence of the drug. In the test trial, the
Epstein et al. 2006), animals are trained to self- animal is allowed, while in a drug-free state, to move
administer a drug by pressing one of two levers, and freely between the area previously paired with the
are then exposed to a period when the drug is no drug and the unpaired environment. Using this proce-
longer available. During this abstinence period, dure, we have tested the idea that a priming injection of
animals may simply be left in their home cages the drug used to develop the CPP, given after an
(Grimm et al. 2001; Fuchs et al. 2006) or they may extinction training, acts to restore the salience or
be free to try to obtain drug in the testing chambers attractiveness of the environment previously paired
(extinction training). In extinction training, the sight with drug. It has been found that following the
of the lever and stimuli previously associated with extinction of the CPP by repeatedly pairing both the
drug delivery are usually present; in the case of tests compartments with saline or by giving repeated tests in
for cue-induced reinstatement, however, the cues the absence of drug, the former preference for the
previously associated with drug delivery are absent. ‘drug-paired’ compartment can be completely
When animals reduce responding to very low levels, reinstated by giving a single injection of the drug
tests for reinstatement can begin. During these tests, before the test (Mueller & Stewart 2000; Parker &
animals are given access to the levers, but drugs remain McDonald 2000; Mueller et al. 2002).
unavailable. It is on this background of renewed Results from a study on stress-induced reinstatement
drug seeking, or reinstatement, that we are able to lend further support to this idea (Liu & Weiss 2002).
begin a search for pharmacological and neurochemical During training, ethanol-reinforced responses were
manipulations that can block or attenuate such behavi- accompanied by a light that served as a conditioned
our. Using this procedure, the periods of self- stimulus. After extinction, given in the absence of both
administration training, abstinence, extinction and ethanol and the light, lever pressing was reinstated by
reinstatement can be separated by days and weeks response-contingent presentations of the conditioned
allowing for the study of factors such as the extent light stimulus or by prior brief exposure to intermittent
and amount of initial exposure to drug taking and the footshock stress. Rats tested with the conditioned light
effect of the passage of time since last exposure on stimulus present after a brief period of footshock
the susceptibility to relapse. showed greatly enhanced responding compared with
those tested with either the light stimuli or footshock
alone, suggesting that the stress state induced by
3. HOW MIGHT DRUGS AND STRESSORS footshock enhanced the salience of the drug-related
INITIATE REINSTATEMENT OR RELAPSE IN stimuli augmenting drug-seeking behaviour.
EXPERIENCED DRUG USERS Another more direct approach to this question was
The observation that a brief exposure to stress or an taken in an experiment in which rats were given pairings
abused drug reinstates drug-seeking behaviour implies of a compound stimulus with passive intravenous
a change in the motivational state of the animal that infusions of cocaine (0, 0.5 or 1.0 mg kgK1 infusionK1).
alters responses to stimuli in its environment. After training, rats were allowed to lever press for
Traditionally, the term motivation is invoked by the conditioned stimulus under extinction conditions,
the observation that a particular goal-directed and the amount of pressing was shown to be depen-
behaviour, such as food seeking, occurs at some times dent on the training dose. After extinction of lever
and not others, with more or less vigour and pressing, a single priming injection of cocaine
persistence. The ease with which a behaviour is (20 mg kgK1 intraperitoneally) or exposure to foot-
engaged by environmental stimuli, its persistence and shock stress reinstated lever pressing for the condi-
the energy expended to obtain the goal all appear to tioned stimulus, in a training dose-dependent manner,
depend on internal changes that alter stimulus even though the rats had never been trained to
effectiveness and readiness to act. administer cocaine (Goddard & Leri 2006). Again,
We have argued, on the basis of our studies showing these data support the view that both a priming drug
that a priming injection of previously self-administered injection and exposure to stress induce reinstatement
drug in experienced drug users can reinstate drug by restoring the incentive salience or value of the drug-
seeking, that the priming injection acts to renew the related cues that previously activated appetitive
significance or salience of the learned stimulus–drug behaviour. In cocaine-dependent men, it was shown
associations. Such drug-related stimuli gain con- using fMRI that the activation by cocaine cues of brain
ditioned incentive value, drawing the animal to regions associated with reward processing and atten-
approach the lever and to engage in lever pressing tion was enhanced in the presence of stress (Duncan
(Stewart et al. 1984; Stewart 1992). Thus, after et al. 2007).

