 |
 Previous Article | Next Article 
The Journal of Neuroscience, October 1, 2000, 20(19):7489-7495
Dissociation in Conditioned Dopamine Release in the Nucleus
Accumbens Core and Shell in Response to Cocaine Cues and during
Cocaine-Seeking Behavior in Rats
Rutsuko
Ito,
Jeffrey W.
Dalley,
Simon R.
Howes,
Trevor
W.
Robbins, and
Barry J.
Everitt
Department of Experimental Psychology, University of Cambridge,
Cambridge CB2 3EB, United Kingdom
 |
ABSTRACT |
The dopaminergic innervation of the nucleus accumbens is generally
agreed to mediate the primary reinforcing and locomotor effects of
psychostimulants, but there is less consensus on conditioned dopamine
(DA) release during drug-seeking behavior. We investigated the
neurochemical correlates of drug-seeking behavior under the control of
a drug-associated cue [a light conditioned stimulus (CS+)] and to
noncontingent presentations of the CS+ in the core and shell subregions
of the nucleus accumbens. Rats self-administered cocaine under a
continuous reinforcement schedule in which a response on one of two
identical levers led to an intravenous cocaine infusion (0.25 mg/infusion) and a 20 sec light CS+. Response requirements for cocaine
and the CS+ were then progressively increased until stable responding
was established under a second-order schedule of reinforcement. During
microdialysis, rats were presented noncontingently with a set of 10 sec
CS+ and neutral tone stimuli (CS ) before and after a 90 min period
during which they responded for cocaine under a second-order schedule.
Results showed the following: (1) nucleus accumbens DA increased
in both the core and shell during intravenous cocaine
self-administration; (2) noncontingent presentations of a
cocaine-associated CS+ led to increased DA release selectively in the
nucleus accumbens core; and (3) extracellular DA levels were unaltered
in both core and shell during a protracted period of drug-seeking
behavior under the control of the same cocaine-associated cue. These
results indicate that the mesolimbic dopamine system is activated after
exposure to drug-associated stimuli under specific conditions.
Key words:
cocaine; dopamine; nucleus accumbens; second-order
schedule; conditioned reinforcement; microdialysis
| |
INTRODUCTION |
Exposure to environmental stimuli
associated with the effects of stimulant drugs can evoke intense
craving and cause relapse in detoxified and abstinent addicts (O'Brien
et al., 1990 , 1998; Ehrman et al., 1992; Tiffany and Carter, 1998).
Such stimuli, through pavlovian conditioning, acquire
conditioned reinforcing and incentive motivational properties and are
thereby able to generate and maintain drug-seeking behavior (Davis and
Smith, 1979; de Wit and Stewart, 1981; Stewart et al., 1984; Phillips and Fibiger, 1990). The mesolimbic dopamine (DA) system innervating the
nucleus accumbens (NAcc) is implicated in the primary reinforcing and
locomotor effects of psychostimulants (Roberts et al., 1980; Di Chiara
and Imperato, 1988; Hurd et al., 1989; Robledo et al., 1992), as well
as in potentiating the conditioned reinforcing properties of
reward-associated stimuli (Taylor and Robbins, 1984, 1986). In
vivo monitoring studies (Fontana et al., 1993; Gratton and Wise,
1994; Kiyatkin and Stein, 1996; Di Ciano et al., 1998) have reported
conditioned DA release in the NAcc in response to exposure to
environmental or discrete drug-associated stimuli in rats, but there
have also been failures to observe such conditioned neurochemical
effects, despite evidence of behavioral activation (Barr et al., 1983;
Brown and Fibiger, 1992) or concurrent operant drug-seeking behavior
(Neisewander et al., 1996; Bradberry et al., 2000). Such apparent
discrepancies may have arisen because of differences or
limitations in the techniques and protocols used or because of a
failure to take into account the anatomical and functional
heterogeneity of the NAcc when placing dialysis probes or electrodes.
The elucidation of neurochemical responses associated specifically with
craving or drug-seeking has also been limited by self-administration protocols that fail to distinguish clearly between drug-seeking and
drug-taking behavior. Self-administration procedures using low fixed
ratio (FR) or progressive ratios of reinforcement cannot clearly
dissociate cue-elicited neurochemical responses from drug-induced responses, because the period of responding before any drug infusion is
necessarily very brief. In contrast, the use of a second-order schedule
of drug reinforcement (Goldberg, 1973; Whitelaw et al., 1996; Arroyo et
al., 1998) helps to overcome this problem. Thus, in a typical
second-order schedule, a drug-paired light conditioned stimulus (CS+)
is presented contingent on a fixed ratio of lever pressing, and a high
rate of such responding can be maintained for prolonged periods of time
until the drug itself becomes available, upon completion of a specific
number of FR units of responses, after a fixed interval (FI) has
elapsed, or both. This allows the investigation of drug-seeking
behavior that is both under the control of drug-associated conditioned
stimuli and also unconfounded by the reinforcing and response
rate-altering effects of the self-administered drug (Goldberg and Tang,
1977; Arroyo et al., 1998).
The NAcc, although a primary site mediating the reinforcing effects of
psychomotor stimulants, is also a heterogenous structure with at least
two anatomically and functionally distinct subregions: a medial and
ventral "shell" region and a more lateral "core" region. (Zahm
and Heimer, 1990; Heimer et al., 1991; Jones et al., 1996; David et
al., 1998). It has been suggested that the DA innervation of the shell
region is especially responsive to primary rewards, such as food (Tanda
et al., 1998; Bassareo and Di Chiara, 1999) and drugs of abuse (Di
Chiara et al., 1993; Pontieri et al., 1995; Carlezon and Wise,
1996; Tanda et al., 1997). In contrast, the NAcc core region has been
implicated in response-reinforcement (instrumental) learning (Kelley et
al., 1997) and in subserving behavioral responses to motivationally
significant conditioned stimuli (Bassareo and Di Chiara, 1999; Di
Chiara, 1998; Parkinson et al., 1999, 2000). Therefore, in the present
study, we have used a second-order schedule of cocaine reinforcement
(Arroyo et al., 1998) combined with in vivo microdialysis in
both the shell and core subregions of the NAcc to investigate the
neurochemical correlates of a protracted period of drug-seeking
behavior under the control of a cocaine-associated discrete light
stimulus, as well as responses to the same drug cue presented noncontingently.
| |
MATERIALS AND METHODS |
Animals. Male Lister hooded rats (Charles River,
Kent, UK), weighing between 290 and 360 gm at the beginning of
the experiment, were housed in pairs and then individually after
surgery, under a reversed 12 hr light/dark cycle (lights off 9:00
A.M.). Water was available ad libitum, and food was
made available immediately after a training session, each animal
receiving 20 gm Purina lab chow per day, sufficient to maintain
preoperative body weight and growth. All experimental sessions were
performed during the dark phase, between 9:00 A.M. and 6:00 P.M., and
in accordance with the United Kingdom 1986 Animals (Scientific
Procedures) Act Project License 90/1324.
