Neural mechanisms underlying the vulnerability
to develop compulsive drug-seeking
habits and addiction
Barry J. Everitt*, David Belin, Daina Economidou, Yann Pelloux,
Jeffrey W. Dalley and Trevor W. Robbins
Behavioural and Clinical Neuroscience Institute, Department of Experimental Psychology,
University of Cambridge, Downing Street, Cambridge CB2 3EB, UK
We hypothesize that drug addiction can be viewed as the endpoint of a series of transitions from initial
voluntary drug use through the loss of control over this behaviour, such that it becomes habitual and
ultimately compulsive. We describe evidence that the switch from controlled to compulsive drug
seeking represents a transition at the neural level from prefrontal cortical to striatal control over drug-
seeking and drug-taking behaviours as well as a progression from ventral to more dorsal domains
of the striatum, mediated by its serially interconnecting dopaminergic circuitry. These neural
transitions depend upon the neuroplasticity induced by chronic self-administration of drugs in
both cortical and striatal structures, including long-lasting changes that are the consequence of toxic
drug effects. We further summarize evidence showing that impulsivity, a spontaneously occurring
behavioural tendency in outbred rats that is associated with low dopamine D2/3receptors in the
nucleus accumbens, predicts both the propensity to escalate cocaine intake and the switch to
compulsive drug seeking and addiction.
Keywords: vulnerability; compulsion; addiction; striatum; dopamine; habits
The central hypothesis guiding our research during the
past decade or more has been that drug addiction can
be understood in terms of the operation of the brain’s
learning and memory systems (Robbins & Everitt
1999; Everitt et al. 2001; Everitt & Robbins 2005). In
particular, that chronically self-administered drugs
may in some way pathologically subvert these memory
systems and so lead to the establishment of compulsive
drug-seeking habits (Everitt & Robbins 2005). Initially,
our approach to the understanding of drug addiction
built upon the clinical insight embodied within the
DSM-IV (1994) criteria for ‘substance abuse’ and
‘substance dependence’. Therefore, we began experi-
mentally to decompose and augment the DSM-IV
diagnostic framework in terms of specified learning and
cognitive processes deriving from animal learning
theory and that increasingly have been attributed to
the operation of specific neural, especially limbic
cortical–striatal, systems (Everitt et al. 2001).
The early focus of much experimental drug addic-
tion research was to understand the reinforcing, or
‘rewarding’, effects of abused drugs; this has led to
great advances in defining the primary molecular
targets of addictive drugs as well as, more recently,
the adaptations in these targets that develop with
chronic drug self-administration (Nestler 2004;
Koob & Le Moal 2005). However, it has been
appreciated for some time that the molecular and
neurochemical correlates of acute and chronic drug
administration must be interpreted in behavioural and
cognitive terms if the psychological processes and
neurobiological mechanisms determining human drug
addiction are to be specified. Therefore, we and others
have increasingly come to view drug addiction as the
endpoint of a series of transitions from initial drug
use—when a drug is voluntarily taken because it has
reinforcing, often hedonic, effects—through the loss of
control over this behaviour, such that it becomes
habitual and ultimately compulsive. We have recently
reviewed the evidence that these transitions depend
upon interactions between Pavlovian and instrumental
learning processes (Everitt & Robbins 2005). Further-
more, we have hypothesized that the ‘switch’ from
voluntary drug use to habitual and progressively
compulsive drug use represents a transition at the
neural level from prefrontal cortical to striatal control
over drug-seeking and drug-taking behaviours, as well
as a progression from ventral to more dorsal domains of
the striatum, mediated at least in part by its stratified
dopaminergic innervation (Everitt & Robbins 2005).
Phil. Trans. R. Soc. B (2008) 363, 3125–3135
Published online 18 July 2008
One contribution of 17 to a Discussion Meeting Issue ‘The
neurobiology of addiction: new vistas’.
Electronic supplementary material is available at http://dx.doi.org/10.
1098/rstb.2008.0089 or via http://journals.royalsociety.org.
*Author for correspondence (firstname.lastname@example.org).
This journal is q 2008 The Royal Society
We summarize here recent evidence in support of
the hypothesis that drug-seeking habits are associated
with a shift from ventral to dorsal striatal control over
behaviour. We also address the major issue of vulner-
ability to drug addiction—that some individuals are
more likely than others to take drugs, lose control over
and escalate their drug intake, and ultimately to seek
drugs compulsively. Experimental models of addiction,
rather than drug self-administration, must reflect
such individual differences and also incorporate
extended periods of drug taking if the underlying
neural mechanisms of addiction are to be identified
(Koob & Le Moal 2005).
2. FROM VOLUNTARY TO HABITUAL DRUG
SEEKING: THE SHIFT FROM VENTRAL TO
With drugs such as cocaine, there is wide, though
not universal, agreement that the dopaminergic
innervation of the nucleus accumbens shell (AcbS),
and even more ventral regions of the striatum, such as
the olfactory tubercle, underlies its primary reinforcing
effects (Di Chiara et al. 2004; Wise 2004; Ikemoto et al.
2005) as measured in drug self-administration
procedures. We term this ‘drug taking’ to distinguish
it from ‘drug-seeking’ behaviour, which must often
be maintained over long periods of time and is
profoundly influenced by environmental stimuli
associated with self-administered drugs through
Pavlovian conditioning (Everitt et al. 2001). In
humans, these conditioned stimuli (CSs) can induce
subjective states such as craving, as well as drug
seeking and relapse after abstinence (Grant et al.
