Neuron
Article
Cocaine Seeking Habits Depend upon
Dopamine-Dependent Serial Connectivity
Linking the Ventral with the Dorsal Striatum
David Belin1,* and Barry J. Everitt1
1Department of Experimental Psychology, University of Cambridge, Downing Street, Cambridge CB2 3EB, UK
*Correspondence: bdb26@cam.ac.uk
DOI 10.1016/j.neuron.2007.12.019
SUMMARY
A neuroanatomical principle of striatal organization
has been established through which ventral do-
mains, including the nucleus accumbens, exert
control over dorsal striatal processes mediated by
so-called ‘‘spiraling,’’ striato-nigro-striatal, circuitry.
We have investigated the functional significance of
this circuitry in the control over a cocaine-seeking
habit by using an intrastriatal disconnection proce-
dure that combined a selective, unilateral lesion of
the nucleus accumbens core and infusion of a dopa-
mine receptor antagonist into the contralateral dorso-
lateral striatum, thereby disrupting striato-midbrain-
striatal serial connectivity bilaterally. We show that
this disconnection selectively decreased drug-seeking
behavior in rats extensively trained under a second-
order schedule of cocaine reinforcement. These data
thereby define the importance of interactions between
ventral and dorsal domains of the striatum, mediated
by dopaminergic transmission, in the neural mecha-
nisms underlying the development and performance
of cocaine-seeking habits that are a key characteristic
of drug addiction.
INTRODUCTION
During the development of drug addiction, drug seeking be-
comes progressively established as a maladaptive stimulus-
response (S-R) habit (Everitt et al., 2001; Everitt and Robbins,
2005; Volkow et al., 2006; Redish, 2004). Thus, although drug-
seeking behavior is initially a goal-directed behavior in which
a drug is sought and taken for its reinforcing or rewarding effects,
it ultimately becomes persistently elicited and maintained by
drug-associated discriminative stimuli in the environment, espe-
cially when they are presented contingent on responding as
conditioned reinforcers (Everitt and Robbins, 2005). At a neural
level, this transition from goal-directed action to a S-R habit re-
flects a shift from ventral to dorsal striatal control over drug seek-
ing (Everitt and Robbins, 2005; Vanderschuren et al., 2005). But
the neural mechanisms underlying such a shift and, more gener-
ally, the ways in which ventral striatal activity interacts with and
influences dorsal striatal function in providing the link between in-
432 Neuron 57, 432–441, February 7, 2008 ª2008 Elsevier Inc.
centive motivation, reward, and instrumental behavior (Haber
et al., 2000; Haber, 2003) have not been established. However,
a recently described feature of striatal circuitry appears to allow
processing within dorsal corticostriatal loops (Alexander et al.,
1986, 1990) to be recruited by activity in the ventral striatum.
Both in primates (Haber et al., 2000) and in rats (Ikemoto,
2007), a cascading serial connectivity has been described that
links the nucleus accumbens with progressively more dorsal
regions of the striatum through so-called ‘‘spiraling’’ connections
with midbrain dopamine (DA) neurons. Thus, nucleus accumbens
shell (AcbS) neurons project to the ventral tegmental area DA
neurons that not only project to the AcbS but also to the more dor-
sal nucleus accumbens core (AcbC). In turn, AcbC neurons pro-
ject both to DA neurons from which they receive their DA input
and also to DA neurons that innervate more dorsal territories of
the striatum, and so on (Haber et al., 2000) (Figure 1A).
We have therefore investigated the functional significance of
this circuitry in the neural control over cocaine-seeking behavior
in which both animal and human studies have demonstrated
a clear shift in the locus of control from nucleus accumbens
to dorsal striatum. Thus, acquisition of the drug-seeking task
used in the present experiment, in which the conditioned rein-
forcing properties of drug-associated stimuli mediate delays to
reinforcement by intravenous cocaine self-administration (Gold-
berg and Gardner, 1981; Everitt and Robbins, 2000), depends
upon the integrity of the AcbC and its afferents from the basolat-
eral amygdala (Ito et al., 2004; Cardinal et al., 2002; Di Ciano and
Everitt, 2001, 2004; Whitelaw et al., 1996). However, with pro-
longed training, a clear correlate of cocaine seeking is increased
DA efflux in the dorsolateral (DL) striatum, but not in the AcbC or
AcbS (Ito et al., 2002). Moreover, bilateral DA receptor antago-
nism at this time in the DL striatum, but not in the AcbC, greatly
diminishes cocaine seeking (Vanderschuren et al., 2005). In ad-
dicted but drug-free humans, cue-elicited craving also activates
the dorsal striatum (Garavan et al., 2000; Volkow et al., 2006) in
addition to limbic prefrontal cortical areas and the amygdala
(Childress et al., 1999; Grant et al., 1996), findings paralleled
by observations in rats (Kelley et al., 2005).
In studies with ingestive reinforcers, the transition from goal-
directed behavior, initially established through action-outcome
(A-O) learning, to a S-R habit has also been shown to depend
upon a shift in control from the ventral to the DL striatum; for
example, cell body lesions or DA denervation of the DL striatum
impair habit learning, leaving instrumental behavior under A-O
control and persistently sensitive to reinforcer devaluation (Yin
Neuron
Intrastriatal Disconnection and Cocaine Seeking

Figure 1. The Striato-Nigro-Striatal Dopamine-Dependent Spiraling Circuitry in the Rat Brain and Disconnection of the Nucleus Accumbens
Core and the Dorsolateral Striatum
Schematic representation of (A) striato-nigro-striatal serial connectivity through which the nucleus accumbens influences the dopaminergic projections to the
dorsal striatum (after Haber et al. [2000] and Ikemoto [2007]) and (B) disconnection of the AcbC from the DL striatum. (Adapted from Paxinos and Watson,
1986, with permission of Elsevier.)
