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The Journal of Neuroscience, December 1, 2001, 21(23):9471-9477
Differential Involvement of NMDA, AMPA/Kainate, and Dopamine
Receptors in the Nucleus Accumbens Core in the Acquisition and
Performance of Pavlovian Approach Behavior
Patricia
Di Ciano,
Rudolf N.
Cardinal,
Rosie A.
Cowell,
Simon J.
Little, and
Barry J.
Everitt
Department of Experimental Psychology, University of Cambridge,
Cambridge, CB2 3EB, United Kingdom
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ABSTRACT |
Stimuli paired with primary rewards can acquire emotional valence
and the ability to elicit automatic, Pavlovian approach responses that
have been shown to be mediated by the nucleus accumbens. The present
experiment investigated the effects of infusions of glutamatergic or
dopaminergic receptor antagonists into the core of the nucleus
accumbens on the acquisition and performance of Pavlovian discriminated
approach to an appetitive conditioned stimulus. Rats were trained on an
autoshaping task in which a conditioned stimulus (CS+; a lever)
was inserted into the operant chamber for 10 sec, after which a food
pellet was delivered. Presentation of another lever (CS ) was never
followed by food. Subjects developed a conditioned response of
approaching and contacting the CS+ selectively, although food delivery
was not in any way contingent on the animals' response. A triple
dissociation in the effects of AP-5, LY293558 [(3SR,
4aRS, 6RS,
8aRS)-6-[2-(iH-tetrazol-5-yl)ethyl]-1,2,3,4,4a,5,6,7,8,8a-decahydroiso-quinoline-3-carboxylic acid], and  -flupenthixol infused into the nucleus accumbens core on
the acquisition and performance of this conditioned response was
observed. The AMPA/kainate receptor antagonist LY293558 disrupted discriminated approach performance but not acquisition, as evidenced by
increased approaches to the CS. In contrast, the NMDA receptor antagonist AP-5 impaired only the acquisition, but not performance, of
autoshaping whereas the dopamine D1/D2 receptor antagonist -flupenthixol decreased approaches to the CS+ during both
acquisition and performance. The data are discussed with reference to
dissociable interactions of these receptor types with limbic cortical
and dopaminergic afferents to the nucleus accumbens core during the acquisition and expression of Pavlovian conditioned approach.
Key words:
glutamate; dopamine; conditioned stimulus; autoshaping; nucleus accumbens core; NMDA; AMPA
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INTRODUCTION |
Stimuli paired with natural rewards,
such as food, or with drugs of abuse can acquire powerful motivational
properties, one consequence of which is that they elicit approach
responses that serve to bring the subject into contact with goals and,
in the case of drug-associated stimuli, can induce craving and relapse to drug use. With an "autoshaping" procedure, it was demonstrated that pigeons approached and pecked a key light presented before the
delivery of grain (Brown and Jenkins, 1968 ). The acquisition of
autoshaped key pecking by pigeons (Williams and Williams, 1969) and
autoshaped lever pressing by rats (Locurto et al., 1976) was minimally
affected when responding prevented delivery of the reinforcer, indicating that autoshaping is subserved by Pavlovian mechanisms (because it is relatively insensitive to the introduction of this instrumental contingency). Autoshaping, therefore, provides the best
animal model of the automatic Pavlovian approach behavior elicited by
stimuli paired with primary rewards.
Using this procedure, the approach-eliciting properties of Pavlovian
cues have been shown to depend on the nucleus accumbens (NAcc) and
specific limbic cortical afferents. Thus, selective excitotoxic lesions
of the NAcc core (Parkinson et al., 1999) and dopaminergic depletions
of the NAcc (Parkinson et al., 2001) abolished the acquisition of
autoshaping. Moreover, lesions of the anterior cingulate cortex (ACC)
disrupted the acquisition of autoshaping (Bussey et al., 1997), whereas
lesions of the basolateral amygdala and dorsal or ventral subiculum
were without effect (Parkinson et al., 2000a). In addition, the
disruption of discriminated approach after ACC lesions was
characterized by an increase in approaches to the cue not associated
with reward [conditioned stimulus (CS)] (Bussey et al., 1997),
whereas lesions of the NAcc core and its DA innervation were associated
with decreased approach responses to the stimuli paired with reward
(CS+). The finding that lesions that functionally disconnected the ACC
and NAcc core produced both decreased approaches to the CS+ and
increased approaches to the CS (Parkinson et al., 2000b) underscores
the critical role of interactions between the NAcc and its limbic
cortical afferents in this form of appetitive emotional learning.