1996; Childress et al. 1999; Garavan et al. 2000).
We have therefore developed a general model of
drug seeking—a second-order schedule of cocaine
reinforcement—in which this behaviour is sensitive
not only to the contingency between instrumental
responses and drug administration, but also to the
presence of drug-associated CSs that have a powerful
effect on performance by acting as conditioned
reinforcers (Everitt & Robbins 2000). We have
established that the acquisition of this cocaine-seeking
behaviour depends upon the integrity of the nucleus
accumbens core (AcbC) and its afferents from the
basolateral amygdala (BLA). Thus, selective lesions
of the BLA prevented the acquisition of cocaine
seeking under a second-order schedule (Whitelaw
et al. 1996), as expected given its fundamental role
in conditioned reinforcement (Cador et al. 1989;
Cardinal et al. 2002). Similarly, selective lesions
of the AcbC also greatly impaired the acquisition of
cocaine seeking (Ito et al. 2004). Simple drug taking,
on the other hand, was unimpaired by BLA or AcbC
lesions (Whitelaw et al. 1996; Ito et al. 2004). As we
have reviewed elsewhere, the AcbC region of the
ventral striatum is also a key locus not only for
conditioned reinforcement but also for other Pavlo-
vian influences on appetitive behaviour, including
approach, as measured in autoshaping procedures,
and Pavlovian–instrumental transfer, the process by
which Pavlovian CSs energize ongoing instrumental
behaviour, an example of conditioned motivation,
each of which also depends upon processing in
sub-regions of the amygdala (Cardinal et al. 2002;
Cardinal & Everitt 2004).
These observations indicate that the BLA and AcbC
may function together as nodes within a limbic
cortical–ventral striatopallidal system that underlies
the acquisition of drug seeking. This notion is further
supported by the observation that disconnecting these
structures by unilateral pharmacological blockade of
dopamine and AMPA receptors in the BLA and AcbC,
respectively, on opposite sides of the brain also greatly
diminished cocaine seeking (Di Ciano & Everitt 2004).
Thus, the acquisition and early performance of cocaine
seeking that is maintained over protracted periods of
time by the contingent presentation of drug-associated
conditioned reinforcers depends upon the integrity of
the AcbC and its afferent input from the BLA. It can be
assumed that, at this stage, drug seeking is under the
control of instrumental response–outcome contingen-
cies in which animals respond in a voluntary and goal-
directed way for intravenous cocaine infusions. Indeed,
we have clear evidence that this is so from studies using
a ‘seeking–taking’ chained schedule in which animals
perform a drug-seeking response in the initial link of
the chain, which then gives access to a drug-taking
response in the second link, performance of which
delivers cocaine (Olmstead et al. 2001). After a limited
experience with the drug, cocaine seeking was shown to
be a goal-directed action in that its performance was
sensitive to devaluation of the drug-taking link
(Olmstead et al. 2001). This devaluation effect
demonstrates that cocaine seeking at early stages of
acquisition and performance is mediated by the
knowledge of the contingency between the seeking
response and its outcome.
This response–outcome process can be contrasted
with a second, stimulus–response (S–R) instrumental
process in which seeking behaviour is a response habit
triggered and maintained by drug-associated stimuli
(Everitt et al. 2001). Tiffany (1990), O’Brien &
McClellan (1996) and ourselves (Robbins & Everitt
1999; Everitt et al. 2001; Everitt & Robbins 2005) have
all advanced the hypothesis that drug addiction
encompasses changes in the associative structure
underlying drug seeking such that it becomes ‘auto-
matic’ or habitual. We have additionally hypothesized
that the progressive engagement of dorsal striatal
mechanisms underlies this transition (Everitt & Robbins
2005), based upon evidence that the dorsolateral
(DL) striatum mediates S–R habit learning—evidence
that has been considerably strengthened through the
recent studies of instrumental responding for food and
its resistance to reinforcer devaluation, a canonical test
of the development of S–R habits (Yin et al. 2004,
2006). What then is the evidence that the dorsal
striatum mediates the performance of well-established
drug-seeking habits that depend initially upon ventral
striatal mechanisms during acquisition? Correlative
evidence came from in vivo microdialysis measurement
of extracellular dopamine in rats that had attained
over a two-month period stable responding under a
second-order schedule of cocaine seeking. While self-
administered cocaine increased dopamine release in
the AcbS, AcbC and caudate–putamen, extracellular
3126B. J. Everitt et al. Review. Mechanisms of compulsive drug seeking
Phil. Trans. R. Soc. B (2008)
dopamine was increased selectively in the AcbC in
response to unexpected (i.e. non-response contingent)
presentations of a cocaine-associated stimulus.