Intracerebral cannulation surgery. Animals were anesthetized
with Avertin [10 gm of 99% 2,2,2-tribromoethanol (Sigma-Aldrich, Dorset, UK) in 5 mg of tertiary amyl alcohol and 4.5 ml of PBS (Dulbecco "A"; Unipath Ltd, Basingstoke, UK) in 40 ml of absolute alcohol; 1 ml/100 gm body weight, i.p.]. A unilateral guide cannula (BAS Technicol, Congleton, UK) was then lowered and positioned above
the nucleus accumbens shell [anteroposterior (AP), +1.2 mm; lateral
(L), ±0.8 mm; ventral (V), 1.75 mm; incisor bar, 3.3 mm] or core
(AP, +1.2 mm; L, ±1.6 mm; V, 1.75 mm) subregion and secured to the
skull using dental cement, anchored by four stainless steel screws (BAS
Technicol). A removable stainless steel stylet, cut flush with the tip
of the cannula, was placed inside the cannula to maintain its patency
throughout the training period.
Intravenous catheterization. After stereotaxic surgery, rats
were allowed a recovery period for at least 5 d with food
available ad libitum. They were then anesthetized with
Avertin and implanted with chronic intravenous jugular catheters as
described previously (Caine et al., 1992). The catheter was inserted
into the right jugular vein, secured in place by a suture and
Superglue, and was passed subcutaneously over the right shoulder to
exit dorsally between the scapulae. Antibiotic treatment [flushing
daily with 0.1 ml of Timentin 3.2 g: 200 mg of potassium
clavulanate with 3 gm of ticarcillin (Beecham Research, Welwyn, UK); 66 mg/1 ml 0.9% sterile saline (Animal Care Ltd., Dunnington, UK)] was
given for 5 d after surgery and was reinstated 3 weeks afterward
for 5 d to minimize postoperative primary and secondary infection. Thereafter, before each self-administration session, the animals were
flushed with 0.1 ml of sterile 0.9% saline and, at the end of the
session, with 0.1 ml of hepranized saline (30 U/ml 0.9% sterile
saline; CP Pharmaceuticals Ltd., Wrexham, UK) to maintain catheter patency.
Apparatus. Six operant chambers (24 × 20 × 22 cm; Med Associates, St. Albans, UK) contained within a
sound-attenuating box with a ventilating fan were used in the
experiment. Each chamber contained a side wall with two 4-cm-wide
retractable levers, positioned equidistantly, 10 cm apart and 5 cm from
the grid floor. Placed 3 cm above each lever was a round disk (2 cm in
diameter) that could be illuminated by a 2.5 W, 24 V light bulb, to
serve as a stimulus light. The whole chamber was illuminated by a red
1.8 W, 17 V house light positioned at the top corner of the
chamber. The chamber was also equipped with a tone generator (RS
Components, Northants, UK) located centrally above the two levers.
Intravenous infusions of cocaine were delivered by a software-operated
infusion pump (Semat Technical Ltd., St. Albans, UK) placed outside the sound-attenuating box, through a counterbalanced single-channel or a
dual-channel liquid swivel and an extra length of plastic tubing
enclosed in a metal spring, connecting the swivel to the external guide
cannula of the catheter mounted on the animal's back or to the
external head mount.
Each session could be initiated manually by three rapid presses on one
of the two levers, thereby designating the active or drug lever,
as opposed to the second, inactive lever on which responding had no
programmed consequence. The active and inactive levers were
counterbalanced between rats. The beginning of the session was also
marked by illumination of the house light. Subsequent depression of the
active lever resulted in the retraction of both levers, extinction of
the house light and simultaneous illumination of the drug stimulus
light for 20 sec, and the activation of the infusion pump for 4 sec,
delivering 0.1 ml of intravenous infusion of cocaine solution (0.25 mg/infusion). On completion of the 20 sec time-out period, the levers
were re-extended, the house light was illuminated, and the stimulus
light was extinguished. Additional active lever presses resulted in the
same sequence of events leading to cocaine infusions.
The apparatus was controlled by an Acorn Archimedes microcomputer
(Acorn Computers Ltd., Cambridge, UK) running a program written in the
BASIC control language Arachnid.
Drugs. Cocaine hydrochloride (McFarlan-Smith, Edinburgh, UK)
was dissolved in sterile 0.9% saline. The dose of cocaine was calculated as the salt.
Self-administration training. Animals were first trained
during 2 hr sessions of cocaine self-administration under a continuous reinforcement schedule (fixed ratio 1). Once stable rates of
self-administration had been established (10 d), a second-order
FRx(FRy:S) schedule of cocaine reinforcement was
introduced. Under this schedule, rats were required to make
y responses to obtain a single presentation of a 2 sec light
CS+, whereas completion of x of these response units
resulted in the delivery of cocaine, the illumination of the light CS+
for 20 sec, the retraction of both levers, and extinction of the house
light during a 20 sec time-out period. In the initial stage of
training, x was set at 5 and y was 1. The value
for x was then increased to 10 and remained at this value
throughout the training. The value for y was progressively
increased from 1 to 10 until stable responding was established at
FR10(FR10:S). At this stage, a 2 hr delay period before each daily
session was gradually introduced over 10 d for the rats to become
accustomed to the baseline collection period during the dialysis
experiment. Furthermore, for 3 d before the test day, rats were
pre-exposed to noncontingent presentations of a neutral tone stimulus
(CS) to avoid possible effects of novelty on the neurochemical response.
In vivo microdialysis. A 2 mm microdialysis probe (BAS
Technicol) was lowered into the nucleus accumbens via the guide cannula ~18 hr before the start of the experiment. On the test day, the probe
was continuously perfused with artificial CSF (aCSF) (in mM: 147 NaCl, 3 KCl, 1.3 CaCl2, 1 MgCl2, 0.2 NaH2PO4, and 1.3 Na2HPO4) at a rate of 2 µl/min. After a 60 min equilibration period, six 10 min
baseline samples were collected in plastic vials containing 4 µl of
aCSF (Fig. 1). For the next three
10 min samples, the rats received five noncontingent 10 sec light CS
presentations at 1 min intervals starting at 50 sec into the 10 min
sample. The same pattern of presentation was subsequently repeated with the tone (clicker) for 30 min. A 90 min self-administration session under a second-order fixed interval schedule FI20 min(FR10:S) was then
commenced. No priming injections were ever given. In this newly
introduced schedule, animals received a cocaine infusion on the
completion of the first FR10 responses made after a fixed interval of
20 min had elapsed. The animals could thus self-administer a maximum of
four cocaine infusions within 90 min. Using this fixed interval/fixed
ratio schedule allowed at least two samples to be obtained during the
initial drug-free first interval of drug-seeking behavior. At the end
of the session, the levers were retracted, and the house light was
extinguished. Nine additional samples were taken for baseline levels to
be re-established, and then CS+ and CS presentations were given in
reverse order and an additional six samples were collected. Sampling
continued for another 30 min. On completion of testing, animals were
returned to their home cages.
View larger version (12K):
[in this window]
[in a new window]
|
Figure 1.
A schematic diagram of the sampling protocol on
the dialysis test day. BASAL, Baseline sample
collection; SA, self-administration period;
CS+, CS+ presentations; CS, CS
presentations. The whole session lasted 390 min.
|
|
HPLC procedure. DA was determined in dialysate samples by
HPLC and electrochemical detection. Separation was achieved by using a
Hypersil analytical column (100 × 4.6 mm inner diameter, 3 µm) and a mobile phase consisting of 8.82 gm/l trisodium citrate, 2.03 gm/l NaH2PO4, 500 mg/l
Na-1-octane sulfonic acid, 22.5% methanol, 25 mg/l EDTA, and 1 ml/l
triethylamine, pH 2.7 adjusted using orthophosphoric acid. DA was
detected by oxidation using a Coulochem II detector (ESA 5014) equipped
with a guard cell (+300 mV) and a dual electrode analytical cell (E1,
150 mV; E2, +150 mV). Chromatographic data were acquired and
processed using Gyncosoft V4.4. The detection limit of DA in aqueous
standards was ~2 fmol on column.