Limbic afferents to the NAcc have been shown to interact with dopamine
(DA) in the NAcc in a manner that is glutamate dependent (Wu and
Brudzynski, 1995; Blaha et al., 1997; Floresco et al., 1998;
Taepavarapruk et al., 2000). In this regard, infusion of the NMDA
receptor antagonist D-()-2-amino-phosphonopentanoic acid
(AP-5) into the NAcc core has been shown to impair the acquisition, but
not performance, of an instrumental response (Kelley et al., 1997). In
contrast, AMPA/kainate (KA) receptors have been shown to have a
selective role in the control over behavior by Pavlovian conditioned
stimuli (Di Ciano and Everitt, 2001; Roullet et al., 2001). Important
questions still remain, however, as to the differential involvement of
glutamatergic and dopaminergic receptors in the acquisition and
expression of a Pavlovian appetitive conditioned response. The present
experiment, therefore, investigated the effects of antagonism of NMDA,
AMPA/KA, and DA receptors in the NAcc core on the acquisition and
performance of discriminated Pavlovian approach to an appetitive CS in
an autoshaping paradigm.
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MATERIALS AND METHODS |
Animals
Sixty-two male Lister hooded rats (Charles River, Kent,
UK) weighing 250-300 gm at the time of surgery were individually
housed under a reversed 12 hr light/dark cycle (lights on at 8:00
P.M.). During training and testing, rats were maintained on a
restricted diet of 12 gm of Purina lab chow per day. Water was
available ad libitum, and food was given <2 hr after daily
testing. Experiments were performed between 9:00 A.M. and 8:00 P.M., 6 or 7 d/week, and experiments were conducted in accordance with the
United Kingdom 1986 Animals (Scientific Procedures) Act (Project
License PPL 80/1324).
Apparatus
Rats were tested in operant chambers (29.5 × 32.5 × 23.5 cm; Med Associates Inc., E. Fairfield, VT). Three sides were
constructed from Perspex, and the fourth was made of stainless steel,
on which two 4-cm-wide retractable levers were situated. The two levers were 12 cm apart and 8 cm from the grid floor. Above each lever was a
2.5 W white cue light, and a 2.5 W white house light was located on the
opposite wall. Food was delivered through a magazine that was
equidistant from the two levers and 3 cm above the floor. The floor of
the chamber was lined with absorbent paper and 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. The operant chamber was interfaced to software
running on an Acorn Archimedes microcomputer (Acorn Computers Ltd.,
Cambridge, UK), programmed in the BASIC control language Arachnid.
Surgery
Rats were anesthetized with ketamine hydrochloride (100 mg/kg,
i.p.; Ketaset; VetDrug, Dunnington, UK) and xylazine (9 mg/kg, i.p.;
Rompun; VetDrug) and supplemented with ketamine as needed (~20 mg).
Guide cannulas consisted of 24 ga thin-walled stainless steel
tubing (Coopers Needle Works, Birmingham, UK) and were lowered to 2.5 mm above the target site [NAcc core: +1.2 mm anteroposterior; ±1.8 mm mediolateral; 4.7 mm dorsoventral from skull; incisor bar, 3.3 mm (Paxinos and Watson, 1986)]. Cannulas were secured with
stainless steel screws and dental acrylic; 29 ga wire stylets (Coopers
Needle Works) were inserted into the length of the guide cannulas to
maintain patency.
Microinfusions
Intracerebral microinfusions were made through a 28 ga cannula
(Semat Technical, St. Albans, UK), which was lowered to the site
of injection in the core of the NAcc (7.2 mm dorsoventral relative to
skull), 2.5 mm below the guide cannula. All infusions were 0.5 µl/side, over 90 sec, delivered using a syringe pump (model 975A;
Harvard Apparatus) and followed by a 90 sec diffusion time. After all
infusions, stylets were replaced, and the animal was left in a holding
box for 5 min before testing. All rats received one infusion of
phosphate-buffered vehicle before testing, to habituate the animal to
the injection procedure [0.1 M phosphate-buffered water
(PB); composition of 0.07 M
Na2HPO4 and 0.028 M NaH2PO4, giving an approximate pH of 7.3]. The habituation session and all drug
infusions were separated by at least 1 d of stable performance without treatment.