(A) The AcbS (yellow) projects back (black arrow) to regions of the VTA (pink) from which it receives its DA innervation (pink arrow) and to more lateral DA neurons
that innervate the more dorsal AcbC (soft blue) (bold dotted arrow). Similarly, the AcbC projects to areas of the VTA from which it receives its DA innervation (black
arrow), but also to DA neurons that project to the DM striatum (bold dotted black arrow). This spiral continues through more dorsal striatal regions (dark blue)
innervated by the more lateral SNc (pink arrow). The spiraling loop organization is depicted as the alternation of pink and black arrows from the ventral to the
more dorsal parts of the circuit.
(B) In unilateral AcbC-lesioned rats (black shaded area), the AcbC relay of the loop is lost on one side of the brain. However, on the nonlesioned side, the spiraling
circuitry is intact and functional. When a-flupenthixol (green dots) is infused in the DL striatum contralateral to the lesion, it blocks the DAergic input from the SNc,
hence impairing the striatal output of the spiraling circuitry on the nonlesioned side of the brain. Therefore, after unilateral a-flupenthixol infusions in the contra-
lateral DL striatum of AcbC-lesioned animals, functional activity within the striatum is disrupted bilaterally.
(C) Timeline of the procedure. Subjects underwent stereotaxic neurosurgery, namely unilateral lesion of the AcbC combined with bilateral cannulation of the stria-
tum (lesioned subjects) or bilateral cannulation of the DL striatum (control subjects), followed a week later by intravenous (IV) catheterization. After a week of
recovery, unilaterally AcbC-lesioned rats and control subjects were initially trained to acquire cocaine self-administration (SA) under a fixed-ratio (FR)1 schedule,
with each cocaine infusion associated with illumination of a light stimulus (CS). They were then progressively trained to respond under fixed interval (FI) schedules
of reinforcement, from FI1min to FI15min again with the light CS being presented with each cocaine infusion. Subsequently, the cocaine-associated CS was
presented contingent upon every tenth lever press response (FR10:S). The animals were at this stage seeking cocaine under a second-order schedule of rein-
forcement described as FI15(FR10:S) (Arroyo et al., 1998) and were tested daily for 30 days so that their cue-controlled drug seeking was well established.
Lesioned subjects then received vehicle or a-flupenthixol infusions into the DL striatum contralateral to the lesioned AcbC; control subjects received bilateral
infusions. Control subjects also received a unilateral infusion of a-flupenthixol into the DL striatum. Seven days after the final cocaine self-administration session,
both lesioned and control groups were trained for 6 days to acquire a novel chain-pulling response for a 15% sucrose solution under a FR1 schedule of reinforce-
ment. Unilateral AcbC-lesioned subjects then received an infusion of a-flupenthixol into the contralateral DL striatum, whereas nonlesioned controls received
bilateral infusions of the DA receptor antagonist at the same dose.

et al., 2004; Faure et al., 2005). It is therefore of considerable im-
portance that following protracted cocaine self-administration in
monkeys and rats, neuroadaptations that are initially restricted to
more ventral striatal areas at the earliest stages of drug use pro-
gressively involve DL striatal presynaptic markers and metabolic
activity (Letchworth et al., 2001; Porrino et al., 2004). Taken
together, these multiple sources of evidence indicate that an in-
creased engagement of dorsal striatal mechanisms, promoted
by the actions of self-administered cocaine, underlies the devel-
opment of persistent drug-seeking habits.
To test the hypothesis that the serial cascade of striato-nigro-
striatal connectivity (Haber et al., 2000; Ikemoto, 2007) underlies
this progressively greater control over well-established cocaine-
seeking behavior by the DL striatum (Ito et al., 2002; Vanderschu-
ren et al., 2005), we have used an intrastriatal ‘‘disconnection’’
procedure in which the AcbC was selectively lesioned on one

Neuron 57, 432–441, February 7, 2008 ª2008 Elsevier Inc. 433

 Neuron
Intrastriatal Disconnection and Cocaine Seeking

side of the brain and combined with DA receptor blockade in the Representative photomicrographs of unilateral AcbC lesions
contralateral DL striatum, thereby functionally disconnecting se- are shown in Figure 2C.