Histological assessment of microdialysis probe placement.
Within a week after the completion of the testing, rats were deeply anesthetized with Euthatal (sodium pentobarbitone, 200 mg/ml) and
perfused with 0.9% PBS followed by 4% paraformaldehyde (PFA) in PBS.
Brains were then removed, stored in PFA, and transferred to a 20%
sucrose cryoprotectant solution the day before sectioning. Coronal
sections (60 µm) of the brain were cut and stained with cresyl violet
for verification of probe placement.
Data analysis. All analyses were conducted using GBStat
(V3.0; Dynamic Microsystems Inc.). Neurochemical data were analyzed using two-way repeated measures ANOVA, with region (two
levels: core and shell) as the between subjects factor and time bin as the repeated within-subjects factor (three levels: basal plus CS1, 50
to 60 min; FI, 70-240 min; CS2 plus basal, 250-330 min). In addition,
the 20 min drug-seeking period was analyzed using a two-way ANOVA with
region and time as factors. The preceding point (60 min) was included
in this analysis. Fisher's least significant difference post
hoc test was used for multiple comparisons. Behavioral data were
analyzed using two- or three-way repeated measures of ANOVA with region
as the between subjects factor and interval and lever as the repeated measures.
| |
RESULTS |
Histological assessment of dialysis probe locations
Figure 2 shows a schematic
representation of the locations of the 2 mm dialysis probe membrane
within the NAcc core (n = 8) and shell
(n = 6) subregions. Data from four animals in which probes were placed outside their intended target were excluded from the
study.
View larger version (37K):
[in this window]
[in a new window]
|
Figure 2.
Schematic representation of the locations of the 2 mm dialysis probe membrane within the nucleus accumbens core
(gray; n = 8) and shell
(black; n = 6) compartments
(distances are in millimeters from the bregma) (adapted from Paxinos
and Watson, 1986).
|
|
Behavioral data
Figure 3 shows the mean rate of
responding on the drug-paired active lever during the four intervals of
cocaine self-administration under a FI20(FR10:S) schedule of
reinforcement in rats in the NAcc core and shell groups. Every 10th
lever press was followed by the presentation of a 2 sec light stimulus
(CS+) associated previously with cocaine self-administration during
training, and the completion of the first 10 lever responses after an
interval of 20 min resulted in an intravenous cocaine infusion (0.25 mg/infusion) that was also paired with a 20 sec CS+ presentation. All
animals received the maximum number (four) of infusions within the 90 min session. As shown in Figure 4, the
rate of responding on the active lever showed significant increases
with each successive interval in both groups of rats (interval effect,
F(3,36) = 14.35, p = 0.0001). Although overall responding in the shell group was higher than
in the core group of animals, ANOVA showed this was not significant
(F(1,12) = 1.82, p = 0.2). Responding on the inactive lever was significantly lower in both
groups of rats as shown in Figure 4 (lever effect,
F(1,12) = 169, p = 0.0001).
View larger version (17K):
[in this window]
[in a new window]
|
Figure 3.
Cumulative response record during the
period of responding under a second-order FI20 min(FR10:S) schedule,
both before and after the self-administration of cocaine The
arrow represents the delivery of a cocaine infusion
(0.75 mg/infusion), which was paired with a 20 sec CS+
presentation.
|
|
View larger version (26K):
[in this window]
[in a new window]
|
Figure 4.
Responses on active and inactive levers before
(Interval 1) and after (Intervals
2-4) the self-administration of cocaine. Error bars
represent the mean ± SEM total of active and inactive lever
presses made during each of the four intervals in the shell
(black; n = 6) and core
(white; n = 8) groups of animals.
Every 10th lever press on the active lever resulted in the presentation
of a 2 sec light CS+, whereas responding on the inactive lever had no
programmed consequence.
|
|
Neurochemical data
Basal concentrations of DA
Basal levels of DA in the NAcc core and shell, taken as the
mean ± SEM fmol/10 min of the first six values obtained before the presentation of the CS+, were 11.81 ± 0.075 and 11.85 ± 0.12, respectively, and thus were not significantly different between the two regions (F(5,60) = 0.39). Mean
changes in the extracellular DA levels in the NAcc core and shell
subregions expressed as a percentage of baseline are shown in Figure
5, and absolute values are shown in
Figure 6.
View larger version (26K):
[in this window]
[in a new window]
|
Figure 5.
Mean changes in extracellular DA levels
in the core and shell subregions in the NAcc (expressed as percentage
of baseline ± SEM). A significant elevation in DA levels
(*p < 0.05; **p < 0.01)
compared with baseline levels was observed during the first CS+
presentations selectively in the core subregion. No significant changes
in extracellular DA were seen in either region during the first 20 min
of the self-administration session, which provided a measure of
drug-seeking behavior unaffected by cocaine itself (gray
shading). The ensuing cocaine infusions caused significant
increases in DA levels in both core and shell subregions
(arrows represent time points of cocaine
infusions).
|
|
View larger version (22K):
[in this window]
[in a new window]
|
Figure 6.
Absolute extracellular DA levels in the
core (filled circles) and shell (white
circles) subregions during the first set of CS+ presentations
and during responding under the second-order schedule both before and
after the self-administration of cocaine. The bars indicate the period
of CS+ and CS presentations; 10 sec CS+/CS were presented five
times within a 10 min sample. There was a significant increase in DA
levels in the core subregion in response to the CS+ presentations
(*p < 0.05; **p < 0.01). The
drug-seeking period, indicated by gray shading, was not
accompanied by a rise in DA levels in either region of the NAcc,
whereas during the drug-taking period, significant increases in DA
levels were observed in both subregions (*p < 0.05; **p < 0.01).
|
|
Noncontingent CS+ and CS presentations
As shown in Figures 5 and 6, the first set of noncontingent
presentations of the cocaine-associated light CS+ resulted in a
significant 150-200% increase in extracellular DA at time points 10 and 20 min (p < 0.01) selectively in the core
subregion (time effect, F(11,132) = 2.363, p < 0.01; region × time interaction, F(11,132) = 2.12, p < 0.02). In contrast, the presentation of a non-cocaine-associated CS
did not elevate extracellular DA in either region.
CS+ presentation contingent on cocaine-seeking behavior
At 60 min, levers were extended into the operant chambers
signaling the commencement of the self-administration session. The first 20 min of the session allowed the measure of the neurochemical correlates of cocaine-seeking behavior maintained by the CS+ contingent on lever pressing, unaffected by any pharmacological effects of cocaine. As shown in Figures 5 and 6, there were no significant changes
in extracellular DA seen during this period of drug-free cocaine-seeking behavior in either of the NAcc subregions (region, F(1,12) < 0.02; time,
F(2,24) < 0.73; region × time,
F(2,24) < 0.42).