Phil. Trans. R. Soc. B (2008)

 Review. Neurobiology of relapse J. Stewart 3149

drug projections from the ventral tegmental area (VTA) to

the nucleus accumbens (NAc) and medial prefrontal
mPFC cortex (mPFC), and glutamatergic inputs to VTA from
mPFC, peduncular pontine and laterodorsal tegmental
nuclei and from the mPFC to the NAc. There is
evidence that DA receptor antagonists attenuate drug-
NAc induced reinstatement more effectively when given into
the shell region of the NAc (Anderson et al. 2003,
2006; Schmidt et al. 2006), although there is some
VP / SNr evidence that they are effective in the core as well
(Bachtell et al. 2005). Evidence that DA in the shell is
effective in inducing reinstatement is consistent with
previous work showing the importance of the shell in
VTA DA stimulant drug-induced enhancement of responding in
the presence of conditioned stimuli (Parkinson et al.
1999). Interestingly, however, reversible inactivation of
either core or shell blocks drug-induced reinstate-
PPT / LDT ment (McFarland & Kalivas 2001), suggesting, as
discussed in §6, that increases in DA in the shell facilit-
Figure 1. Diagram showing the primary circuits and neuro- ate the effectiveness of cues acting through the core.
transmitters implicated in drug-induced reinstatement. VTA, A great number of studies have shown the import-
ventral tegmental area, cell body regions of mesocorticolim- ance of glutamatergic projections in this circuitry for
bic DA pathway; NAc, nucleus accumbens; mPFC, medial
reinstatement. Though studies have found effects of
prefrontal cortex; VP/SNr, ventral pallidum/substantia nigra
reticulata; PPT/LDT, peduncular pontine and laterodorsal
glutamate agonists and antagonists in tests for drug-
tegmental nuclei. Grey, dopamine; black, glutamate. induced reinstatement (Cornish & Kalivas 2000), it is
not clear to what extent these effects are important to
the mediation of the drug effects, per se, or to the
4. PRIMARY NEURAL PATHWAYS mediation of the effects of drug-related cues in drug-
MEDIATING RELAPSE induced reinstatement (see §6).
Studies carried out in a number of laboratories have
provided evidence that the brain systems mediating the
effects of conditioned stimuli, priming injections of 6. CUE- AND CONTEXT-INDUCED
drugs and stress on the reinitiation of drug seeking are REINSTATEMENT
to some degree dissociable (Shaham et al. 2000a; Contexts or environments where drugs are used can
Stewart 2000; McFarland & Kalivas 2001), although serve as conditioned stimuli (cues), eliciting expec-
common pathways are beginning to be identified tations, thoughts, neural and neurochemical responses,
(McFarland & Kalivas 2001; See 2002; Saal et al. emotional and motivational responses, and behavioural
2003; McFarland et al. 2004; Stewart 2004; Wang et al. responses such as approach. Discrete stimuli such as
2005; Weiss 2005; Rodaros et al. 2007). In the odours, sounds, etc. can have similar effects. Although
following sections, I briefly review evidence concerning these stimuli are paired with the effects of drugs when
the role of different brain systems, regions and they are self-administered, their effectiveness can best
transmitters involved in cue-, drug- and stress-induced be studied using classical conditioning procedures
reinstatement. where stimuli are explicitly paired with drug injections.
Discrete stimuli paired with either passive infusions
(classical conditioning) or response-contingent presen-
5. DRUG-INDUCED REINSTATEMENT tation of a drug (instrumental learning) can come to
The reinstatement of drug craving or seeking by serve as conditioned reinforcers, maintaining responses
priming injections of the abused or training drug, such as lever pressing in the absence of drugs. Finally,
drugs of a similar class or drugs that activate pathways cues that predict the availability/non-availability of
in common with the training drug is a robust drugs (discriminative stimuli) can differentially control
phenomenon in both humans and laboratory animals. the occurrence of drug-seeking/taking behaviours.
As expected, specific receptor antagonists for drugs The neural systems involved in mediating cue-
opioids and nicotine or, in the case of cocaine and induced reinstatement have been studied using sys-
amphetamines, dopamine (DA) receptor antagonists, temic injections of receptor antagonists, intracranial
will block reinstatement induced by priming injections. infusions of receptor agonists and antagonists and
Furthermore, and inasmuch as most, if not all, reversible or non-reversible lesions of specific regions.
addictive drugs activate the mesocorticolimbic path- A sketch of the circuits identified and the primary
ways of the brain, it is not surprising that, in general, neurotransmitters implicated in cue-induced reinstate-
DA receptor agonists induce the reinstatement of drug ment is shown in figure 2. The principal regions
seeking in experienced users, whereas antagonists associated with cue- and context-induced reinstate-
attenuate or block drug-induced reinstatement. A ment are the basolateral amygdala (BLA), the hippo-
sketch of the circuits identified and the primary campus, the mPFC, the NAc core, the DAergic inputs
neurotransmitters implicated in drug-induced rein- to BLA, mPFC and NAc from the VTA, glutamatergic
statement is shown in figure 1. These include DAergic inputs to the VTA and glutamatergic inputs from the