rial interactions between these ventral and dorsal striatal do-
mains on both sides of the brain (Figure 1B). This disconnection Acquisition of Responding under a Second-Order
greatly and selectively decreased cocaine seeking in rats trained Schedule of Cocaine Reinforcement
to respond for cocaine under a second-order schedule of rein- Both groups, i.e., control and unilateral AcbC-lesioned animals,
forcement, indicating both the functional significance of striato- acquired cocaine seeking under the fixed interval 15 min (FI15)
nigro-striatal circuitry and its engagement in persistent, or habit- schedule of reinforcement as shown in Figure 3. Control and uni-
ual, drug seeking. lateral AcbC-lesioned rats increased their responses as the
schedule requirements increased, from FR1 to FI15 (Figure 3A)
(significant effect of schedule: F8, 104 = 22.892, p < 0.0001, lever:
RESULTS
F1, 13 = 48.832, p < 0.0001, and significant lever 3 schedule inter-
action: F8, 104 = 17.288, p < 0.0001). When rats reached the train-
Overview of Experimental Procedure
ing criterion under FI15, i.e., <15% within-day variation, the
Unilaterally AcbC lesioned rats implanted bilaterally with cannu-
cocaine-associated CS was introduced contingent on every
lae in the DL striatum, together with control subjects with bilateral
tenth response, thus rats were responding under a second-order
DL striatum cannulation, initially acquired cocaine self-adminis-
schedule FI15(FR10:S). This resulted in a significant increase in
tration under a fixed ratio (FR) 1 schedule in which each cocaine
the total number of active lever presses in both groups (Figure 3A)
infusion was paired with a light stimulus (conditioned stimulus,
(significant effect of schedule: F9, 117 = 9.1045, p < 0.0001, lever:
CS). They were then progressively trained to respond on a lever
F1, 13 = 95.183, p < 0.0001, and a schedule 3 lever interaction:
under fixed interval (FI) schedules of reinforcement, increasing
F9, 117 = 9.3674, p < 0.0001) while inactive lever presses were
from FI1 min to FI15 min. In interval schedules there is a weak
not affected (Figure 3B) (effect of schedule: F9, 117 = 1.0559, p =
relationship between response and outcome that encourages
0.4). Post hoc analysis revealed that active lever presses during
the development of responding under habit control (Adams
each day of responding under the second-order schedule of rein-
and Dickinson, 1981). Subsequently, every tenth lever press
forcement were higher than during each day of responding under
resulted in the presentation of the cocaine-associated CS; this
the FI15 schedule in both groups (p < 0.01 for each day compar-
second-order schedule of cocaine reinforcement results in
ison), thereby demonstrating the marked impact of the cocaine-
prolonged periods of vigorous drug seeking, since the cocaine-
associated reinforcer on instrumental drug-seeking responses.
associated CS both reinforces responding and bridges delays
to primary reinforcement by cocaine (Everitt and Robbins,
Bilateral Infusion of the DA Receptor Antagonist
2000). Omission of the CS results in a marked reduction of
a-Flupenthixol into the Dorsal Striatum
responding that is readily reinstated by reintroduction of the CS
Dose-Dependently Impairs Cocaine Seeking
(Arroyo et al., 1998), provided that it is presented contingent
Bilateral infusion of the DA receptor antagonist a-flupenthixol into
upon instrumental responses (Di Ciano and Everitt, 2003). Rats re-
the DL striatum dose-dependently reduced cocaine seeking,
sponded under this second-order schedule of cocaine reinforce-
confirming our earlier results (Vanderschuren et al., 2005). Thus,
ment FI15(FR10:S) for 30 days before intrastriatal drug infusions
there was a significant, dose-dependent decrease in responding
commenced. Unilateral lesioned subjects then received either ve-
during the first 15 min interval of the session (Figure 4) (significant
hicle or a-flupenthixol infusions into the DL striatum contralateral
effect of dose: F3, 12 = 6.8277, p < 0.01, lever: F1, 4 = 21.734, p <
to the lesioned AcbC; control subjects received the same infu-
0.01, and a dose 3 lever interaction: F3, 12 = 6.6798, p < 0.01). This
sions either unilaterally or bilaterally. Seven days following the
effect of a-flupenthixol was specific to the active lever (Figure 4A)
last cocaine self-administration session, both lesioned and con-
(F3, 12 = 6.7582, p < 0.01); responding on the inactive lever was un-
trol groups were trained for 6 days to acquire a new chain-pulling
affected (Figure 4B) (F3, 12 = 1.1111, p = 0.38). Post hoc analysis
response for a 20% sucrose solution under a FR1 schedule of
revealed that the three doses of a-flupenthixol tested decreased
reinforcement; unilaterally AcbC-lesioned rats received a contra-
significantly the number of responses made on the active lever
lateral DL striatum infusion of a-flupenthixol, whereas controls
compared to vehicle (Figure 4A) (p < 0.05, p < 0.01, p < 0.01 for
received a bilateral intra-DL striatal a-flupenthixol infusion. The
the doses 5, 10, and 15 mg/infusion, respectively).
experimental procedure timeline is summarized in Figure 1C.
Infusion of a-flupenthixol unilaterally into the DL striatum was,
in controls, without effect on cocaine seeking. Figure 5 shows
Histological Assessment that control rats infused unilaterally with the effective dose of
Histological analysis was performed blind to behavioral results. 10 mg of the DA antagonist showed no decrease in the total num-
The cannulae in both groups were located within the dorsolateral ber of active (Figure 5A) (F1, 4 < 1) or inactive (Figure 5B) (F1, 4 =
striatum (Figures 2A–2B). One lesioned and one control subject 1.1406, p = 0.345) lever presses.
were excluded from the analysis because of misplacement of
the cannulae. Unilateral lesions of the AcbC included the majority DA-Dependent Disconnection of the AcbC
of the core subregion; neuronal loss and associated gliosis and the Dorsal Striatum Impairs Cocaine Seeking
extending from approximately +2.5 mm to +0.5 mm relative to Combining an otherwise ineffective unilateral infusion of a-
bregma (Figure 2A). One rat was excluded from the analysis flupenthixol into the dorsal striatum in rats having previously
because of damage to the ventromedial caudate-putamen. received a contralateral lesion of the AcbC resulted, however,

434 Neuron 57, 432–441, February 7, 2008 ª2008 Elsevier Inc.

Neuron
Intrastriatal Disconnection and Cocaine Seeking

Figure 2. Schematic and Histological Illus-

tration of Unilateral Nucleus Accumbens
Core Lesions and Bilateral Dorsolateral
Striatum Cannula Placements
(A) Schematic representation of the extent of the
quinolinic acid-induced unilateral AcbC lesions
and contralateral DL striatum cannula placements
(filled circles) in left (n = 6) and right (n = 4) AcbC-
lesioned animals. Areas shaded in gray and black
represent the largest and smallest extent of
neuronal damage. Coronal sections are +2.2 mm
anterior through +0.48 mm posterior to Bregma.