CS+ presentations contingent on cocaine-seeking behavior after the
self-administration of cocaine
After the first cocaine infusion at 90 min, extracellular DA
levels were significantly elevated above baseline levels, and this
increase was sustained over subsequent cocaine infusions (maximum of
four) in the range of 150-250% in the core and 200-310% in the
shell (F(17,204) = 7.93, p = 0.0001). Fisher's post hoc analyses
revealed that this increase from baseline reached significance at time
points 130-160 min in the core (p < 0.01) and
at time points 90-180 min in the shell (p < 0.01). There was no interaction between region and time with respect to
the dopamine response during the self-administration session
(F < 1). Within 50-60 min after the termination of
the self-administration period, extracellular DA declined to levels
slightly below the initial baseline (73-85% in core group; 93-97%
in shell group), but these changes were not statistically different
between the two subregions (F = 1.01).
In the final phase of the experiment, presentations of the CS+ and CS
were reversed in order. The increase in extracellular DA (150%)
in the core subregion during the passive presentation of the CS+ (Fig.
5) was again significantly greater than baseline at time points 290 and
300 min (p < 0.05), whereas those in the shell
did not change on presentation of the CS+ (p > 1.0). As before, presentations of the CS were not accompanied by any
change in extracellular DA.
| |
DISCUSSION |
Noncontingent presentations of a cocaine-associated cue were
associated with significantly increased DA efflux in the core, but not
the shell, subregion of the nucleus accumbens. In contrast, presentations of cocaine-associated cues contingent on responding during drug-seeking behavior were not accompanied by any changes in DA
efflux. However, after self-administration of cocaine, extracellular DA
levels were significantly increased in both the NAcc core and shell subregions.
Unconditioned effects of cocaine
The finding of increased extracellular DA in both the core and
shell during cocaine self-administration is in contrast to the findings
suggesting preferential responsiveness of the DA innervation of the
NAcc shell to psychomotor stimulants and other drugs of abuse (Pierce
and Kalivas, 1995; Pontieri et al., 1995; Heidbreder and Feldon, 1998;
Cadoni and Di Chiara, 1999). One explanation for these different
results may lie in the route and method of drug administration. Thus,
in the present study cocaine was self-administered, whereas in the
earlier studies the drugs were given noncontingently by the
experimenter. However, there are several demonstrations that contingent
and noncontingent administration of cocaine differentially affect
extracellular DA levels in the nucleus accumbens (Hemby et al., 1997)
and amygdala (Wilson et al., 1994), with greater increases occurring
after contingent versus noncontingent drug. Cocaine-induced alterations
in the activity of NAcc neurons also depend on the passive or active nature of drug administration (Carelli and Deadwyler, 1994). Thus, cocaine self-administration in the present experiment may have allowed
increases in extracellular DA in the core more readily to be measured.
Drug-seeking behavior
The failure to observe a DA response during active drug-seeking
maintained by conditioned stimuli in the present experiment is
consistent with the observation of Neisewander et al. (1996) that
response-contingent presentations of a CS+ associated previously with
cocaine self-administration in rats responding in extinction failed to
induce an increase in DA overflow in the NAcc (probe placements being
predominantly in the core subregion). Moreover, drug-seeking triggered
by a visual cue in monkeys was also not associated with changes in
extracellular DA in the ventral striatum (Bradberry et al., 2000).
These data lead to the speculation that the absence of increases in DA
levels in the NAcc concomitant with response-contingent presentations
of a CS+ could be attributable to the automated, or habitual, nature of
responding under the second-order schedule, the control of which has
devolved to a neural system not encompassing the NAcc (Robbins and
Everitt, 1999). Not only has drug-seeking behavior been suggested to
become compulsive and habitual in the transition from drug abuse to
addiction (O'Brien and McLellan, 1996; Robbins and Everitt, 1999), but
electrophysiological studies have shown that, after extensive
over-training, the response of midbrain DA neurons to conditioned
stimuli is gradually attenuated (Ljungberg et al., 1992; Redgrave et
al., 1999).
These results are therefore inconsistent with the hypothesis that
mesolimbic DA is invariably activated during drug-seeking behavior (de
Wit and Stewart, 1981; Robinson and Berridge, 1993). Although it has
been shown that DA receptor agonists and antagonists can increase or
decrease, respectively, drug-seeking responses (Ettenberg et al., 1996;
Shaham and Stewart, 1996; DeVries et al., 1999; Pilla et al., 1999) or
reinstate such responses after extinction (Wise et al., 1990; Self et
al., 1996; McFarland and Ettenberg, 1997), it remains possible that
these effects occur relatively early in the acquisition of drug-seeking
or drug-taking behavior or are mediated at sites other than the NAcc,
such as the amygdala (Hitchcott and Phillips, 1998; Everitt et al.,
1999). Moreover, in these studies of reinstatement of drug-seeking
behavior, the subjects' responding has been subjected both to a
sometimes long period of extinction and also drug withdrawal. Neither
condition was present in these studies, and it remains possible that
dopaminergic mechanisms in cue-dependent drug-seeking might become more
prominent after extinction and withdrawal.
The present data also do not support the suggestion that the magnitude
of the DA response in the NAcc is correlated with lever pressing rates,
as has been reported under high ratio schedules of food reinforcement
(Sokolowski et al., 1998; Salamone et al., 1999). Dopamine depletion
from the NAcc induced by 6-hydroxydopamine (Robbins et al., 1983;
Sokolowski and Salamone, 1998) or infusions of DA receptor antagonists
into the NAcc (Cory-Slechta et al., 1997; Salamone et al.,
1999) have been shown to depress instrumental lever pressing,
particularly under schedules demanding high response rates. Yet despite
the high numbers of responses made by rats under the FI20 min(FR10:S)
second-order schedule used in the present study, no increase in
extracellular DA in the NAcc was observed until cocaine had been
self-administered. These different results may again reflect the degree
of pretraining and the extent to which the instrumental behavior has
devolved to habit rather than action-outcome control.
Effect of noncontingent CS+ presentations
In contrast to the absence of a measurable DA response in the NAcc
during drug-seeking behavior, noncontingent presentations of a
cocaine-associated CS+ evoked a selective increase in extracellular DA
in the core, but not the shell, of the NAcc. This result extends the
observation of Di Ciano et al. (1998) who found conditioned increases
in DA oxidation currents in the NAcc in response to passive
presentation of a flashing light stimulus that had been paired
previously with either self-administered or noncontingent amphetamine
administration. Similarly, presentations of a drug-associated CS+ alone
before a self-administration session were also accompanied by an
increased DA signal in the NAcc (Gratton and Wise, 1994; Kiyatkin and
Stein, 1995, 1996).
The selective DA response to noncontingent presentations of the CS+ in
the core subregion supports the observation of Bassareo and Di Chiara
(1999), who also reported that a CS+ associated with a highly palatable
and calorific food elicited strong appetitive behavioral responses and
a concomitant rise in DA levels selectively in the core subregion of
the NAcc. Moreover, the increased DA efflux in the NAcc core that
followed "unexpected" presentations of the CS+ in the present study
is consistent with electrophysiological data showing that midbrain DA
neurons increased their activity specifically to the unexpected
presentation of rewards or conditioned stimuli, whereas such responses
were not evident for expected positively reinforcing stimuli, whether
conditioned or not (Romo and Schultz, 1990; Schultz et al., 1994;
Schultz, 1998).