However, during a prolonged period of cocaine
seeking maintained by contingent presentations of
the same cocaine-associated CS, dopamine release was
increased only in the dorsal striatum, not in the AcbC
or AcbS (Ito et al. 2000, 2002). Furthermore,
dopamine release in the dorsal striatum was sub-
sequently shown to be causally important for the
maintenance of drug seeking, since it was greatly
reduced by dopamine receptor blockade at this site,
whereas this treatment was without effect in the AcbC
(Vanderschuren et al. 2005). This apparent shift from
ventral to dorsal striatal control over drug seeking
provides support for the hypothesis that it is under
S–R, or ‘habit’, control owing to accumulated
evidence implicating the dorsal striatum in habit
learning (Yin et al. 2004, 2006). Moreover, the fact
that the second-order schedule we have principally
used is of a fixed-interval type encourages this view,
since interval schedules are known to result in the
more rapid development of S–R habits through the
weaker relationship between response and outcome
that obtains, when compared with ratio schedules
(Dickinson 1985). In addition, studies with orally self-
administered cocaine and alcohol have shown the
more rapid development of habitual drug seeking
compared with the seeking of a natural sweet reward
(Dickinson et al. 2002, Miles et al. 2003).
These observations supporting the increasing
importance of the dorsal striatum in well-established,
or habitual, drug seeking raise the issue of how, in
neural terms, such a shift in the locus of control from
ventral to dorsal striatum might occur. The obser-
vations of Haber et al. (2000) in primates and, more
recently, Ikemoto (2007) in rats provide a possible
neuroanatomical basis. They showed that ventral tiers
of the striatal complex regulate the dopaminergic
innervation of more dorsal tiers through so-called
‘spiralling’ connections with the midbrain (figure 1a).
Thus, the AcbS projects to dopamine neurons in the
ventral tegmental area that innervate not only the shell
but also the more dorsally situated AcbC. Neurons in
the AcbC innervate dopamine neurons projecting
to both the AcbC and the immediately dorsal regions
of the dorsomedial caudate–putamen and so on, in
a serially cascading pattern ultimately to encompass
α-flupenthixol ( g per infusion)
Figure 1. Within striatum serial processing underlies the establishment of cocaine-seeking habits. (a) Schematic of the
intrastriatal dopamine-dependent spiralling circuitry functionally connecting the ventral with the dorsal striatum in the rat
(modified from Belin & Everitt 2008). The spiralling loop organization is depicted as the alternation of pink and black arrows
from the ventral to the more dorsal parts of the circuit, i.e. from the AcbS (yellow) to the AcbC (light blue) via the ventral
tegmental area (pink) and from the AcbC, via the substantia nigra to the dorsal striatum (dark blue). (b) Cocaine seeking is dose
dependently impaired by bilateral infusions of the DA receptor antagonist a-flupenthixol (depicted as green dots) into the DL
striatum. a-Flupenthixol infusions into the DL striatum dose dependently decreased responding on the active lever under a
second-order schedule of cocaine reinforcement, but had no effect on responding on the inactive lever (Belin & Everitt 2008).
(c) Disconnecting the AcbC from the dopaminergic innervation of the dorsal striatum impairs habitual cocaine seeking. In
unilateral AcbC-lesioned rats, the AcbC relay of the loop is lost on the one side of the brain. However, on the non-lesioned side,
the spiralling circuitry is intact and functional. When a-flupenthixol (green dots) is infused in the DL striatum contralateral to
the lesion it blocks the DAergic innervation from the midbrain, impairing the output structure of the spiralling circuitry on the
non-lesioned side of the brain. Therefore, this asymmetric manipulation disconnects the core of the nucleus accumbens from the
DL striatum bilaterally and greatly diminishes cocaine seeking (figure adapted with permission from Belin & Everitt (2008)).
Review. Mechanisms of compulsive drug seeking
B. J. Everitt et al.
Phil. Trans. R. Soc. B (2008)
more lateral parts of the dorsal striatum—the site at
which dopamine release is increased during habitual
drug seeking and where dopamine receptor antagonist
infusions impair this behaviour.
We tested the hypothesis that the serial cascade
of striato-nigro-striatal connectivity underlies this
progressively greater control over well-established
cocaine-seeking behaviour by the DL striatum using a
novel ventral–dorsal striatal ‘disconnection’ (figure 1b).
Thus, the AcbC was selectively lesioned on one side of
the brain and combined with dopamine receptor
blockade in the contralateral DL striatum, thereby
functionally disconnecting serial interactions between
these ventral and dorsal striatal domains bilaterally
(Belin & Everitt 2008). This disconnection greatly and
selectively decreased cocaine seeking in rats tested
some weeks after stable responding had been attained
under a second-order schedule of reinforcement
(figure 1c). Two important additional observations
underlined the specificity of the ventral–dorsal striatal
disconnection effect. (i) The same animals were trained
to perform a novel chain-pulling response for sucrose
under a fixed ratio 1 schedule of reinforcement and
again underwent the disconnection manipulation, or
bilateral dorsal striatal dopamine receptor antagonist
infusions (in non-lesioned rats), immediately after
acquisition when the behaviour was under response–
outcome control; neither manipulation had any effect
(Belin & Everitt 2008). (ii) In separate groups of
animals, either bilateral dorsal striatal dopamine
receptor blockade or AcbC-dorsal striatal disconnec-
tion was performed at a much earlier stage of acqui-
sition of the cocaine seeking, second-order schedule
when responding was under ratio, rather than interval,
control and when response–outcome mechanisms
dominate performance. Again, neither manipulation
had any effect on cocaine seeking (D. Belin & B. J.
Everitt 2008, unpublished observations).