Phil. Trans. R. Soc. B (2008)

3150 J. Stewart Review. Neurobiology of relapse

cue disappeared after extinction training (You et al. 2007),

suggesting that drug-related cues normally activate
mPFC
glutamate release in the VTA where they would serve
to activate the VTA DAergic system. Thus, cue-
HIPP induced reinstatement probably involves the activation
of glutamatergic receptors in both the NAc and
BLA NAc the VTA.

VP / SNr
7. STRESS-INDUCED REINSTATEMENT
In our initial work on stress-induced reinstatement, rats
trained to self-administer heroin intravenously were
given 7–10 days of extinction training and were then
VTA DA
exposed to 10 min of intermittent footshock (acute
stress). Footshock reinstated heroin seeking as it did
again four to six weeks later (Shaham & Stewart 1995).
PPT / LDT Similar effects of footshock were seen in cocaine-
trained rats (Erb et al. 1996) and in rats trained to self-
Figure 2. Diagram showing the primary circuits and neuro- administer nicotine (Buczek et al. 1999) and ethanol
transmitters implicated in cue-induced reinstatement. VTA, (Lê et al. 1998), but interestingly not in rats trained to
ventral tegmental area, cell body regions of mesocortico- lever press for food (Ahmed & Koob 1997) or sucrose
limbic DA pathway; NAc, nucleus accumbens; mPFC, solutions (Buczek et al. 1999). These findings show
medial prefrontal cortex; VP/SNr, ventral pallidum/substantia that exposure to stress reinstates drug seeking in
nigra reticulata; PPT/LDT, peduncular pontine and laterodor- animals experienced in the self-administration of
sal tegmental nuclei; BLA, basolateral amygdala; HIPP, drugs of abuse from several different pharmacological
hippocampus. Grey, dopamine; black, glutamate. classes. In a search for the hormonal and neurochem-
ical systems involved in stress-induced relapse, we
BLA and PFC to the NAc (Ito et al. 2000; Fuchs & See found that stress-induced corticosterone release was
2002; See 2002; Bossert et al. 2004, 2006; Fuchs et al. not responsible for the effect in either cocaine- or
2007; Weiss 2005). In a recent study, an attempt was heroin-trained rats (Shaham et al. 1997; Erb et al.
1998). This finding led us to explore the role of
made using reversible inactivation to assess the role of
corticotropin-releasing factor (CRF) systems of the
the NAc core and shell and dorsal striatum in a number
brain. We found that infusions of CRF given intra-
of behaviours controlled by a conditioned reinforcer
cerebroventricularly (i.c.v.) or into the bed nucleus of
(Di Ciano et al. 2008). Cue-induced reinstatement of
the stria terminalis (BNST) induce reinstatement in
responding was dependent on the NAc core, as were all
the absence of an external stressor, whereas infusions
other conditioned stimulus-controlled behaviours stu-
into the CRF-containing regions of the amygdala,
died (see also Di Ciano & Everitt 2001, 2004), again
central nucleus of the amygdala (CeA), have no effect.
suggesting a special role for the circuits involving the
Infusions of CRF receptor antagonists block footshock-
NAc core in cue-induced reinstatement and relapse. induced reinstatement when given i.c.v. (Shaham et al.
Recently, Kalivas and colleagues have argued for a 1997; Erb et al. 1998) or into the ventrolateral BNST,
key role for glutamate projections from the PFC to the but have no effect in the amygdala (Erb & Stewart
core of the NAc in the precipitation of relapse to drug 1999). Similar effects for central CRF systems have
seeking in general (Kalivas & McFarland 2003; Kalivas been found for rats trained to self-administer alcohol
2004), serving as the final common pathway for all (Lê et al. 2000; Liu & Weiss 2002; figure 3).
events that induce relapse. Glutamatergic agonists In studies of the role of central noradrenergic systems
given into the NAc induce reinstatement (Cornish & in stress-induced relapse, we and others found that
Kalivas 2000), whereas antagonists (Backstrom & systemic injections of agents that reduce cell firing
Hyytia 2007) and mGLU 2/3 receptor agonists, and the release of noradrenaline in the brain, such as the
which reduce glutamate release, given systemically or a2-adrenoceptor agonists, clonidine and lofexidine,
into the NAc (Bossert et al. 2006) block cue-induced block stress-induced reinstatement in cocaine- (Erb
reinstatement. mGLU 2/3 receptor agonists given into et al. 2000), heroin- (Shaham et al. 2000b) and alcohol-
the VTA block both cue-induced reinstatement of trained rats (Lê et al. 2005). Interestingly, in both rats
heroin seeking (Bossert et al. 2004) and cue- and and monkeys, the a2-antagonist, yohimbine, induces
nicotine-induced reinstatement of nicotine (Liechti reinstatement, acting like a stressor (Lee et al. 2004;
et al. 2007), suggesting that the glutamatergic Shepard et al. 2004; Gass & Olive 2007). In addi-
activation of DAergic neurons may play an important tional experiments, we determined that noradrenergic
role in both cue and drug seeking especially when neurons arising from the lateral tegmental nuclei and
the drugs have their effects by activating DAergic projecting to the CeA and BNST were of primary
neurons. In a recent study, it was shown that the importance in stress-induced reinstatement (Shaham
initiation of self-administration in cocaine-trained rats et al. 2000b). These findings, combined with those
was accompanied by a sharp transient release of showing the importance of extra-hypothalamic CRF
glutamate in the VTA and that this was a conditioned activity, led us to study the role of noradrenergic activity
response associated with drug-related cues and that it in the BNST and CeA regions in stress-induced

Phil. Trans. R. Soc. B (2008)