(B) Schematic representation of the location of the
tips of injection cannulae within the dorsal striatum
(filled circles) of nonlesioned control animals (n = 5).
Coronal sections are +1.7 through +0.7 mm ante-
rior to Bregma (Vanderschuren et al., 2005). Dis-
tances are in millimeters from bregma (adapted
from Paxinos and Watson, 1986, with permission
of Elsevier). AP, anteroposterior.
(C) Representative photomicrograph of a Cresyl
Violet-stained coronal section of a left AcbC-le-
sioned rat with a right intact AcbC at magnification
233. Arrows indicate the placement of the injector
(C.a) and the reduction in area with attendant glio-
sis following the AcbC lesion; (C.b), the AcbS is in-
tact on both the left and right sides (C.c), as is the
AcbC on the right side of the brain (C.d). Dotted
circles delimit the lesioned area (bold dots) and
the intact (normal dots) AcbC.

in a significant, dose-dependent suppression of responding (Fig- acquired a novel chain-pulling response for sucrose and were in-
ure 6) (significant effect of dose: F3, 27 = 5.9380, p < 0.01 and lever: fused with a-flupenthixol into the contralateral DL striatum or bi-
F1, 9 = 26.220, p < 0.001, and a significant dose 3 lever interac- laterally into the DL striatum, respectively. Both lesioned (n = 10)
tion: F3, 27 = 5.8847, p < 0.01). The effect of a-flupenthixol was
selective for responding on the active lever (Figure 6A) (F3, 27 =
5.9153, p < 0.01) and had no effect on responding on the inactive
lever (Figure 6B) (F3, 27 = 2.7671, p = 0.061). Post hoc analysis re-
vealed that the three doses of a-flupenthixol tested decreased
significantly the number of responses made on the active lever
compared to vehicle (Figure 6A) (p < 0.05, p < 0.05, p < 0.01 for
the doses 5, 10, and 15 mg/infusion, respectively).
When comparing statistically the effect of the disconnection
procedure with bilateral infusion of the DA receptor antagonist
in control animals, no differences were observed between the
groups for responses on either the active (F3,39 < 1) (Figure 7A)
or the inactive lever (F3, 39 = 2.4837, p = 0.075) (Figure 7B).
Thus, disconnection of the AcbC and DL striatum had the
same magnitude of effect in reducing cocaine seeking as did Figure 3. Acquisition of Responding under the Second-Order
bilateral DL striatal DA receptor blockade. Schedule of Cocaine Reinforcement Was Not Affected by a Unilateral
AcbC Lesion
The total number of active lever presses increased in parallel with the in-
creased behavioral requirement from FR1 to FI10 min in both lesioned (n = 10)
DA-Dependent Disconnection of the AcbC and the DL
and control (n = 5) animals (Fschedule = 22.39, p < 0.0001, Fgroup < 1). The intro-
Striatum Does Not Impair Instrumental Responding
duction of the second-order schedule of reinforcement [FI15(FR10:S), indi-
for Sucrose under a Continuous Reinforcement Schedule cated with an arrow] resulted in the expected, marked increase in responding
To control for any effects of disconnection on instrumental on the active lever in both groups (Fgroup < 1, Fschedule = 9.10, p < 0.0001,
responding per se, unilaterally AcbC-lesioned and control rats Fschedule x lever = 9.37, p < 0.0001). Data are group means ± SEM.

Neuron 57, 432–441, February 7, 2008 ª2008 Elsevier Inc. 435


Figure 4. Cocaine Seeking Was Dose-Dependently Impaired by
Bilateral Infusions of the DA Receptor Antagonist a-Flupenthixol
into the DL Striatum
The schematic shows the cannulae placements in the DL striatum of control
rats. Infusions of a-flupenthixol into the DL striatum of control rats (n = 5)
dose-dependently decreased responding on the active lever (A) (Fdose = 6.76,
p < 0.01) but had no effect on inactive lever presses (B) (Fdose = 1.11, p = 0.38).
*p < 0.05, **p < 0.01. Data are group means ± SEM.
and control rats (n = 5) acquired the new behavioral response
within 3 days (Figure 8A). In both groups, the response rate mea-
sured during the first 15 min of the session did not exceed 20%
of variation from the third to the sixth day of training (effect of day:
F3, 39 < 1, group: F1, 13 < 1, group 3 day interaction: F3, 39 < 1).
Uni- or bilateral DL striatum infusions of the effective dose of
10 mg/side of a-flupenthixol in AcbC-lesioned and control ani-
mals, respectively, did not affect the responses on the chain
compared to baseline (i.e., mean of the last 4 days of training)
(Figures 8A–8B) (treatment effect F1, 9 < 1 and F1, 4 < 1 for
lesioned and control rats, respectively).
DISCUSSION
The results of this study show that disconnecting the AcbC from
the DL striatum, by the asymmetric combination of unilateral
blockade of DA receptors in the dorsal striatum contralateral to
a selective excitotoxic lesion of the AcbC, greatly decreased
cocaine-seeking behavior measured in rats responding under
a second-order schedule of reinforcement, whereas these uni-
lateral manipulations were ineffective in isolation. The discon-
nection had the same effect of diminishing cue-controlled co-
caine seeking as did bilateral DA receptor blockade in the DL
striatum (see Vanderschuren et al., 2005, and replicated in this
study) and also bilateral lesions or glutamate receptor blockade
of the AcbC that we have reported previously (Ito et al., 2004; Di
Ciano and Everitt, 2001). These results enhance our understand-
ing of the mechanisms of information processing within the stria-
tal complex. In particular, they demonstrate the importance of
interactions between the AcbC and the dopaminergic innerva-
tion of the DL striatum in controlling a well-established instru-
mental drug-seeking response that, like drug seeking in human
addicts, is under the control of drug-associated conditioned
reinforcers. Such persistent drug-seeking habits are a key char-
acteristic of drug addictive behavior, and the present data dem-
onstrate an underlying neural mechanism.