Drugs
The competitive NMDA receptor antagonist AP-5 was obtained from
Sigma (Poole, UK) and was dissolved in sterile PB. The selective AMPA/KA receptor antagonist (3SR, 4aRS,
6RS,
8aRS)-6-[2-(iH-tetrazol-5-yl)ethyl]-1,2,3,4,4a,5,6,7,8,8a-decahydroiso-quinoline-3-carboxylic acid (LY293558) is the ()-isomer of the racemic compound
(±)LY215490, is 10-fold selective for AMPA over NMDA receptors
(Schoepp et al., 1995), and was a gift from Eli Lilly & Co.
(Indianapolis, IN). LY293558 was dissolved in sterile PB, divided into
aliquots, and frozen at 5°C until use. The dopamine receptor
antagonist cis-(Z)-flupenthixol was obtained from Sigma and
was dissolved in distilled water.
Procedure
During daily training, rats were placed in the operant chambers
immediately before the start of each session when the house light was
illuminated. Sessions lasted on average 1 hr and consisted of 50 trials. During 25 of these trials, the CS+ lever was inserted into the
operant chamber for 10 sec, followed immediately by delivery of one 45 mg food pellet (Rodent Diet Formula P; Noyes, Lancaster, NH) after
retraction of the lever. The remaining 25 trials consisted of insertion
of the CS lever into the chamber for 10 sec, but food was not
delivered. Contacts with each lever were recorded but had no programmed
consequences. The intertrial interval ranged between 45 and 75 sec, and
the order of presentation of the CS+ and CS was random. The CS+ and
CS levers were counterbalanced left-right across rats.
Acquisition experiment. Naïve rats were implanted
with intracerebral cannulas (see above). Five to 7 d after
surgery, rats were randomly assigned to one of four treatment groups:
AP-5, LY293558, -flupenthixol, or vehicle control. The lowest
effective dose from the dose-response study was used, such that each
rat received 0.02 µg (0.067 nmol equivalent) of LY293558, 10 µg (20 nmol equivalent) of -flupenthixol, or an equal volume of PB, before
each of the first 6 d of acquisition of autoshaping. For the NMDA
receptor antagonist group, rats were infused with 1 µg (5 nmol
equivalent) of AP-5 because this dose has been shown previously to be
effective in blocking the acquisition of an instrumental response for
food reward (Kelley et al., 1997). All other parameters were the same
as described above.
Performance experiment. Unoperated naïve rats were
trained until stable approach responses to the CS+ and CS stimuli was observed, after ~14 d of training, and were then implanted with guide
cannulas bilaterally in the NAcc core (see above). After 5-7 d of
recovery from surgery, rats were given additional training sessions
until their performance returned to preoperative levels (~3 d). Rats
were randomly assigned to receive intracore infusions of one of
LY293558, AP-5, or -flupenthixol intracerebrally. All drugs were
given in four doses counterbalanced according to a Latin square design
(Keppel, 1991). The doses administered to the three groups were as
follows: AP-5, 0.2, 1, and 2 µg of PB(equivalent to 1, 5, and 10 nmol, respectively); LY293558, 0.002, 0.02, and 0.04 µg of
PB(equivalent to 0.0067, 0.067, and 0.13 nmol, respectively); and
-flupenthixol, 1, 10, and 25 µg of ddH2O
(equivalent to 2, 20, and 50 nmol, respectively).
Histological assessment of cannula placements
At the end of testing, rats were killed with an overdose of
sodium pentobarbitone (1.5 ml, i.p.; Euthatal;
Rhône-Mérieux, Hertfordshire, UK) and perfused
transcardially with PBS, followed by 4% paraformaldehyde in
0.01 M PBS. Brains were then removed and post-fixed in 4%
paraformaldehyde at least 24 hr before being transferred to a 20%
sucrose solution in 0.01 M PBS for 24 hr before being
sectioned at 60 µm using a freezing microtome. Every third section
was mounted and stained with cresyl violet, and cannula placements were
verified under a light microscope.
Statistical analyses
Data were recorded as number of lever presses during each CS
presentation and were presented as the probability of approach to each
CS, calculated by dividing the number of trials in which each lever was
pressed at least once by the number of presentations of that CS (i.e.,
25). Data are presented as mean ± SEM.
Acquisition experiment. The effect of administration of
AP-5, LY293558, or -flupenthixol into the core during acquisition of
autoshaping was analyzed with a repeated-measures day (six levels) × stimulus (two levers) × group (four levels) ANOVA.
Performance experiment. To confirm that the three groups of
rats had comparable rates of acquisition and baseline performance before treatments, the probability of approaching each stimulus during
the first 10 d of acquisition was analyzed with a
repeated-measures group (three levels) × stimulus (two
levels) × day (10 levels) ANOVA. To investigate the effects of
drug administration on performance of discriminated approach, a
dose-response analysis was conducted with a repeated-measures group
(three levels) × dose (four levels) × stimulus (two levels) analysis.