 Review. Neurobiology of relapse J. Stewart 3151

stress drug/cue/stress
mPFC
mPFC

HIPP
HIPP
BLA NAc
BLA NAc

VP / SNr
CeA BNST VP / SNr
CeA BNST

VTA DA
VTA DA

PPT / LDT
LTN NA PPT / LDT
Figure 3. Diagram showing the primary circuits and neuro-
Figure 4. Diagram showing the primary circuits and neuro-
transmitters implicated in stress-induced reinstatement.
transmitters implicated in reinstatement by drugs, cues and
VTA, ventral tegmental area, cell body regions of mesocorti-
stressors. VTA, ventral tegmental area, cell body regions of
colimbic DA pathway; NAc, nucleus accumbens; mPFC,
mesocorticolimbic DA pathway; NAc, nucleus accumbens;
medial prefrontal cortex; VP/SNr, ventral pallidum/substan-
mPFC, medial prefrontal cortex; VP/SNr, ventral pallidum/
tia nigra reticulata; PPT/LDT, peduncular pontine and
substantia nigra reticulata; PPT/LDT, peduncular pontine
laterodorsal tegmental nuclei; BLA, basolateral amygdala;
and laterodorsal tegmental nuclei; BLA, basolateral amyg-
HIPP, hippocampus; CeA, central nucleus of the amygdala;
dala; HIPP, hippocampus; CeA, central nucleus of the
BNST, bed nucleus of the stria terminalis. Dark grey,
amygdala; BNST, bed nucleus of the stria terminalis; LTN,
dopamine; black, glutamate; light grey, CRF.
lateral tegmental nuclei; NA, noradrenaline. Dark
grey, dopamine; black, glutamate; light grey, CRF; black
dots, noradrenaline.
reinstatement. We found a dose-dependent reduction of
stress-induced reinstatement after infusions of
b-receptor antagonists into the BNST, and a complete These findings, combined with those showing that
blockade after infusions into the CeA at all doses tested inactivation of the shell or core blocks stress-induced
without an effect on cocaine-induced reinstatement at reinstatement (McFarland et al. 2004), establish a role
either site (Leri et al. 2002). for the DAergic system in stress-induced reinstate-
These data suggest that the mediation of the effects ment. In addition, these findings, taken together with
of footshock on reinstatement of drug seeking is via the those discussed above for cue-induced reinstatement,
release of noradrenaline in the amygdala and the confirm the idea that the PL region of the mPFC serves
BNST. Through the effects at b-noradrenergic as a common pathway for cue-, drug- and stress-
receptors, noradrenaline may activate CRF-containing induced reinstatement of drug seeking. Sketches of the
cells in both the regions. Some of these CRF neurons circuits and neurotransmitters implicated in stress-
appear to project from the CeA to the BNSTand others induced reinstatement are shown in figures 3 and 4.
are intrinsic to the BNST itself. Interference in this In an earlier section, we saw how drugs and stressors
circuit has no effect on cocaine-induced relapse, might have their effects on relapse by renewing the
suggesting that the brain systems mediating stress- effectiveness of drug-related cues in the instigation of
induced relapse could be dissociated from those appetitive, drug-seeking, behaviours. Another issue is
mediating drug-induced relapse. Furthermore, we how the activation of the CRF systems, found to be
had found that stress-induced reinstatement of heroin critical for stress-induced relapse, gain access to those
seeking was relatively unaffected by systemic injections systems that mediate appetitive behaviours such as
of DA D1 or D2 receptor antagonists, and that only drug seeking.
sustained treatment with a mixed antagonist was CRF systems are known to be activated in response to
effective (Shaham & Stewart 1996). However, the stressors and to mediate a wide variety of physiological
role of DA in stress-induced relapse was shown in and behavioural responses to stress including fear and
subsequent studies to include the mPFC, where anxiety (Schulkin et al. 2005; Davis 2006); in addition,
infusions of a D1 receptor antagonist, SCH23390, CRF has been shown to facilitate locomotor activity
into the prelimbic (PL) region block footshock stress- (Kalivas et al. 1987; Cador et al. 1993) and responses to
induced, but not cocaine-induced, reinstatement positive incentive stimuli (Pecina et al. 2006), responses
(Capriles et al. 2003). mPFC infusions of the D1/ D2 involved in appetitive behaviour. Little is known about
antagonist fluphenazine block footshock stress- the pathways through which the activation of CRF
induced reinstatement and, interestingly, the inacti- systems facilitates appetitive behaviour. In a recent
vation of PL by tetrodotoxin infusions blocked both study, it was found, however, that CRF is released
footshock (McFarland et al. 2004) and cocaine- directly into the VTA during footshock stress and that,
induced reinstatement (McFarland & Kalivas 2001). in cocaine-experienced rats, intra-VTA infusions of a

Phil. Trans. R. Soc. B (2008)