436 Neuron 57, 432–441, February 7, 2008 ª2008 Elsevier Inc.
Neuron
Intrastriatal Disconnection and Cocaine Seeking
Figure 5. Unilateral Infusions of the DA Receptor Antagonist
a-Flupenthixol into the DL Striatum of Control Rats Did Not Reduce
Cocaine Seeking
The infusion of the effective dose of 10 mg/infusion of a-flupenthixol into
one side of the DL striatum of control animals (n = 5) did not alter responding
on either the active (Ftreatment < 1) (A) or the inactive lever (Ftreatment = 1.14,
p = 0.34) (B) as compared to baseline. Data are group means ± SEM.
The interpretation of the present results on a background of
evidence of a progressive dominance of the dorsal over the ven-
tral striatum in the control over drug seeking (Everitt and Rob-
bins, 2005) depends in turn upon the theoretical interpretation
of disconnection manipulations of the brain. Disconnections
have previously been used successfully to define the limbic
cortical-striatal circuitry underlying reward-related learning
(Floresco et al., 1997; Parkinson et al., 2000; Baxter et al.,
2000; Setlow et al., 2002), visual attention (Christakou et al.,
2001), and also drug seeking (Di Ciano and Everitt, 2004), but
have not before been used to probe the functions of serial pro-
cesses engaged by intrastriatal connectivity in the control over
instrumental behavior. Disconnection procedures involve unilat-
eral manipulation of one structure in a neural system combined
with manipulation of another, intimately connected structure
within the same system but on the opposite side of the brain,
Figure 6. Unilateral Infusions of a-Flupenthixol into the DL Striatum
Contralateral to the Unilaterally Lesioned AcbC Dose-Dependently
Impaired Cocaine Seeking
The schematic shows the cannulae placements in the DL striatum of left AcbC-
lesioned rats. Unilateral infusions of the DA receptor antagonist a-flupenthixol
dose-dependently decreased responding on the active lever (A) (Fdose = 5.91,
p < 0.01) but not the inactive lever (B) (Fdose = 2.77, p = 0.061). *p < 0.05,
**p < 0.01. Data are group means ± SEM.
Neuron
Intrastriatal Disconnection and Cocaine Seeking
Figure 7. Disconnecting the AcbC from the DL Striatum or Bilat-
eral Infusion of the DA Receptor Antagonist a-Flupenthixol into the
DL Striatum of Nonlesioned Animals Similarly Reduced Cocaine
Seeking
(A) Active lever presses following drug infusion in both AcbC-lesioned (n = 10)
and control animals (n = 5). The reduction in responding on the active lever
after unilateral infusion of a-flupenthixol into the DL striatum contralateral to
the lesioned AcbC or after bilateral infusion of the DA receptor antagonist
into the DL striatum of control subjects was of the same magnitude (Fgroup < 1).
(B) Infusion of a-flupenthixol had no effect on inactive lever responding. Data
are group means ± SEM.
thereby disrupting the function of the serially interacting struc-
tures bilaterally. Thus, the disconnection manipulation should
have behavioral effects that are very similar, if not identical, to
the consequences of bilateral manipulations of either structure
alone within the system (Everitt et al., 1991; Baxter et al., 2000;
Han et al., 1997), but will have little or no effect if the structures
are less directly, or serially, connected within a more diffuse neu-
ral system (Gaffan and Murray, 1990).
In these experiments, we made a pretraining unilateral excito-
toxic lesion of the AcbC; this prevented AcbC recruitment of the
DL striatum on one side of the brain. This unilateral lesion, as
expected, had no effect on the acquisition of cocaine seeking,
which was readily supported by the intact system in the contra-
lateral hemisphere. However, when this unilateral AcbC lesion
was combined with DA receptor blockade in the contralateral
DL striatum, thereby functionally disconnecting the ventral and
dorsal striatum bilaterally, we observed a marked decrease in
cocaine-seeking responses. This supports the hypothesis that
a well-established cocaine-seeking habit depends ultimately
upon the operation of striato-nigro-striatal circuitry. The neuro-
anatomical demonstration of this circuitry in both primates
(Haber et al., 2000) and rats (Ikemoto, 2007) therefore provides
the basis for integrating the present with previous data on the
neural mechanisms underlying drug seeking. Previous studies
have revealed the importance of the AcbC (Ito et al., 2004), inter-
acting with the basolateral amygdala (Whitelaw et al., 1996) in the
acquisition of drug seeking through the regulation of conditioned
reinforcement, but with mechanisms dependent upon dorsolat-
eral striatal dopamine ultimately exerting dominant control over
behavior (Ito et al., 2002; Vanderschuren et al., 2005). Here we
show that this control depends upon AcbC recruitment of dorsal
striatal function.