Pavlovian conditioning, conditioned reinforcement, and
drug-seeking behavior
The results of these experiments indicate important and subtle
differences in the ways in which drug-associated stimuli influence drug-seeking behavior and the extent to which this involves activation of the mesolimbic DA system. Thus, although the pavlovian CS+ eliciting
property of a cocaine-conditioned reinforcer is sufficient to increase
DA selectively in the NAcc core, this effect is apparently unnecessary
for the maintenance of drug-seeking behavior by the contingent
presentation of the stimulus as a conditioned reninforcer. Therefore,
this aspect of the maintenance of drug-seeking is independent of the
mesolimbic DA system, whereas the primary reinforcing action of cocaine
clearly is not. The observation that conditioned reinforcement (i.e.,
response-produced CS+ presentations) did not increase DA levels in the
NAcc during drug-seeking is also consistent with our earlier results
that DA depletion from the NAcc (Taylor and Robbins, 1986) or DA
receptor blockade in the NAcc (Wolterink et al., 1993) does not
decrease the effects of conditioned reinforcers per se but only their
amplification by stimulant drugs.
The particular circumstances under which a drug-associated CS+ does
affect drug-seeking behavior via activation of the mesolimbic DA system
therefore remain uncertain. One circumstance may be the elicitation of
drug-seeking or drug-taking behavior because, after extinction, such
cues are known to reinstate drug self-administration (de Wit and
Stewart, 1981; Stewart et al., 1984) and drug-seeking under a
second-order schedule of reinforcement (Arroyo et al., 1998). Moreover,
Weiss et al. (2000) have shown that DA is increased in the NAcc and
amygdala by exposure to a cocaine cue that also reinstated responding
after a prolonged period of extinction of cocaine self-administration.
Another possibility, yet to be studied directly, is that unexpected
presentation of drug-cues may facilitate, that is increase the rate of,
drug-seeking behavior, much as has been demonstrated for the
facilitative effect of a pavlovian CS+ on responding for an ingestive
reward (Lovibond, 1983). Indeed, this influence of a CS+ on a seeking
response for food is abolished by lesions of the NAcc core, but not
shell (Hall et al., 1999), and by the DA receptor antagonist pimozide
(Dickinson et al., 2000), whereas intra-accumbens infusions of
D-amphetamine potentiate the response-incremental effects
of a pavlovian CS+ (Wyvell and Berridge, 2000), much as they potentiate
conditioned reinforcers (Taylor and Robbins, 1984).
In summary, this study has helped to resolve apparent discrepancies in
the literature in which conditioned stimuli have been reported to
increase, or to have no effect on, DA overflow in the NAcc. The present
investigation has shown both effects: a lack of impact when the CS+ is
acting to maintain drug-seeking behavior under a second-order schedule
(analogous to habitual responding postulated in human drug abusers)
(O'Brien and McLellan, 1996; Tiffany and Carter, 1998); and a
significant increase when the same CS+ is presented noncontingently for
the first occasion after a history of contingent presentation, possibly
consistent with the postulated role of such stimuli in eliciting drug
craving and reinstatement behaviors.
| |
FOOTNOTES |
Received June 1, 2000; revised July 13, 2000; accepted July 20, 2000.
This work was supported by Medical Research Council (MRC) Program Grant
G9537855 (to B.J.E. and T.W.R.) and an MRC Cooperative in Brain,
Behavior, and Neuropsychiatry.
Correspondence should be addressed to Prof. B. J. Everitt,
Department of Experimental Psychology, University of Cambridge, Downing
Street, Cambridge CB2 3EB, UK. E-mail: bje10{at}cus.cam.ac.uk.
| |
REFERENCES |
-
Arroyo M,
Markou A,
Robbins TW,
Everitt BJ
(1998)
Acquisition, maintenance and reinstatement of intravenous cocaine self-administration under a second-order schedule of reinforcement in rats: effects of conditioned cues and unlimited access to cocaine.
Psychopharmacology
140:331-344[Medline].
-
Barr GA,
Sharpless NS,
Cooper S,
Schiff SR
(1983)
Classical conditioning, decay and extinction of cocaine-induced hyperactivity and stereotypy.
Life Sci
33:1341-1351[Medline].
-
Bassareo V,
Di Chiara G
(1999)
Differential responsiveness of dopamine transmission to food-stimuli in nucleus accumbens shell/core compartments.
Neuroscience
89:637-641[Web of Science][Medline].
-
Bradberry CW,
Barrett-Larimore RL,
Jatlow P,
Rubino SR
(2000)
Impact of self-administered cocaine and cocaine cues on extracellular dopamine in mesolimbic and sensorimotor striatum in rhesus monkeys.
J Neurosci
20:3874-3883[Abstract/Free Full Text].
-
Brown EE,
Fibiger HC
(1992)
Cocaine-induced conditioned locomotion: absence of associated increases in dopamine release.
Neuroscience
48:621-629[Medline].
-
Cadoni C,
Di Chiara G
(1999)
Reciprocal changes in dopamine responsiveness in the nucleus accumbens shell and core and in the dorsal caudate-putamen in rats sensitized to morphine.
Neuroscience
90:447-455[Web of Science][Medline].
-
Caine SB,
Lintz R,
Koob GF
(1992)
Intravenous drug self-administration techniques in animals.
In: Behavioural neuroscience: a practical approach (Sahgal A,
ed), pp 117-143. Oxford: Oxford UP.
-
Carelli RM,
Deadwyler SA
(1994)
A comparison of nucleus accumbens neuronal firing patterns during cocaine self-administration and water reinforcement in rats.
J Neurosci
14:7736-7746.
-
Carlezon WA,
Wise RA
(1996)
Rewarding actions of phencyclidine and related drugs in nucleus accumbens shell and frontal cortex.
J Neurosci
16:3112-3122[Abstract/Free Full Text].
-
Cory-Slechta DA,
Pazmino R,
Bare C
(1997)
The critical role of nucleus accumbens dopamine systems in the mediation of fixed interval schedule-controlled operant behaviour.
Brain Res
764:253-256[Medline].
-
David JD,
Zahnister NR,
Hoffer BJ,
Gerhardt GA
(1998)
In vivo electrochemical studies of dopamine clearance in subregions of rat nucleus accumbens: differential properties of the core and shell.
Exp Neurol
153:277-286[Medline].
-
Davis WM,
Smith SG
(1979)
Role of conditioned reinforcers in the initiation, maintenance and extinction of drug-seeking behaviour.
Pavlov J Biol Sci
11:222-236.
-
De Vries TJ,
Schoffelmeer ANM,
Binnekade R,
Vanderschuren LJMJ
(1999)
Dopaminergic mechanisms mediating the incentive to seek cocaine and heroin following long-term withdrawal of IV drug self-administration.
Psychopharmacology
143:254-260[Medline].
-
de Wit H,
Stewart J
(1981)
Reinstatement of cocaine-reinforced responding in the rat.
Psychopharmacology
75:134-143[Medline].
-
Di Chiara G
(1999)
Drug addiction as dopamine-dependent associative learning disorder.
Eur J Pharmacol
375:13-30[Web of Science][Medline].
-
Di Chiara G,
Imperato A
(1988)
Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats.