3152 J. Stewart Review. Neurobiology of relapse

CRF receptor antagonist block stress-induced reinstate- processes initiated in the cell body region of DAergic
ment (Wang et al. 2005). These findings point to an neurons are responsible for sensitized functioning
interaction between the CRF-containing cell groups within the system. The relevance of such drug-induced
and the DAergic neurons in the VTA, providing a sensitization within the mesolimbic DAergic system to
possible pathway for stress activation of CRF to the motivational effects of drugs and drug-related
modulate appetitive behaviour. Interestingly, prior stimuli has recently been reviewed by Vezina (2007).
exposure to stress facilitates glutamatergic synaptic The long-lasting changes induced by stimulant
transmission in DAergic neurons in the VTA, in a drugs suggest structural modifications in neuronal
manner similar to prior exposure to drugs of abuse circuitry and, in fact, studies have shown selective
(Saal et al. 2003). Furthermore, CRF applied directly and persistent changes in transcription factors known
to a VTA slice preparation has a similar effect (Ungless to be involved in neuroplasticity (Chen et al. 1995;
et al. 2003). Little is known, however, about the sources Nestler et al. 1999, 2001), drug-induced changes
of CRF-containing fibres in the VTA. An under- in synaptic facilitation and long-term potentiation of
standing of the sources of the CRF innervation of DA neurons in the VTA (Bonci & Williams 1996;
the VTA would help explain the role of stress and Ungless et al. 2001; Borgland et al. 2004; Liu et al.
CRF in the modulation of appetitive behaviours. 2005), long-term depression and potentiation in the
We recently found using a fluorescent retrograde NAc ( Thomas et al. 2001; Kourrich et al. 2007), and
tracer and fluorescence immunocytochemistry for structural changes in the VTA, NAc and mPFC
CRF that the VTA region receives CRF projections neurons following repeated exposure to these drugs
from the oval nucleus of the BNST, the CeA and the (Robinson & Kolb 1997; Hu et al. 2002; Mueller et al.
paraventricular nucleus of the hypothalamus (Rodaros 2006; Sarti et al. 2007). The fact that many of the
et al. 2007), pointing to a means whereby stressor important long-lasting changes are enhanced by the
activation of CRF systems of the brain could facilitate passage of time after the termination of drug exposure
the DAergic activity in the VTA and, thus, appetitive and involve structural changes in neurons suggests that
behaviour. A final summary sketch showing all these neurotrophic factors are involved. We found, for
circuits and primary neurotransmitters implicated example, that amphetamine induces increases in the
in drug-, cue- and stress-induced reinstatement is neurotrophic factor, basic fibroblast growth factor
shown in figure 4. (bFGF or FGF-2), in astrocytes in the VTA, which
are seen early after the termination of drug treatment
and last for at least one month (Flores et al. 1998). As
8. SOURCES OF PLASTICITY WITHIN PATHWAYS is the case for the development of behavioural
MEDIATING RELAPSE sensitization to amphetamine (see Wolf 1998), the
The major sources of plasticity within pathways induction of bFGF by amphetamine is prevented by
mediating relapse derive from exposure to the pharma- the co-administration of glutamate antagonists, and
cological effects of the drugs themselves, and from the inactivation of bFGF in the VTA prevents the
conditioning and learning associated with drugs. development of behavioural sensitization to amphet-
The idea that long-term changes within specific amine ( Flores et al. 2000). We proposed that repeated
circuitry might alter the motivational effects of drugs exposure to stimulant drugs increases the demands
has received considerable attention within the field on DAergic cell functioning, and by stimulating
of drug abuse (e.g. Piazza et al. 1990; Robinson & glutamate release recruits neurotrophic and neuropro-
Berridge 2000; Nestler et al. 2001). The circuitry found tective substances such as bFGF ( Flores & Stewart
to undergo lasting changes as a result of repeated 2000). More recent studies have pointed to a major
exposure to stimulant drugs is the mesocorticolimbic role for brain-derived neurotrophic factor (BDNF) in
DAergic system and its targets in striatum, amygdala the long-lasting changes induced by drugs of abuse
and mPFC. Stimulant and opioid drugs induce (Grimm et al. 2003; Lu et al. 2004; Liu et al. 2006;
increases in extracellular DA in all of these regions, as Berglind et al. 2007; Graham et al. 2007). Earlier
well as in the BNST (see Di Chiara et al. 1999). studies suggested that BDNF can induce long-lasting
Repeated exposure to stimulant drugs, such as changes in the sensitivity of the mesolimbic DAergic
amphetamine and cocaine, results in the enhancement pathway to motivationally significant stimuli (Shen
of their behavioural activating effects. This phenom- et al. 1994; Horger et al. 1999). Support for this view
enon, known as behavioural sensitization, develops comes from a study showing that the potentiation
over time, is observed months after the termination of of excitatory synapses at DAergic neurons in the
drug treatment (Paulson et al. 1991; Castner & VTA after withdrawal from cocaine is dependent on
Goldman-Rakic 1999) and is accompanied by an BDNF TrkB receptor signalling (Pu et al. 2006). A
increased responsiveness of the mesolimbic DAergic time-dependent enhancement of cue-induced rein-
system (see Robinson & Becker 1986; Kalivas & statement in rats has been found days and months
Stewart 1991). This enhancement develops gradually, after the termination of cocaine self-administration
is long-lasting, and appears to result from a series of (Grimm et al. 2001). This phenomenon, referred to
changes within the DAergic system and its targets as ‘an incubation effect’, is accompanied by the
that occur over time after the termination of drug increased expression of BDNF in the VTA, NAc and
treatment. Importantly, it has been found that these amygdala over many days (Grimm et al. 2003).
changes in behaviour and DAergic function can be Recently, it was found that if BDNF was infused into
mimicked by the direct application of amphetamine the NAc of rats immediately following daily cocaine
in the VTA (see Vezina 2004), demonstrating that self-administration sessions, reinstatement of cocaine