Taken together, the above results clearly indicate the
devolution of control over drug seeking from ventral to
dorsal striatum and also strongly suggest that this shift
is progressive. Other data also support the notion of
this shift. For example, using autoradiographic
methods, Porrino and colleagues showed the develop-
ment of neuroadaptations in D2/3dopamine receptors
and other neurochemical, or metabolic, markers in the
dorsal striatum following chronic, but not acute,
cocaine self-administration by monkeys (Letchworth
et al. 2001; Porrino et al. 2004). At earlier stages of
training, these adaptations were largely restricted to the
more ventral, nucleus accumbens region. The DL
striatum has also been shown to be involved in ‘relapse’
to a cocaine-seeking habit, since neural inhibition
induced by g-aminobutyric acid receptor agonist
infusion into this area, but not into the AcbS or
AcbC, prevented the reinstatement of cocaine seeking
after protracted withdrawal (Fuchs et al. 2006; See
et al. 2007). Moreover, the presentation of drug cues to
human cocaine addicts both induced drug craving (that
has been shown to be correlated with the activation of
the amygdala and limbic prefrontal cortical areas;
Grant et al. 1996; Childress et al. 1999; Garavan et al.
2000) and also marked the activation of the dorsal
striatum (Garavan et al. 2000; Volkow et al. 2006).
These observations therefore strongly indicate a link
between limbic cortical mechanisms and the engage-
ment of the dorsal striatum in long-term drug abusers
exposed to drug cues, whereas the results of our
ventral/dorsal striatal disconnection experiments reveal
that this recruitment is mediated by antecedent limbic
cortex-dependent activity in the AcbC and its
regulation of dorsal striatal dopaminergic projections.
It seems likely that the ventral to dorsal striatum shift
is not specific to drug seeking, but would apply equally
to the control over instrumental responding for natural
reinforcers under appropriate conditions. Indeed,
lesion or inactivation of the AcbC, dorsomedial or
DL striatum in rats responding for ingestive reinforcers
does not globally impair instrumental behaviour, but
instead has major effects that depend upon the
response–outcome or S–R associative structure under-
lying the behaviour. Lesions or N-methyl-D-aspartate
receptor blockade of the AcbC (Kelley et al. 1997;
Corbit et al. 2001) or dorsomedial striatum (Yin et al.
2004, 2005), impair instrumental behaviour under
response–outcome control, but actually enhance the
development of S–R habits in which responding
persists after reinforcer devaluation (Yin et al. 2004).
By contrast, DL striatal lesions, inactivation or
dopamine denervation return previously habitual
responding to response–outcome control, reinstating
sensitivity to reinforcer devaluation (Yin et al. 2004;
Faure et al. 2005) or action–outcome contingency
degradation (Yin et al. 2006). These observations
emphasize that response–outcome and S–R learning
mechanisms are probably engaged not serially, but in
parallel, with DL striatum-dependent S–R mechanisms
eventually dominating the control over behaviour.
However, it is possible that the shift from ventral to
dorsal striatal control occurs more rapidly in animals
seeking drugs owing to the effects of these agents
themselves on the plasticity mechanisms involved,
particularly in the case of psychomotor stimulants
which so powerfully increase dopamine transmission.
Thus, an amphetamine sensitization treatment regi-
men leads to the more rapid instantiation of habit
learning in animals responding for food (Nelson &
Killcross 2006). Moreover, animals that had escalated
their cocaine intake showed, when subsequently
challenged with cocaine, a marked enhancement of
stereotyped behavioural responses that have long been
known to depend upon the dorsal, rather than the
ventral, striatal dopaminergic innervation (Ferrario
et al. 2005). Finally, Schoenbaum and colleagues have
demonstrated a shift in the balance of associative
encoding from ventral to dorsal striatum correlated with
concomitant enhancement of cue-evoked neuronal
firing in the dorsal striatum (Takahashi et al. 2007).
This finding resonates with the observation of drug-
associated CS-induced activation of the dorsal striatum
in human cocaine abusers (Garavan et al. 2000; Volkow
et al. 2006). Therefore, the unique properties of drugs
as reinforcers, especially stimulant drugs, might accel-
erate, or more effectively consolidate, the development of
drug seeking as a S–R habit (Everitt et al. 2001).
But it should also be appreciated that while all
animals responding for drugs or natural reinforcers
will engage the dorsal striatal habit mechanism under
3128 B. J. Everitt et al.Review. Mechanisms of compulsive drug seeking
Phil. Trans. R. Soc. B (2008)
appropriate reinforcement contingencies, not all indi-
viduals that take addictive drugs will become addicted.
That is, not all individuals self-administering drugs will
escalate their intake and go on to develop compulsive
drug seeking that persists in the face of negative or
aversive outcomes, the key characteristics of addiction,
or substance dependence, in DSM-IV. Thus, some
individuals are vulnerable in terms of these charac-
teristics, a proportion that is often estimated to be
approximately 20% or less of those initially exposed to
addictive drugs (Anthony et al. 1994). We have shown
recently that impulsivity is a behavioural characteristic
that both predicts the escalation of cocaine intake and
the progression to compulsive drug seeking, as well as
an increased propensity to relapse after abstinence.