Several sources of neurobiological and psychological data, in-
cluding data on drug seeking, support this hypothesized ventral-
Figure 8. Infusion of the DA Receptor Antagonist a-Flupenthixol
Bilaterally into the DL Striatum of Control Rats or the Contralateral
DL Striatum of Unilateral AcbC-Lesioned Rats Did Not Impair
Performance of a Novel Chain-Pulling Response for Sucrose under
Continuous Reinforcement
(A) Both control and lesioned animals learned to pull a chain to obtain 15%
sucrose within 3 days. Both groups then displayed stable responding (Fday < 1)
and did not differ in their responding during 4 baseline test days (Fgroup < 1).
(B) Infusion of the effective dose of 10 mg/side of a-flupenthixol did not affect
the chain-pulling response in lesioned (B, left) or control animals (B, right) com-
pared to baseline (i.e., mean of the last 4 days of stable responding) (Ftreatment < 1
for both groups). Data are group means ± SEM.
to-dorsal striatal shift in control over instrumental behavior. For
example, following an extended, but not a brief, cocaine self-
administration history in monkeys, neuroadaptations involving
neurochemical (dopaminergic) and metabolic markers that are
initially restricted to more ventral and anterior parts of the stria-
tum, become progressively more prominent in the dorsal and
posterior striatum (Porrino et al., 2004; Letchworth et al.,
2001). Moreover, increased extracellular DA in the DL striatum,
but not in either the AcbS or AcbC, is seen following several
weeks of drug-seeking experience under the second-order
schedule we have used here (Ito et al., 2000, 2002). At this point,
DA receptor antagonist infusion into the same region of the
dorsal striatum in which the increased extracellular DA was
observed dose-dependently reduced cocaine seeking (a finding
replicated in the present study), whereas the same infusion into
the nucleus accumbens was without effect (Vanderschuren
et al., 2005). In related studies, stimulant drugs have been shown
to lead to the more rapid instantiation of habit learning (Nelson
and Killcross, 2006) and a shift in the balance of associative en-
coding from ventral to dorsal striatum that underpins an atten-
dant enhancement of cue-evoked neuronal firing in the dorsal
striatum (Takahashi et al., 2007). In addition, the DL striatum is
involved in relapse to a cocaine-seeking habit, since neural inhi-
bition induced by GABA receptor agonist infusion into the DL
striatum, but not in the AcbS nor the AcbC, prevents the rein-
statement of cocaine seeking after protracted withdrawal (Fuchs
et al., 2006; See et al., 2007). Finally, the presentation of drug
cues to human cocaine addicts not only induces drug craving
that is correlated with activation of the amygdala and limbic pre-
frontal cortical areas (Grant et al., 1996; Childress et al., 1999;
Garavan et al., 2000; Volkow et al., 2002), but also results in
marked activation of the dorsal striatum (Garavan et al., 2000;
Volkow et al., 2006). The latter observations therefore strongly
Neuron 57, 432–441, February 7, 2008 ª2008 Elsevier Inc. 437

indicate a link between limbic cortical mechanisms and engage-
ment of the dorsal striatum in long-term drug abusers exposed to
drug cues, while the present results reveal that this recruitment is
mediated by antecedent activity in the AcbC and its regulation of
dorsal striatal dopaminergic projections.
It is important to emphasize that the effects of the disconnec-
tion manipulation used in these experiments cannot be attrib-
uted to a simple impairment in instrumental responding, since
it did not affect performance of a newly acquired chain-pulling
response for sucrose (or for cocaine; unpublished observations)
under continuous reinforcement (FR1), a response that under
such conditions remains goal directed and sensitive to reinforcer
devaluation (Adams and Dickinson, 1981; Balleine, 2005). In-
deed, lesions or inactivation of the AcbC, DM, or DL striatum
do not globally impair instrumental responding, but instead
have major effects that depend upon the action-outcome (A-O)
or S-R associative structure underlying the behavior. Lesions
or NMDA receptor blockade of the AcbC (Corbit et al., 2001;
Kelley et al., 1997) or DM striatum (Yin et al., 2004, 2005), while
impairing instrumental behavior under A-O control, actually
promote the development of S-R habits in which responding
persists after reinforcer devaluation (Yin et al., 2004). Dorsolat-
eral striatal lesions, inactivation, or DA denervation, on the other
hand, return previously habitual responding to A-O control and
hence continuing sensitivity to reinforcer devaluation (Yin et al.,
2004; Faure et al., 2005) or action-outcome contingency degra-
dation (Yin et al., 2006). Such observations further emphasize
that A-O and S-R learning processes are likely engaged in paral-
lel, with dorsolateral striatum-dependent S-R mechanisms even-
tually dominating the control over behavior. This is especially
evident under conditions in which responding is relatively di-
vorced from the outcome or goal, such as that seen in interval,
as opposed to ratio, schedules of reinforcement (Adams and
Dickinson, 1981) and which are exemplified by the second-order
schedule of reinforcement used in the present experiment to
measure drug-seeking behavior.
An important issue for future research concerns the ways in
which drug-seeking habits, elicited and maintained by environ-
mental drug-associated stimuli and under dorsal striatal control,
become compulsive. Such compulsive behavior, defined as per-
sisting despite negative consequences (see also the Diagnostic
and Statistical Manual IV; American Psychiatric Association,
1994) emerges only after long self-administration sessions and
an extended, but not a brief, drug-taking history (Deroche-Gam-
onet et al., 2004; Vanderschuren and Everitt, 2005; Pelloux et al.,
2007) and may depend upon a variety of influences (Everitt and
Wolf, 2002). These have been suggested to include the behav-
ioral sensitization that follows repeated drug exposure—which
can enhance both S-R habit learning (Nelson and Killcross,
2006) and incentive motivational processes manifested as
enhanced drug ‘‘wanting’’ (Robinson and Berridge, 1993)—as
well as the negative reinforcement resulting from the dysregula-
tion of hedonic processes following escalated drug intake and
withdrawal (Koob and Le Moal, 2006). However, impairments
in top-down, or ‘‘executive,’’ control mechanisms as a result
of drug-induced neuroadaptations in prefrontal cortical areas
(Everitt et al., 2007) may also play an important role in the devel-
opment of compulsion through the attendant loss of control over
438 Neuron 57, 432–441, February 7, 2008 ª2008 Elsevier Inc.
Neuron
Intrastriatal Disconnection and Cocaine Seeking
maladaptive drug-seeking habits (Everitt and Robbins, 2005;
Schoenbaum et al., 2006). The ways in which these various influ-
ences interact with cortico-striatal mechanisms underlying the
acquisition and performance of drug-seeking behavior and its
emergence as a compulsive habit require further investigation.