Proc Natl Acad Sci USA
85:5274-5278[Abstract/Free Full Text].
-
Di Chiara G,
Tanda G,
Frau R,
Carboni E
(1993)
On the preferential release of dopamine in the nucleus accumbens by amphetamine: further evidence obtained by vertically implanted concentric dialysis probes.
Psychopharmacology Berl
112:398-402[Medline].
-
Di Ciano P,
Blaha CD,
Phillips AG
(1998)
Conditioned changes in dopamine oxidation currents in the nucleus accumbens of rats by stimuli paired with self-administration or yoked-administration of d-amphetamine
Eur J Neurosci
10:1121-1127[Web of Science][Medline].
-
Dickinson A,
Smith J,
Mirenowicz J
(2000)
Dissociation of Pavlovian and instrumental learning under dopamine antagonism.
Behav Neurosci
114:468-483[Web of Science][Medline].
-
Ehrman RN,
Robbins SJ,
Childress AR,
O'Brien CP
(1992)
Conditioned responses to cocaine-related stimuli in cocaine abuse patients.
Psychopharmacology
107:523-529[Medline].
-
Ettenberg A,
MacConnell LA,
Geist TD
(1996)
Effects of haloperidol in a response-reinstatement model of heroin relapse.
Psychopharmacology
124:205-210[Medline].
-
Everitt BJ,
Parkinson JA,
Olmstead MC,
Arroyo M,
Robledo P,
Robbins TW
(1999)
Associative processes in addiction and reward: the role of amygdala-ventral striatal systems.
Ann NY Acad Sci
877:412-438[Web of Science][Medline].
-
Fontana DJ,
Post RM,
Pert A
(1993)
Conditioned increases in mesolimbic dopamine overflow by stimuli associated with cocaine.
Brain Res
629:31-39[Medline].
-
Goldberg SR
(1973)
Comparable behavior maintained under fixed-ratio and second-order schedules of food presentation, cocaine injection or D-amphetamine injection in the squirrel monkey.
J Pharmacol Exp Ther
186:18-30[Abstract/Free Full Text].
-
Goldberg SR,
Tang AH
(1977)
Behavior maintained under second-order schedules of intravenous morphine injection in squirrel and rhesus monkeys.
Psychopharmacology
51:235-242[Medline].
-
Gratton A,
Wise RA
(1994)
Drug- and behavior-associated changes in dopamine-related electrochemical signals during intravenous cocaine self-administration.
J Neurosci
14:4130-4146[Abstract].
-
Hall J,
Parkinson JA,
Connor TMF,
Di Ciano P,
Dickinson A,
Everitt BJ
(1999)
The role of amygdala-ventral striatal sub-systems in Pavlovian to instrumental transfer.
Soc Neurosci Abstr
41:2.
-
Heidbreder C,
Feldon J
(1998)
Amphetamine-induced neurochemical and locomotor responses are expressed differentially across the anteroposterior axis of the core and shell subterritories of the nucleus accumbens.
Synapse
29:310-322[Web of Science][Medline].
-
Heimer L,
Zahm DS,
Churchill L,
Kalivas PW,
Wohltmann C
(1991)
Specificity in the projection patterns of accumbal core and shell in the rat.
Neuroscience
41:89-125[Web of Science][Medline].
-
Hemby SE,
Co C,
Koves TR,
Smith JE,
Dworkin TR
(1997)
Differences in extracellular dopamine concentrations in the nucleus accumbens during response-dependent and response-independent cocaine administration in the rat.
Psychopharmacology
133:7-16[Medline].
-
Hitchcott PK,
Phillips GD
(1998)
Double dissociation of the behavioural effects of R(+) 7-OH-DPAT infusions in the central and basolateral amygdala nuclei upon Pavlovian and instrumental conditioned appetitive behaviours.
Psychopharmacology
140:458-469[Medline].
-
Hurd Y,
Weiss F,
Koob GF,
Ungerstedt U
(1989)
Cocaine reinforcement and extracellular DA overflow in rat nucleus accumbens: an in vivo microdialysis study.
Brain Res
498:199-204[Web of Science][Medline].
-
Jones SR,
O'Dell SJ,
Marshall JF,
Wightman RM
(1996)
Functional and anatomical evidence for different dopamine dynamics in the core and shell of the nucleus accumbens in slices of rat brain.
Synapse
23:224-231[Web of Science][Medline].
-
Kelley AE,
Smith-Roe SL,
Holahan MR
(1997)
Response-reinforcement learning is dependent on N-methyl-D-aspartate receptor activation in the nucleus accumbens core.
Proc Natl Acad Sci USA
94:12174-12179[Abstract/Free Full Text].
-
Kiyatkin EA,
Stein EA
(1995)
Fluctuations in nucleus accumbens dopamine during cocaine self-administration behaviour: an in vivo electrochemical study.
Neuroscience
54:599-617.
-
Kiyatkin EA,
Stein EA
(1996)
Conditioned changes in nucleus accumbens dopamine signal established by intravenous cocaine in rats.
Neurosci Lett
211:73-76[Web of Science][Medline].
-
Ljungberg T,
Apicella P,
Schultz W
(1992)
Responses of monkey midbrain dopamine neurons during learning of behavioural reactions.
J Neurophysiol
67:145-163[Abstract/Free Full Text].
-
Lovibond PF
(1983)
Facilitation of instrumental behaviour by a Pavlovian appetitive conditioned stimuli.
J Exp Psychol Anim Behav Process
9:225-247[Web of Science][Medline].
-
McFarland K,
Ettenberg A
(1997)
Reinstatement of drug-seeking behavior produced by heroin-predictive environmental stimuli.
Psychopharmacology
131:86-92[Medline].
-
Neisewander JL,
O'Dell LE,
Tran-Nguyen LTL,
Castaneda E,
Fuchs RA
(1996)
Dopamine overflow in the nucleus accumbens during extinction and reinstatement of cocaine self-administration behavior.
Neuropsychopharmacology
15:506-514[Web of Science][Medline].
-
O'Brien CP,
McLellan AT
(1996)
Myths about the treatment of addiction.
Lancet
347:237-240[Web of Science][Medline].
-
O'Brien CP,
Childress AR,
McLellan T,
Ehrman R
(1990)
Integrating systemic cue exposure with standard treatment in recovering drug dependent patients.
Addict Behav
15:355-365[Web of Science][Medline].
-
O'Brien CP,
Childress AR,
Ehrman R,
Robbins SJ
(1998)
Conditioning factors in drug abuse: can they explain compulsion?
J Psychopharmacol
12:15-22.
-
Parkinson JA,
Olmstead MC,
Burns LH,
Robbins TW,
Everitt BJ
(1999)
Dissociation in effects of lesions of nucleus accumbens core and shell in appetitive Pavlovian approach behavior and the potentiation of conditioned reinforcement and locomotor activity by D-amphetamine.
J Neurosci
19:2401-2411[Abstract/Free Full Text].
-
Parkinson JA,
Willoughby PJ,
Robbins TW,
Everitt BJ
(2000)
Disconnection of the anterior cingulate cortex and nucleus accumbens core impairs Pavlovian approach behavior: further evidence for limbic cortical-ventral striatopallidal systems.
Behav Neurosci
114:42-63[Web of Science][Medline].