For all analyses, significant interactions were further analyzed with
simple main effects and planned comparisons. The criterion for
significance was set at p  0.05, and the Huynh-Feldt
correction for nonsphericity was used for all within-subjects analyses
(denoted as pHF).
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RESULTS |
Cannula placements
Figure 1 illustrates the location of
the tips of injection cannulas within the NAcc core for the performance
(A) and acquisition (B)
experiments. Four rats were excluded from the analyses of the
acquisition experiment because the tips of their cannulas were not in
the NAcc core. One rat from each of the LY293558 and flupenthixol
groups was excluded because of illness. Final group sizes were
n = 8.
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Figure 1.
Location of the tips of injection cannulas within
the NAcc core for the performance (A) and
acquisition (B) experiments.
Symbols represent the bilateral placement of the
injections for individual animals. Schematics of coronal sections are
taken from Paxinos and Watson (1986).
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-Flupenthixol and AP-5, but not LY293558, infused into the
nucleus accumbens core disrupted acquisition of autoshaping
Acquisition
Infusion of AP-5, LY293558, -flupenthixol, or vehicle into the
NAcc core was associated with differential effects on the acquisition
of Pavlovian discriminated approach to the two stimuli. After infusions
of LY293558 into the NAcc core, rats acquired the discrimination by the
fourth day of training no differently from controls who received PB
infusions into the NAcc core (Fig. 2). In
contrast, after infusion of AP-5 or -flupenthixol, rats failed to
acquire the discrimination between the two stimuli. A dissociation in
the effects of these treatments on the acquisition of autoshaping was
confirmed by a significant three-way group × day × stimulus
interaction (n = 8;
F(5,140) = 2.95, pHF = 0.003) (Fig. 2).
Additional analysis of the interaction revealed stimulus × day
interactions for both the vehicle (Fig. 2A) and
LY293558 groups (n = 8; for vehicle,
F(5,35) = 8.31, pHF = 0.000; for LY293558, F(5,35) = 6.28, pHF = 0.000) (Fig.
2B), confirming that these two groups of rats
acquired the discrimination. Additional analysis of these interactions
with planned comparisons revealed that, for both of these groups, the
probability of approach to the levers was different on days 5 and 6 only (for vehicle: day 5, F(1,7) = 8.66, pHF = 0.02; day 6, F(1,7) = 14.88, pHF = 0.006; for LY293558: day 5, F(1,7) = 9.11, pHF = 0.019; day 6, F(1,7) = 10.04, pHF = 0.016).
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Figure 2.
Effects of infusion of vehicle
(A), the AMPA/KA antagonist LY293558 (0.02 µg)
(B), the DA antagonist -flupenthixol (10 µg)
(C), and the NMDA antagonist AP-5 (1 µg)
(D) on the acquisition of autoshaping. Day × stimulus interaction: for vehicle, p < 0.001;
for LY293558, p < 0.001. *indicates days at which
approach to the two levers was significantly different;
p < 0.05 (planned comparisons).
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-Flupenthixol and LY293558, but not AP-5, infused into the
nucleus accumbens core disrupted performance of conditioned
approach
Acquisition
Figure 3 illustrates the
preoperative acquisition of discriminated approach to a stimulus paired
with food reward. The three groups represent the treatment conditions
that the animals received in subsequent performance tests and
demonstrated that the three groups were similar before treatments. All
three groups progressively learned to discriminate between the two
stimuli by day 4. Asymptotic performance was reached by day 10, with a
probability of approach of ~0.8 and ~0.15 to the CS+ and CS
stimuli, respectively. A three-way stimulus × group × day
ANOVA revealed a significant stimulus × day interaction,
confirming that all three groups of rats learned the discrimination by
day 10 (n = 8;
F(9,189) = 24.48, pHF < 0.001).
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Figure 3.
Acquisition of autoshaping. Filled
and open symbols represent the probability of approach
to the CS+ and CS stimuli, respectively. Squares,
triangles, and diamonds represent the
LY293558, AP-5, and -flupenthixol treatment groups, respectively,
that the rats were assigned to after acquisition. Day × stimulus
interaction, p < 0.001.
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Performance
All rats returned to preoperative levels of responding within
2 d of postoperative training. A triple dissociation in the effects of -flupenthixol, AP-5, and LY293558 on discriminated approach to the stimuli was observed. Thus, LY293558 infusions resulted
in increased approaches to the CS only, whereas flupenthixol decreased approaches to the CS+ only, and AP-5 was without effect on
approaches to either stimulus (Fig. 4).