3. IMPULSIVITY, VENTRAL STRIATAL DOPAMINE
RECEPTORS AND VULNERABILITY
Studies of human addicts have implicated individual
differences in impulsivity, or other traits, such as
‘sensation seeking’, in the vulnerability to drug use
and abuse (Verdejo-Garcia & Perez-Garcias 2007);
although it has neverbeen clear whether the impulsivity
observed in drug addicts predates the onset of addictive
behaviour or is a consequence of protracted exposure
to drugs (Dom et al. 2006; Zilberman et al. 2007). We
have investigated this issue experimentally by defining
in rats an operational measure of the human trait of
impulsivity as premature responses in a five-choice
serial reaction-time task (5-CSRTT; Dalley et al.
2007). A proportion (less than 10%) of the outbred
Lister-hooded strain of rats in our study were impulsive
on this task in that they showed high levels of
anticipatory responses made before the presentation
of a food-predictive, brief light stimulus—especially
under conditions when the stimulus presentation was
delayed after trial onset (Dalley et al. 2007). This
impulsivity we term ‘waiting impulsivity’, as it is related
to impulsivity measured as an inability to tolerate
delays of reinforcement (Robinson et al. 2008), but
appears different from the response impulsivity
measured by the stop-signal reaction time in STOP-
signal reaction-time tasks (Eagle et al. 2008; E. S. J.
Robinson, D. M. Eagle, D. Economidou, D. E. H.
Theobald, A. C. Mar, E. R. Murphy, T. W. Robbins &
J. W. Dalley 2008, unpublished observations).
the impulsive rats showed a marked escalation of their
cocaine intake compared with non-impulsive controls.
They did not acquire cocaine self-administration more
rapidly, but responded at a much higher rate for their
et al. 2007). This is in marked contrast to rats showing
phenotype), which self-administer cocaine at low doses
that do not sustain self-administration in those rats that
show low locomotor responses to novelty (Piazza et al.
1989). Thus, high impulsivity predicts the tendency to
escalate cocaine intake, which is reminiscent of one of
the diagnostic characteristics of substance dependence in
DSM-IV which describes the taking of drugs in larger
quantities than intended as a core symptom.
Highly impulsive animals were investigated neuro-
biologically using positron emission tomography to
measure binding in the striatum of the selective,
high affinity D2/3 dopamine receptor antagonist
[18F]fallypride (Mukherjee et al. 1999). Impulsive
animals showed markedly reduced fallypride binding
within the ventral, but not the dorsal striatum. More-
over, the reduced D2/3dopamine receptor availability
in the ventral striatum was correlated with impulsivity
on the 5-CSRTT (Dalley et al. 2007). Thus, low D2/3
dopamine receptors in the ventral striatum, encom-
passing the nucleus AcbC and shell regions, are
correlated both with impulsivity and the marked
propensity to escalate cocaine intake. This observation,
taken together with the role of the AcbS in the
reinforcing and stimulant effects of cocaine, as well as
involvement of the AcbC in the acquisition of drug-
seeking behaviour (Ito et al. 2004) and the ability to
tolerate delays to reinforcement (Cardinal et al. 2001),
indicates the importance of the ventral striatum in the
neural mechanisms underlying the propensity to seek
and work for cocaine over extended periods of time.
Nader and colleagues, in studies of socially housed
monkeys, have also demonstrated the significant
relationship between D2 dopamine receptors in the
striatum and cocaine self-administration (Czoty et al.
2004; Nader et al. 2006); these studies are reviewed
comprehensively by Nader et al. (2008).
Impulsive rats having self-administered cocaine
subsequently showed reduced levels of impulsivity
(Dalley et al. 2007)—perhaps related to the reduction
in impulsive behaviour following treatment with the
stimulant methylphenidate seen in humans with
attention-deficit hyperactivity disorder. Moreover,
during a subsequent period in which animals had no
access to cocaine self-administration (‘enforced absti-
nence’), impulsivity returned to near pre-cocaine self-
administration levels (figure 2a). Since impulsivity
predicts the escalation of drug intake, we investigated
whether the return of impulsivity during abstinence
might also be associated with a greater propensity
to relapse, as suggested by de Wit & Richards (2004).
In these experiments (Economidou et al. 2007;
D. Economidou, J. W. Dalley & B. J. Everitt 2007,
unpublished observations), rats were trained in a
cocaine seeking–taking task. Once responding had
stabilized, a punishment contingency was introduced
whereby on a random basis 50% of the seeking
responses were followed by the presentation of the
cocaine taking link in the chain, but 50% were followed
by mild footshock (Pelloux et al. 2007). This schedule
of unpredictable cocaine taking and aversive footshock
outcomes results in the suppression of drug-seeking
responses, especially after a limited, or non-escalated,
history of cocaine self-administration; it can therefore
be viewed as the development of ‘abstinence’, in that
animals voluntarily withhold their drug-seeking
responses when the punishment contingency is present.