Phil. Trans. R. Soc. B (2008)

 Review. Neurobiology of relapse J. Stewart 3153

seeking was greatly enhanced after presentations of immediately after the discontinuation of cocaine (they
drug-associated cues, priming injections of cocaine or were in fact decreased), but are seen after 14 days
footshock stress (Graham et al. 2007). (Boudreau et al. 2007): temporal changes that parallel
Time-dependent effects have been found for stress- changes in sensitivity to glutamatergic input to NAc
induced reinstatement of both heroin (Shalev et al. neurons (Kourrich et al. 2007).
2001) and cocaine seeking (Sorge & Stewart 2005). It It has been proposed that drug-induced changes in
is likely that a number of systems are involved in these cystine–glutamate exchange in the NAc, which would
changes over time, including DAergic, CRF (Orozco- induce changes in glutamatergic tone in the NAc, may
Cabal et al. 2008) and noradrenergic systems (Leri underlie these lasting changes in glutamatergic function
et al. 2002; Macey et al. 2003; Dumont & Williams (Baker et al. 2002, 2003). It is considered that the
2004). Whether BDNF plays a role in these effects is reduced tone affects presynaptic mGlu receptors
not known. causing dysregulation of glutamatergic function
(Moran et al. 2005). The restoration of cystine–
glutamate exchange blocks cocaine-induced reinstate-
9. DRUG-INDUCED PLASTICITY IN ment of cocaine seeking (Baker et al. 2003; Madayag
GLUTAMATERGIC FUNCTION et al. 2007) and cue- and heroin-induced reinstatement
As discussed previously, there is evidence that BDNF of heroin seeking (Zhou & Kalivas 2008). Interestingly,
plays a role in the facilitation of NMDA receptor- chronic treatment with the partial opioid agonist,
mediated glutamatergic transmission at DAergic buprenorphine, a drug used in the treatment of heroin
neurons in the VTA after the termination of cocaine and cocaine abuse, blocks drug-induced reinstatement
exposure (Pu et al. 2006), an effect observed at of both heroin and cocaine seeking and reduces
10–15 days, but not at 1 day, after cocaine exposure. responding to drug-paired cues, and we have found
Furthermore, increases in NMDAR1 subunits have that chronic infusions of this drug increase basal levels
been reported in the VTA for up to 90 days after the of both DA and glutamate in the NAc, suggesting that
termination of cocaine (Lu et al. 2003). The blockade it may have its ‘therapeutic’ effect by stabilizing
of glutamate receptors in the VTA decreases cocaine- dysregulated transmitter function following the termin-
induced reinstatement of cocaine seeking (Sun et al. ation of drug taking (Sorge et al. 2005; Sorge & Stewart
2005a), and intra-VTA infusions of a group II 2006; Placenza et al. in press). In addition, as
metabotropic glutamate receptor agonist, thought to mentioned above, a group II mGluR agonist given
reduce glutamate release, block cue-induced reinstate- into the NAc blocks cue-induced reinstatement of
ment in heroin-trained rats (Bossert et al. 2004). In a heroin seeking and, given systemically, cue- and stress-
study discussed previously, it was shown that after induced ethanol seeking (Zhao et al. 2006). Together,