-
Paxinos G,
Watson C
(1986)
In: The rat brain in stereotaxic coordinates, Ed 2. Sydney: Academic.
-
Phillips AG,
Fibiger HC
(1990)
Role of reward and enhancement if conditioned reward in persistence of responding for cocaine.
Behav Pharmacol
1:269-282[Medline].
-
Pierce RC,
Kalivas PW
(1995)
Amphetamine produces sensitized increases in locomotion and extracellular dopamine preferentially in the nucleus accumbens shell of rats administered repeated cocaine.
Brain Res
567:169-174.
-
Pilla M,
Perachon S,
Sautel F,
Garrido F,
Mann A,
Wermuth CG,
Schwartz JC,
Everitt BJ,
Sokoloff P
(1999)
Selective inhibition of cocaine-seeking behaviour by a partial dopamine D3 receptor agonist.
Nature
400:371-375[Medline].
-
Pontieri FE,
Tanda G,
Di Chiara G
(1995)
Intravenous cocaine, morphine, and amphetamine preferentially increase extracellular dopamine in the "shell" as compared with the "core" of the rat nucleus accumbens.
Proc Natl Acad Sci USA
92:12304-12308[Abstract/Free Full Text].
-
Redgrave P,
Prescott TJ,
Gurney K
(1999)
Is the short-latency dopamine response too short to signal reward error?
Trends Neurosci
22:146-151[Web of Science][Medline].
-
Robbins TW,
Everitt BJ
(1999)
Drug addiction: bad habits add up.
Nature
398:567-570[Medline].
-
Robbins TW,
Roberts DCS,
Koob GF
(1983)
Effects of d-amphetamine and apomorphine upon operant behavior and schedule-induced licking in rats with 6-hydroxydopamine-induced lesions of the nucleus accumbens
J Pharmacol Exp Ther
224:662-673[Abstract/Free Full Text].
-
Roberts DCS,
Koob GF,
Klonoff HC,
Fibiger HC
(1980)
Extinction and recovery of cocaine self-administration following 6-hydroxydopamine lesions of the nucleus accumbens.
Pharmacol Biochem Behav
12:781-787[Web of Science][Medline].
-
Robinson TE,
Berridge KC
(1993)
The neural basis of drug craving: an incentive-sensitization theory of addiction.
Brain Res Rev
18:247-291[Medline].
-
Robledo P,
Maldonado-Lopez R,
Koob GF
(1992)
Role of dopamine receptors in the nucleus accumbens in the rewarding properties of cocaine.
Ann NY Acad Sci
654:509-512[Web of Science][Medline].
-
Romo R,
Schultz W
(1990)
Dopamine neurons of the monkey midbrain and contingencies of responses to active touch during self-initiated arm movements.
J Neurophysiol
63:592-606[Abstract/Free Full Text].
-
Salamone JD,
Aberman JE,
Sokolowski JD,
Cousins MS
(1999)
Nucleus accumbens dopamine and rate of responding: neurochemical and behavioral studies.
Psychobiology
27:236-247.
-
Schultz W
(1998)
Predictive reward signal of dopamine neurons.
J Neurophysiol
80:1-27[Abstract/Free Full Text].
-
Schultz W,
Romo R,
Ljunberg T,
Mirenovicz J,
Hollerman JR,
Dickinson A
(1994)
Reward and related signals carried by DA neurons.
In: Models of information processing in the basal ganglia (Houk,
et al.
eds). Cambridge, MA: MIT.
-
Self DW,
Barnhart WJ,
Lehman DA,
Nestler EJ
(1996)
Opposite modulation of cocaine-seeking behavior by D1-like and D2-like dopamine-receptor agonists.
Science
271:1586-1589[Abstract].
-
Shaham Y,
Stewart J
(1996)
Effects of opioid and dopamine receptor antagonists on relapse induced by stress and re-exposure to heroin in rats.
Psychopharmacology
125:385-391[Medline].
-
Sokolowski JD,
Salamone JD
(1998)
The role of accumbens dopamine in lever pressing and response allocation: effects of 6-OHDA injected into core and dorsomedial shell.
Pharmacol Biochem Behav
59:557-566[Web of Science][Medline].
-
Sokolowski JD,
Conlan AN,
Salamone JD
(1998)
A microdialysis study of nucleus accumbens core and shell dopamine during operant responding in the rat.
Neuroscience
86:1001-1009[Web of Science][Medline].
-
Stewart J,
de Wit H,
Eikelboom R
(1984)
Role of unconditioned and conditioned drug affects in the self-administration of opiates and stimulants.
Psychol Rev
91:251-268[Web of Science][Medline].
-
Tanda GL,
Di Chiara G
(1998)
A dopamine-mu(1) opioid link in the rat ventral tegmentum shared by palatable food (Fonzies) and non-psychostimulant drugs of abuse.
Eur J Neurosci
10:1179-1187[Web of Science][Medline].
-
Tanda G,
Pontieri FE,
Di Chiara G
(1997)
Cannabinoid and heroin activation of mesolimbic dopamine transmission by a common mu 1 opioid receptor mechanism.
Science
276:2048-2050[Abstract/Free Full Text].
-
Taylor JR,
Robbins TW
(1984)
Enhanced behavioural control by conditioned reinforcers following microinjections of d-amphetamine into the nucleus accumbens.
Psychopharmacology
84:405-412[Medline].
-
Taylor JR,
Robbins TW
(1986)
6-Hydroxydopamine lesions of the nucleus accumbens, but not the caudate-nucleus, attenuate enhanced responding with reward-related stimuli produced by intra-accumbens D-amphetamine.
Psychopharmacology
90:390-397[Medline].
-
Tiffany TT,
Carter BL
(1998)
Is craving the source of compulsive drug use?
J Psychopharmacol
12:23-30.
-
Weiss F,
MaldonadoVlaar CS,
Parsons LH,
Kerr TM,
Smith DL,
BenShahar O
(2000)
Control of cocaine-seeking behavior by drug-associated stimuli in rats: effects on recovery of extinguished operant-responding and extracellular dopamine levels in amygdala and nucleus accumbens.
Proc Natl Acad Sci USA
97:4321-4326[Abstract/Free Full Text].
-
Whitelaw RB,
Markou A,
Robbins TW,
Everitt BJ
(1996)
Excitotoxic lesions of the basolateral amygdala impair the acquisition of cocaine-seeking behaviour under a second-order schedule of reinforcement.
Psychopharmacology
127:213-224[Medline].
-
Wilson JM,
Nobrega JN,
Corrigal WA,
Coen KM,
Shannak K,
Kish SJ
(1994)
Amygdala dopamine levels are markedly elevated after self-administration but not passive-administration of cocaine.
Brain Res
668:39-45[Web of Science][Medline].
-
Wise RA,
Murray A,
Bozarth MA
(1990)
Bromocriptine self-administration and bromocriptine-reinstatement of cocaine-trained and heroin-trained lever pressing in rats.
Psychopharmacology
100:355-360[Medline].
-
Wolterink G,
Phillips GD,
Cador M,
Donselaar-Wolterink I,
Robbins TW,
Everitt BJ
(1993)
Relative roles of ventral striatal D1 and D2 dopamine receptors in responding with conditioned reinforcement.
Psychopharmacology
110:355-364[Medline].