After having attained abstinence in this way and some
two weeks after their last cocaine infusion, groups of
impulsive and non-impulsive rats were reintroduced to
the test boxes and again allowed to respond on
the seeking lever, which always resulted in access to the
Review. Mechanisms of compulsive drug seeking
B. J. Everitt et al.
Phil. Trans. R. Soc. B (2008)
taking lever, responses upon which resulted in the
presentation of the cocaine-associated CS, but no
drug. While both groups of animals reinstated their
drug-seeking responses, i.e. ‘relapsed’, responding by
impulsive rats was markedly and significantly greater
than that of non-impulsive subjects (figure 2b). Thus,
impulsivity not only confers an increased predisposition
to escalate cocaine self-administration but also an
increased propensity to relapse to a drug-seeking habit
lying this persisting vulnerability to seek and take drugs
4. FROM IMPULSIVITY TO COMPULSIVE DRUG
SEEKING IN ADDICTION
Demonstrating that impulsivity is a factor underlying
the tendency to escalate drug intake and to relapse after
abstinence leaves open the important issue of whether
impulsivity is also a vulnerability marker for drug
addiction and the compulsive drug seeking this entails.
There are relatively few accepted models of compulsive
drug seeking, or indeed compulsive behaviour in
general, in animals. Perseverative responding in
reversal learning tasks may provide one interesting
example because this form of compulsion is persistently
enhanced following even relatively brief periods of
cocaine treatment (Jentsch et al. 2002; Calu et al.
2007). In theoretical terms, we have suggested
(Everitt & Robbins 2005) that compulsive drug seeking
can be characterized as a maladaptive S–R habit in
which the ultimate goal of the behaviour has been
devalued, perhaps through tolerance to the rewarding
effects of the drug. Instead, drug seeking is increasingly
controlled by a succession of drug-associated discrimi-
native stimuli, which also function as conditioned
reinforcers when presented as a consequence of
instrumental responses, as in the second-order drug-
seeking schedule described above. Central to drug
addiction, then, is the persisting quality of these habits,
which we have suggested (Everitt & Robbins 2005)
may correspond to the subjective state of ‘must do!’—
the persistent reinitiation of habitual acts—not least to
distinguish it from the subjective state of excessive
‘wanting’ embodied in the incentive salience sensi-
tization view of addiction (Robinson & Berridge 1993;
see Robinson & Berridge 2008).
In attempting to model drug addiction in animals,
we have tried to capture the compulsive quality of drug
seeking by measuring its persistence despite negative or
aversive outcomes, as in the DSM-IV. In developing
such behavioural procedures, we have shown that
compulsive drug seeking only emerges following an
extended, or chronic, history of cocaine taking
cocaine seeking under
suppression of cocaine
(i) (ii)(iii) (iv)
Figure 2. (a) The return of impulsive behaviour in highly impulsive rats following withdrawal and abstinence from cocaine self-
administration. The data shown are premature responses in a 5-CSRTT. (i) Highly impulsive rats respond prematurely before
any cocaine experience and (ii) their impulsivity is reduced following sessions of cocaine self-administration; (iii) but premature
responding returns to pre-cocaine levels following an extended period of withdrawal (J. W. Dalley 2007, unpublished
observations). Filled circles, high; open circles, low. (b) Impulsive rats show an increased propensity to relapse after abstinence.
(i) Impulsive and non-impulsive rats were trained to seek and take cocaine under a chained schedule. (ii) Subsequently, 50% of
the seeking responses were followed unpredictably by punishment and 50% by access to the taking lever; this results in the
suppression of drug seeking. (iii) Following a further preiod of abstinence, when no cocaine was available rats were returned to
the self-admininistration setting in which seeking responses resulted in the presentation of a cocaine-associated conditioned
reinforcer, but no drug. (iv) Impulsive rats showed much higher numbers of seeking responses than lowimpulsive rats and hence
showed a greater propensity to ‘relapse’. Filled circles, high; open circles, low.
3130 B. J. Everitt et al. Review. Mechanisms of compulsive drug seeking
Phil. Trans. R. Soc. B (2008)
(Deroche-Gamonet et al. 2004; Vanderschuren &
Everitt 2004; Pelloux et al. 2007). In the study by
Deroche-Gamonet et al. (2004), three addiction-like
behavioural criteria were measured in rats, namely
(i) increased motivation to take the drug, (ii) inability to
refrain from drug seeking, and (iii) maintained drug use
despite aversive consequences. After approximately
40 days of cocaine self-administration, but not at earlier
times, some 17% ofsubjects developed these addiction-
like criteria showing increased break points under a
progressive ratio of cocaine reinforcement, persistent
responding during signalled periods of drug unavail-
ability and, perhaps most importantly, persistence of
the instrumental nose-poke response for cocaine even
Pelloux et al. (2007), rats were trained on the seeking–
taking chained schedule with intermittent punishment
of the seeking response (i.e. on 50% of the seeking
bouts, randomly occurring) to achieve suppression of
drug seeking, or abstinence, as described previously. In
this study too, whereas all rats suppressed their cocaine
seeking after a limited history of cocaine self-adminis-
tration, after an extended history 17–20% of subjects
were completely resistant to punishment, continuing to
seek and take drugs despite the ongoing, daily
experience of the negative outcome. The proportion
of rats compulsively seeking drugs, then, was similar
both to that in the Belin study and to the addiction-
vulnerable subgroup of human subjects, often esti-
mated to be less than 20% of the population that
initially use drugs (Anthony et al. 1994).