cocaine self-administration, CRF released in the VTA these data lend strong support to the idea that
during exposure to stress causes glutamate release (an long-lasting dysregulation of glutamatergic function
effect not seen in cocaine-naive rats) and that stress- involving the mPFC and the NAc contributes impor-
induced reinstatement could be blocked by a glutamate tantly to sensitivity to triggers for, and thus vulnerability
receptor antagonist (Wang et al. 2005). This study to, relapse.
provides another example of long-lasting facilitation of
glutamatergic activity in the VTA after cocaine
exposure, in this case via changes in the effectiveness 10. SUMMARY
of CRF. It is likely that similar changes, perhaps Experience with drug self-administration promotes
mediated by other peptides, will be found within those long-lasting changes in systems of the brain mediating
brain regions already identified as playing critical roles the effects of events that trigger relapse to drug seeking.
in the reinstatement of drug seeking induced by various These lasting changes are induced, in part, by mere
triggers (e.g. Dumont et al. 2005, 2008). exposure to the pharmacological effects of these drugs
Changes in glutamatergic functioning have and, in part, through conditioning and learning.
already been found to play a critical role in the Circuits of the brain involved in relapse are those of
reinstatement of drug seeking. Marked increases in the mesocorticolimbic DAergic system and its gluta-
glutamate release in the NAc core in response to matergic inputs, and the CRF and noradrenergic
drugs or stress have been found after extinction in rats systems of the limbic brain. Exposure to drugs changes
trained to self-administer cocaine or heroin. Simple sensitivity to subsequent exposure to drugs and to the
exposure to drugs does not seem to be sufficient to effects of stressors. Many neurochemical and molecular
induce this effect, again suggesting that learning changes have been found to underlie drug-induced
about drug-associated cues may be critical (McFarland plasticity. These changes develop with repeated
et al. 2003, 2004). These researchers have argued exposure, invade more brain regions over time (Porrino
that this enhanced release of glutamate arises from et al. 2004) and have progressive consequences on
the activation of mPFC inputs to the NAc, and there behaviour (Everitt & Robbins 2005; Kalivas & O’Brien
is other evidence for changes in glutamate receptors 2008). Environmental stimuli that acquire conditioned
in the NAc after cocaine exposure that would incentive properties through pairings with the effects
make cells more sensitive to glutamatergic input of drugs maintain their capacity to instigate drug
(Boudreau & Wolf 2005; Sun et al. 2005b; Gao et al. seeking in spite of long-term abstinence. After extinc-
2006). Interestingly, reported increases in cell surface tion training, when the capacity of these conditioned
glutamatergic AMPA (alpha-amino-3-hydroxy-5-methyl- stimuli to induce relapse is diminished or absent, expos-
4-isoxazolepropionic acid) receptors are not seen ure to a stressor or the drug itself is able to reinstate