-
Wyvell CL, Berridge KC (2000) Intra-accumbens amphetamine
increases the pure incentive salience of a Pavlovian cue for food
reward: enhancement of "wanting" without either "liking" or
reinforcement. J Neurosci, in press.
-
Zahm DS,
Heimer L
(1990)
Two transpallidal pathways originating in the rat nucleus accumbens.
J Comp Neurol
302:437-446[Web of Science][Medline].
Copyright © 2000 Society for Neuroscience 0270-6474/00/20197489-07$05.00/0
This article has been cited by other articles:
|
|
|
|
 
M. R Delgado, J. Li, D. Schiller, and E. A Phelps
The role of the striatum in aversive learning and aversive prediction errors
Phil Trans R Soc B,
December 12, 2008;
363(1511):
3787 - 3800.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. J. K. Balfour
The psychobiology of nicotine dependence
Eur. Respir. Rev.,
December 1, 2008;
17(110):
172 - 181.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. J Everitt, D. Belin, D. Economidou, Y. Pelloux, J. W Dalley, and T. W Robbins
Neural mechanisms underlying the vulnerability to develop compulsive drug-seeking habits and addiction
Phil Trans R Soc B,
October 12, 2008;
363(1507):
3125 - 3135.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Stewart
Psychological and neural mechanisms of relapse
Phil Trans R Soc B,
October 12, 2008;
363(1507):
3147 - 3158.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. O. Tan and D. Bullock
A Dopamine-Acetylcholine Cascade: Simulating Learned and Lesion-Induced Behavior of Striatal Cholinergic Interneurons
J Neurophysiol,
October 1, 2008;
100(4):
2409 - 2421.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Z.-B. You, B. Wang, D. Zitzman, and R. A. Wise
Acetylcholine Release in the Mesocorticolimbic Dopamine System during Cocaine Seeking: Conditioned and Unconditioned Contributions to Reward and Motivation
J. Neurosci.,
September 3, 2008;
28(36):
9021 - 9029.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Lex and W. Hauber
Dopamine D1 and D2 receptors in the nucleus accumbens core and shell mediate Pavlovian-instrumental transfer
Learn. Mem.,
July 14, 2008;
15(7):
483 - 491.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. L.C. Lee and B. J. Everitt
Reactivation-dependent amnesia for appetitive memories is determined by the contingency of stimulus presentation
Learn. Mem.,
May 28, 2008;
15(6):
390 - 393.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Ishikawa, F. Ambroggi, S. M. Nicola, and H. L. Fields
Dorsomedial Prefrontal Cortex Contribution to Behavioral and Nucleus Accumbens Neuronal Responses to Incentive Cues
J. Neurosci.,
May 7, 2008;
28(19):
5088 - 5098.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. W. Shiflett, R. P. Martini, J. C. Mauna, R. L. Foster, E. Peet, and E. Thiels
Cue-Elicited Reward-Seeking Requires Extracellular Signal-Regulated Kinase Activation in the Nucleus Accumbens
J. Neurosci.,
February 6, 2008;
28(6):
1434 - 1443.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. J. Day and R. M. Carelli
The Nucleus Accumbens and Pavlovian Reward Learning
Neuroscientist,
April 1, 2007;
13(2):
148 - 159.
[Abstract]
[PDF]
|
|
|
|
|
|
|
J. A. Hollander and R. M. Carelli
Cocaine-Associated Stimuli Increase Cocaine Seeking and Activate Accumbens Core Neurons after Abstinence
J. Neurosci.,
March 28, 2007;
27(13):
3535 - 3539.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. W. Kalivas and N. D. Volkow
The Neural Basis of Addiction: A Pathology of Motivation and Choice
Focus,
January 1, 2007;
5(2):
208 - 219.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. D. Volkow, G.-J. Wang, F. Telang, J. S. Fowler, J. Logan, A.-R. Childress, M. Jayne, Y. Ma, and C. Wong
Cocaine cues and dopamine in dorsal striatum: mechanism of craving in cocaine addiction.
J. Neurosci.,
June 14, 2006;
26(24):
6583 - 6588.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. A. Crespo, K. Sturm, A. Saria, and G. Zernig
Activation of muscarinic and nicotinic acetylcholine receptors in the nucleus accumbens core is necessary for the acquisition of drug reinforcement.
J. Neurosci.,
May 31, 2006;
26(22):
6004 - 6010.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. J. M. J. Vanderschuren, P. Di Ciano, and B. J. Everitt
Involvement of the Dorsal Striatum in Cue-Controlled Cocaine Seeking
J. Neurosci.,
September 21, 2005;
25(38):
8665 - 8670.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. W. Kalivas and N. D. Volkow
The Neural Basis of Addiction: A Pathology of Motivation and Choice
Am J Psychiatry,
August 1, 2005;
162(8):
1403 - 1413.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Le Foll and S. R. Goldberg
Cannabinoid CB1 Receptor Antagonists as Promising New Medications for Drug Dependence
J. Pharmacol. Exp. Ther.,
March 1, 2005;
312(3):
875 - 883.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Di Ciano and B. J. Everitt
Direct Interactions between the Basolateral Amygdala and Nucleus Accumbens Core Underlie Cocaine-Seeking Behavior by Rats
J. Neurosci.,
August 11, 2004;
24(32):
7167 - 7173.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. A. S. Baptista, R. Martin-Fardon, and F. Weiss
Preferential Effects of the Metabotropic Glutamate 2/3 Receptor Agonist LY379268 on Conditioned Reinstatement versus Primary Reinforcement: Comparison between Cocaine and a Potent Conventional Reinforcer
J. Neurosci.,
May 19, 2004;
24(20):
4723 - 4727.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. L. Peoples, K. G. Lynch, J. Lesnock, and N. Gangadhar
Accumbal Neural Responses During the Initiation and Maintenance of Intravenous Cocaine Self-Administration
J Neurophysiol,
January 1, 2004;
91(1):
314 - 323.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
R. Ito, J. W. Dalley, T. W. Robbins, and B. J. Everitt
Dopamine Release in the Dorsal Striatum during Cocaine-Seeking Behavior under the Control of a Drug-Associated Cue
J. Neurosci.,
July 15, 2002;
22(14):
6247 - 6253.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. J. Everitt and M. E. Wolf
Psychomotor Stimulant Addiction: A Neural Systems Perspective
J. Neurosci.,
May 1, 2002;
22(9):
3312 - 3320.
[Full Text]
[PDF]
|
|
|
|
|
|
|
U. Shalev, J. W. Grimm, and Y. Shaham
Neurobiology of Relapse to Heroin and Cocaine Seeking: A Review
Pharmacol. Rev.,
March 1, 2002;
54(1):
1 - 42.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. M. Kantak, Y. Black, E. Valencia, K. Green-Jordan, and H. B. Eichenbaum
Dissociable Effects of Lidocaine Inactivation of the Rostral and Caudal Basolateral Amygdala on the Maintenance and Reinstatement of Cocaine-Seeking Behavior in Rats
J. Neurosci.,
February 1, 2002;
22(3):
1126 - 1136.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. L. Wyvell and K. C. Berridge
Incentive Sensitization by Previous Amphetamine Exposure: Increased Cue-Triggered "Wanting" for Sucrose Reward
J. Neurosci.,
October 1, 2001;
21(19):
7831 - 7840.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
TOP
ABSTRACT
INTRODUCTION