However, the origins of this propensity to seek
cocaine compulsively have not been established. We
hypothesized that impulsivity, which we have shown
to be associated with low D2/3 dopamine receptor
availability in the ventral striatum and to predict the
escalation of cocaine intake (Dalley et al. 2007), might
also confer a vulnerability to develop compulsive drug
seeking and addiction following extended access to
cocaine. Rats were screened both for impulsivity in the
5-CSSRTand also for the sensation-seeking phenotype
of high locomotor responsiveness to novelty (HR rats)
which has earlier been suggested to be an addiction
vulnerability phenotype (Piazza et al. 1989). The
resultant groups were then studied in the acquisition
of cocaine self-administration, and for the emergence
of the three addiction-like behavioural criteria ident-
ified by Deroche-Gamonet et al. (2004), but particu-
larly persistent responding for the drug in the face of
punishment. As expected, and as reported previously
(Piazza et al. 1989), the HR rats more readily acquired
cocaine self-administration and showed an upward
shift in the cocaine dose–response curve as compared
both with rats with low responses to novelty and also
high impulsivity (Belin et al. 2008). We also confirmed
our earlier finding that impulsivity is not associated
with more rapid acquisition of cocaine self-adminis-
tration, but instead with the escalation of cocaine
intake. However, and in marked contrast, it was high
impulsivity, but not high reactivity to novelty, that
predicted the switch (Leshner 1997) from controlled to
compulsive cocaine taking (Belin et al. 2008). Highly
impulsive rats displayed higher addiction scores and
much greater resistance to punishment than rats with
high or low responses to novelty or low impulsivity
(electronic supplementary material, figure S1). In fact,
highly impulsive rats did not differ from rats showing
the three addiction-like behavioural criteria in any of
their addiction-like behaviours after the extended
period of cocaine self-administration. Therefore, it
seems, perhaps counter-intuitively, that the propensity
to acquire cocaine self-administration when first
encountering the drug and the vulnerability to develop
compulsive cocaine intake (addiction), depend upon
distinct and seemingly orthogonal behavioural charac-
teristics—novelty/sensation-seeking versus impulsivity,
respectively—each of which might have a genetic or
environmental basis. The results of this study also
provide experimental evidence that high levels of
impulsivity can antedate the onset of compulsive drug
use, thereby emphasizing the importance of pre-
existing impulsivity seen in individuals addicted to
drugs (Jentsch & Taylor 1999; Dom et al. 2006).
Now that we have established models of compulsive
drug seeking and addiction, it will be possible to
investigate not only predisposing factors, such as
impulsivity, but also the underlying neurobiological
mechanisms. There are several current views about the
origins of compulsion within the brain, which are often
thought of as being, but in reality are not, mutually
exclusive. The neuroadaptations occurring during
behavioural sensitization to stimulant drugs have been
argued to underlie an extreme incentive motivational
state of drug ‘wanting’ (Robinson & Berridge 1993).
According to this view, addicts experience this state
especially when exposed to drug-associated cues,
which leads to over-activation of the sensitized
dopaminergic innervation of the nucleus accumbens,
in which plasticity-associated structural changes in
dendritic spines have also been observed (Ferrario et al.
2005). This hypothesis is discussed in detail by
Robinson & Berridge (2008). One interpretation of
compulsive drug seeking,then, is that it is a behavioural
manifestation of this potentiated motivational state,
which has been demonstrated in some studies as an
increased break point under progressive ratio schedules
of reinforcement (for a review, see Vezina 2004).
However, as noted above, a sensitization treatment
regimen with amphetamine also leads to the more rapid
instantiation of S–R habits (Nelson & Killcross 2006)
and it is not easy at the behavioural level to differentiate
between an increased tendency to repeat drug-seeking
responses elicited and maintained by drug-associated
stimuli—the ‘must do!’ of compulsive habits discussed
above—from an increased desire for a drug, which
might also seem counter-intuitive given the develop-
ment of tolerance to its rewarding or reinforcing effects.
Perhaps more directly related to the notion of drug
seeking as a compulsive habit, however, is the
observation of reductions in dopamine D2receptors
in the dorsal striatum in abstinent alcoholics, cocaine,
heroin and methamphetamine addicts (Volkow & Wise
2005) and also following chronic, but not acute,
cocaine self-administration in monkeys (Moore et al.
1998; Nader et al. 2002). The consequences of this
underlying instrumental learning and performance is
Review. Mechanisms of compulsive drug seeking
B. J. Everitt et al.
Phil. Trans. R. Soc. B (2008)
within the striatum and involving its dopaminergic
innervation might be considered. Thus, the early
vulnerability to escalate cocaine intake seen in impulsive
rats is predicted by low D2/3dopamine receptor levels in
the ventral, but not the dorsal striatum (Dalley et al.
2007). However, this escalated intake may lead to more
rapid neuroadaptations, including downregulated D2
dopamine receptors, in the dorsal striatum and mediated
in part by aberrant engagement of the spiralling striato-
nigro-striatal circuitry. This would lead to more rapid
consolidation of drug-seeking habits that are difficult to
relinquish, despite negative outcomes and are more
readily reinstated after abstinence following exposure to
response-eliciting drug-associated stimuli.
An alternative account may be provided by the
impact of negative reinforcement, as has been
suggested to underlie obsessive–compulsive disorder,
whereby drug-seeking habits are maintained by the
motivation to alleviate or avoid (self-medicate) the
negative emotional state and dysregulation resulting
from tolerance to, and withdrawal from, drugs taken in
increasing amounts over time (Koob & Le Moal 2001).