Phil. Trans. R. Soc. B (2008)

3154 J. Stewart Review. Neurobiology of relapse

the effectiveness of cues and drug-seeking behaviours. the nucleus accumbens shell attenuates context-induced
Although a number of manipulations have been found to relapse to heroin seeking. Neuropsychopharmacology 31,
reduce reinstatement by cues, drugs and stressors, few 2197–2209. (doi:10.1038/sj.npp.1300977)
are sufficiently broad in their effects to serve as effective Boudreau, A. C. & Wolf, M. E. 2005 Behavioral sensitiza-
tion to cocaine is associated with increased AMPA
treatments.
receptor surface expression in the nucleus accumbens.
Experimental procedures comply with the guidelines of the J. Neurosci. 25, 9144 –9151. (doi:10.1523/JNEUROSCI.
Canadian Council on Animal Care. 2252-05.2005)
Boudreau, A. C., Reimers, J. M., Milovanovic, M. & Wolf,
This work was supported by grants from the Canadian M. E. 2007 Cell surface AMPA receptors in the rat
Institutes of Health Research (CIHR) and Le Fonds de la nucleus accumbens increase during cocaine withdrawal
recherche en santé du Québec (FRSQ). but internalize after cocaine challenge in association with
altered activation of mitogen-activated protein kinases.
J. Neurosci. 27, 10 621–10 635. (doi:10.1523/JNEUR-
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