The results of the present study demonstrate that intrastriatal
connectivity is a key aspect of the functional organization of
the striatum and also a critically important component of the
complex neural mechanisms involved in the development of
drug addiction.
EXPERIMENTAL PROCEDURES
Drugs
Cocaine hydrochloride (McFarlan-Smith) was dissolved in sterile 0.9% saline.
The dose of cocaine was calculated as the salt. a-flupenthixol (Sigma, Poole,
UK) was dissolved in distilled water. Quinolinic acid (Sigma, Poole, UK) was
dissolved in sterile phosphate buffer and infused at a final concentration of
0.09 M with the pH adjusted to 7.4.
Animals
After a week of habituation to the animal facility, adult male Lister Hooded rats
(Charles River Laboratories, Kent, UK) weighing 325 g at the time of surgery
were individually housed under a reversed 12 hr light/dark cycle (lights on at
7:00 P.M.). One week before the start of testing, rats were placed on a re-
stricted diet of 20 g/day lab chow (Purina), sufficient to maintain body weight
and growth throughout the experiment. Water was available ad libitum, and
food was given within 1 hr after daily testing. Experiments were performed
between 9:00 A.M. and 7:00 P.M., 5–7 days/week and were conducted in ac-
cordance with the United Kingdom 1986 Animals (Scientific Procedures) Act
(Project License PPL 80/1767).
Apparatus
Rats were tested in operant chambers (29.5 3 32.5 3 23.5 cm; Med Associ-
ates, St. Albans, VT). For cocaine self-administration, each chamber was
equipped with two 4 cm wide retractable levers. The two levers were 12 cm
apart and 8 cm from the grid floor. Above each lever was a cue light (2.5 W,
24 V), and a white house light (2.5 W, 24 V) was located on the top of the op-
posite wall. The floor of the chamber was covered with a metal grid. The testing
chamber was placed within a sound- and light-attenuating box, equipped with
a ventilation fan that also screened external noise. Silastic tubing shielded with
a metal spring extended from each animal’s intravenous catheter to a liquid
swivel (Stoelting, Wood Dale, IL) mounted on an arm fixed outside of the oper-
ant chamber. Tygon tubing extended from the swivel to a Razel infusion pump
(Semat Technical, Herts, UK) located adjacent to the external chamber.
For chain pulling for sucrose, operant chambers were similar to those de-
scribed above. However, only one lever was available in the box. A sucrose so-
lution (15% w/v) dispenser with a cue light above (2.5 W, 24 V) was placed in
the center of the right wall. A chain (20 cm long) fixed at the center of the roof
was inserted into the chamber. The operant chambers were controlled by
Whisker software (Cardinal and Aitken, http://www.whiskercontrol.com).
Procedure
The general timeline of the procedure is illustrated in Figure 1C. Daily experi-
mental testing began 7–10 days after intravenous surgery. For cocaine self-
administration, active and inactive levers were counterbalanced between left
and right sides for individual animals. ‘‘Priming’’ injections of cocaine were
never given. During initial training, rats acquired a lever press response for co-
caine (0.25 mg/infusion, 0.1 ml/5 s) under a fixed-ratio (FR1) (timeout, 20 s)
schedule of reinforcement. On this schedule, each lever press also resulted
in illumination of the stimulus light above the lever, retraction of both levers,
and extinction of the house light for 20 s. After this 20 s interval, the house light
was again illuminated, the stimulus light was extinguished, and the two levers
were again inserted into the testing box. Presses on the inactive lever had no
programmed consequences but were recorded to assess general levels of
Neuron
Intrastriatal Disconnection and Cocaine Seeking
activity. When the daily variation of lever presses under this schedule, in which
animals were allowed 30 infusions, fell below 15%, a fixed-interval schedule
was introduced, with daily increments from 1 min (FI 1) to 15 min (Lee et al.,
2006). After 3 days of stable responding (i.e., daily operant responding varia-
tion during the first interval %15%), a second-order schedule of reinforcement
was introduced such that every ten lever presses resulted in illumination of the
stimulus light for 1 s; cocaine was delivered after completion of the first ten re-
sponses after the FI 15 min had timed out, i.e., FI15 (FR10:S). During these 2 hr
daily sessions, animals received five self-administered infusions of cocaine,
i.e., there were 5 3 15 min intervals per session.
For the acquisition of chain pulling for sucrose, animals were placed in new
operant chambers at least 24 hr after the last SA session. Animals were trained
under continuous reinforcement, i.e., each chain pull resulted in the insertion
into the chamber recess of the dipper containing a 15% sucrose solution
associated with illumination of the cue light placed above the magazine for
5 s. Each session lasted 30 min, during which the animals received 100
CS-sucrose presentations.