These counter-adaptations are prevalent in the central
and extended amygdala and their motivational impact
on drug self-administration is described in detail by
Koob & Le Moal (2008). These mechanisms are
not of course mutually exclusive. Addiction to drugs
may reflect a combination of increased incentive
motivation mediated by the upregulation of ventral
striatal dopamine transmission, by ‘hyper-consolidated’
habit learning mediated by upregulated dorsal stria-
tum, dopamine-dependent mechanisms and the drive
engendered by negative emotional states in extra-
However, we and others have also hypothesized an
additional neurobiological mechanism perhaps arising
in part as the direct or indirect consequence of toxic
drug effects. This mechanism may be implicated in a
shift in balance of behavioural control processes from
the prefrontal cortex to the striatum, thereby promot-
ing compulsive habitual behaviour. There are abundant
data suggesting prefrontal cortical, especially orbito-
frontal (OFC), dysfunction in addicts, which are
also increasingly supported by experimental studies in
animals (Schoenbaum et al. 2006; Everitt et al. 2007;
Olausson et al. 2007) and humans (see Garavan et al.
2008). Thus, in cocaine and methamphetamine
abusers, reduced activity of the OFC that correlates
with reduced D2/3dopamine receptors in the striatum
(Volkow et al. 2001), and reduced grey matter volume
in this region (Matochik et al. 2003) have been
reported. There are also growing numbers of reports
of impaired behavioural and cognitive functions,
including poor behavioural adjustment (Bechara
2005) and impaired probabilistic reversal learning in
cocaine abusers (Ersche et al. 2008), possibly due to
reduced inhibitory control. Deficits have been reported
in decision-making cognition on computerized versions
of a gambling task, when stimulant abusers chose the
most favourable option less frequently than control
subjects and chose significantly against the odds in
risky conditions, suggesting difficulties in estimating
outcome probabilities (Rogers et al. 1999; Ersche et al.
2005). Similar changes in behaviour are seen in
individuals with OFC damage (Rogers et al. 1999)
and this has encouraged the view that chronic drug
taking may actually be a causal factor in inducing such
prefrontal cortex-dependent deficits. But suboptimal
prefrontal cortical, including OFC and anterior
cingulate cortex, function (Volkow & Fowler 2000;
Kaufman et al. 2003; Hester & Garavan 2004) may also
represent a pre-existing vulnerability trait that results
in poor decisions and/or a lack of sensitivity to the
consequences of such decisions, and hence drug abuse
leading to addiction.
Experimental studies primarily involving psycho-
stimulant treatment of rats and monkeys even after
brief periods of exposure have supported the view that
disrupted OFC function may indeed be a consequence
of toxic drug effects during an addict’s history of
drug abuse (Jentsch & Taylor 1999; Schoenbaum et al.
2006). Short term, usually experimenter-, and not
self-, administered cocaine or amphetamine enhanced
the development of impulsivity (Jentsch & Taylor1999;
Roesch et al. 2007). Reversal learning was impaired
by cocaine treatment in monkeys (Jentsch et al. 2002)
and rats (Schoenbaum et al. 2004). Rats having self-
administered and then been withdrawn from cocaine
exhibited both increased extinction responding and a
marked deficit in reversal learning during withdrawal
(Calu et al. 2007). Schoenbaum and colleagues have
emphasized the similarity between OFC lesions
and these apparently long-lasting effects of relatively
short-term treatment with cocaine, and also showed
that the deficit in reversal learning is reflected in a
change in the properties of OFC neurons, which do
not develop appropriate responses to cues predicting
outcomes (Stalnaker et al. 2006).
It is remarkable that even brief periods of drug
exposure, whether experimenter administered or self-
administered, can result in enduring changes in
behaviour indicative of OFC dysfunction. However, in
the great majority of imaging and neuropsychological
investigations of addicts, there has been an exception-
ally long history of drug abuse and often poly-drug
abuse. These drug-addicted individuals must represent,
therefore, a relatively small proportion of the much
larger number of individuals in a population who have
abused drugs over varying periods of time, but who
have not made the transition to an addicted state as
characterized by compulsive drug use. Thus, it would
seem unlikely that experimental groups of rats receiving
the fairly modest exposure to stimulant drugs in the
experiments described above would in any sense fulfil
the criteria for addiction, yet the changes in behaviour
indicative of OFC dysfunction are seen in the entire
population of treated experimental animals. It will be
important, therefore, to investigate neurobiologically
those models that capture chronic drug self-adminis-
tration (Dalley et al. 2005a,b) and the compulsive drug
seeking that develops in vulnerable sub-populations of
rats if we are to understand the mechanisms underlying
the interaction between predisposing behavioural traits
and chronic drug exposure in the development of
The majority of the theorizing and evidence
summarized above comes from studies of the neural
and psychological basis of the seeking and taking
3132B. J. Everitt et al. Review. Mechanisms of compulsive drug seeking
Phil. Trans. R. Soc. B (2008)
of stimulant drugs such as cocaine. There is clearly
a major need for studies of other drugs, especially
opiates and alcohol, at both the psychological and
neurobiological levels before the generalizability of the
mechanisms so defined becomes clear and the gaps
in our understanding are filled.
This research was supported by grants from the Medical
Research Council and Wellcome Trust and was conducted
within the Behavioural and Clinical Neuroscience Institute in
the University of Cambridge.
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