Surgery
Stereotaxic neurosurgery was conducted under isoflurane anesthesia, fol-
lowed at least 7 days later by IV surgery during which rats were anesthetized
with ketamine hydrochloride (100 mg/kg, i.p.; Ketaset) and xylazine (9 mg/kg,
i.p.; Rompun). Rats were positioned in a stereotaxic frame (David Kopf In-
struments, Tujunga, CA). Lesions of the AcbC were made by infusion of
0.5 ml of 0.09 M quinolinic acid over 2 min at the following coordinates: ante-
roposterior (AP) (Parkinson et al., 1999), mediolateral (ML), and dorsoventral
(DV) coordinates: AP +1.2, ML ± 1.8, DV 7.1. AP and ML coordinates from
bregma, DV coordinate from skull surface (incisor bar at 3.3 mm) (Paxinos
and Watson, 1986). Lesions were counterbalanced on left and right sides of
the brain. All animals were bilaterally implanted with stainless-steel 24 gauge
guide cannulae (Cooper’s Needleworks, Birmingham, UK) so as to lie 2 mm
above the infusion target within the caudate-putamen (+1.2 mm AP; 3.0 mm
ML; 3.50 mm DV; coordinates from bregma, incisor bar at 3.3 mm) (Paxinos
and Watson, 1986). Cannulae were secured with stainless-steel screws and
dental acrylic; 29 gauge wire stylets (Cooper’s Needleworks, Birmingham,
UK) were inserted into the guide cannulae to maintain patency.
For intravenous surgery, rats were anesthetized and implanted with a single
catheter in the right jugular vein (Caine et al., 2001). Catheters were made from
22 gauge steel cannulae with elongated ends. SILASTIC tubing (0.012 inner
diameter) was secured to one end of the cannula, and the top was fixed to
nylon mesh. The mesh end of the catheter was sutured subcutaneously be-
tween the scapulae. To prevent infection, rats were treated from the day before
to 7 days after the surgery with 10 mg/kg Baytril (Bayer, Wuppertal, Germany)
subcutaneously.
Microinfusions
After 30 days of training under an FI15(FR10:S) schedule of reinforcement, at
a time point when we have established previously that there is a major efflux of
DA in the DL striatum (Ito et al., 2002), intracerebral microinfusions (0.5 ml) were
made through a 28 gauge injector (Semat Technical) lowered to the site of in-
jection ( 5.0 mm, i.e., 2 mm below the ventral placement of the guide cannula)
over 90 s using a syringe pump (model 975A; Harvard Apparatus, Holliston,
MA), followed by a 60 s postinfusion diffusion time. After infusion, stylets
were replaced in the guide cannulae, and the animal was left in a holding
box for 5 min before testing.
Before drug infusions and behavioral assessment, all rats were habituated to
insertion of the injectors and infusions. For this, injectors were inserted twice
into each side of the brain of each animal at separate days, after which each
animal received two infusions of vehicle (phosphate-buffered saline, pH 7.4)
on each side of the brain (twice on one side contralateral to the lesion in
AcbC-lesioned rats and both sides simultaneously in control rats). Each habit-
uation session was conducted under the same conditions as for the tests.
Animals were allowed at least 2 days of baseline responding between each
habituation session. Intracerebral infusions of the DA receptor antagonist a-
flupenthixol, were given after 5 days of baseline responding (with a daily
variation of responding during the first interval <25%) subsequent to the
phosphate-buffer infusions. a-Flupenthixol was given at three doses (5, 10,
and 15 mg/infusion) plus vehicle, according to a counterbalanced, Latin square
design, with infusions of each dose being separated by at least 2 days of base-
line responding without treatment.
Histological Assessment of Lesions and Cannulae Placements
At the end of testing, rats were anesthetized with an overdose of sodium pen-
tobarbitone (1.5 ml/animal, i.p., Euthatal; Rhône-Mérieux, Hertfordshire, UK)
and perfused transcardially with isotonic saline, followed by 4% paraformalde-
hyde in 0.2 M phosphate buffer. Brains were then removed and postfixed
before being transferred to a 20% sucrose solution in 0.01 M PBS for 24 hr
before being sectioned at 60 mm using a freezing microtome. Every third
section was mounted and stained with Cresyl Violet. Lesions and cannula
placements were verified under a light microscope.
Statistical Analyses
For all sessions, the number of active and inactive lever presses or chain pulls
was recorded. Figures show group means ± SEM. Data were analyzed using
analysis of variance (ANOVA) with significance accepted at a = 0.05. For
dose-response analysis, acquisition of second-order schedule or chain pull-
ing, a two-, three-, or four-way repeated-measures ANOVA was performed,
with dose or time as the within-subjects factor and either lever (active versus
inactive lever), group (lesioned [n = 10] versus control [n = 5]), or both as be-
tween-subjects factors. For all analyses, upon confirmation of significant
main effects, differences among individual means were analyzed using the
Newman-Keuls post hoc test.
ACKNOWLEDGMENTS
D.B. was supported by the Foundation FYSSEN. This research was supported
by an MRC Program Grant No. G9536855 to B.J.E. and was conducted within
the University of Cambridge Behavioral and Clinical Neuroscience Institute,
supported by a joint award from the Medical Research Council and the Well-
come Trust. The authors would like to thank Yann Pelloux, Jonathan Lee, Mer-
cedes Arroyo, and David Theobald for their important assistance; and Rudolf
Cardinal for constructive comments on the manuscript. Experiments and sta-
tistical analysis were performed by D.B. The manuscript was prepared by D.B.
and B.J.E. The authors declare that they have no competing financial interests.
Received: October 16, 2007
Revised: November 29, 2007
Accepted: December 12, 2007
Published: February 6, 2008
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