This dissociation was confirmed by a significant stimulus × dose × group interaction (n = 8;
F(6,63) = 3.931, pHF = 0.004). Additional analysis of this interaction confirmed that infusion of LY293558 into the core was
associated with differential effects on approach to the two stimuli, as
revealed by a significant stimulus × dose interaction (F(3,21) = 9.55, pHF = 0.008) (Fig.
4A). Additional analysis of this interaction revealed
that LY293558 produced significant increases in approach to the CS
stimulus only (n = 8;
F(3,21) = 4.13, pHF = 0.019) (Fig.
4A). A significant stimulus × dose interaction was also revealed after treatment with -flupenthixol
(F(3,21) = 10.13, pHF = 0.002) (Fig.
4B), whereas -flupenthixol produced significant
decreases in approaches to the CS+ (n = 8;
F(3,21) = 8.76, pHF = 0.003) (Fig.
4B) and small, albeit significant, increases in
approach to the CS (n = 8;
F(3,21) = 3.98, pHF = 0.025). No significant effects
were revealed for AP-5 (Fig. 4C).
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Figure 4.
The effects of infusion of the AMPA/KA antagonist
LY293558 (A), the DA antagonist -flupenthixol
(B), and the NMDA antagonist AP-5
(C) on the performance of Pavlovian discriminated
approach. Filled and open symbols
represent the probability of approach to the CS+ and CS stimuli,
respectively. Dose × stimulus interaction: for LY293558,
p = 0.008; for flupenthixol, p = 0.002.
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DISCUSSION |
The present study was designed to investigate the effects of
antagonism of AMPA/KA, NMDA, or DA receptors in the NAcc core on the
acquisition and performance of discriminated Pavlovian approach to an
appetitive CS using an autoshaping procedure (Brown and Jenkins,
1968). Because this behavior is minimally sensitive to changes in the
instrumental contingency for the reward, it is believed to depend on a
Pavlovian mechanism (Williams and Williams, 1969) and thus provides the
best animal model of the automatic, compulsive approach to conditioned
stimuli paired with rewards. A triple dissociation in the effects of
the three receptor antagonists on the acquisition and performance of
discriminated approach was observed. Infusion of the AMPA/KA receptor
antagonist LY293558 into the core impaired only performance of the
autoshaped approach response by increasing approaches to the CS; it
had no effect on acquisition. In contrast, the NMDA receptor antagonist
AP-5 impaired only the acquisition of autoshaping, whereas the mixed, D1/D2 DA receptor antagonist -flupenthixol decreased approaches to
the CS+ during both acquisition and performance of the conditioned response.
DA and NMDA receptor antagonists infused into the NAcc blocked the
acquisition of autoshaping
Consistent with much evidence implicating both NMDA and DA
receptors in learning (Berke and Hyman, 2000), both AP-5 and
-flupenthixol infused into the NAcc core disrupted the acquisition
of autoshaping. NMDA receptors in particular have been shown to be
involved in processes believed to underlie learning (Davis et al.,
1992; Shimizu et al., 2000) and have been shown to be important in the
acquisition of a variety of behaviors, including spatial learning
(Bannerman et al., 1995; Smith-Roe et al., 1999). Moreover, antagonism
of NMDA receptors blocked the establishment of a Pavlovian conditioned eye-blink response in rabbits (Chen and Steinmetz, 2000), whereas the
firing rate of A10 neurons projecting to the NAcc was increased by a CS
only during the early stages of learning its association with reward
(Ljungberg et al., 1992). Moreover, systemic administration of either
NMDA or DA receptor antagonists blocked the acquisition, but not
expression, of conditioned motor activity (Beninger and Hahn, 1983;
Cervo and Samanin, 1996) and a conditioned place preference (Cervo and
Samanin, 1995).
Direct manipulations of DA and NMDA receptors in the NAcc core have
also been shown to disrupt the acquisition of conditioned responding.
Thus, 6-OHDA lesions blocked the learning of a discriminated approach
response to a CS predictive of food in an autoshaping procedure
(Parkinson et al., 2001), whereas infusion of AP-5 into the NAcc core
at the same doses used in the present study blocked the acquisition of
an instrumental response for food (Kelley et al., 1997; Baldwin et al.,
2000). However, intracore infusion of the NMDA receptor antagonist
MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d]
cyclohepten-5,10-imine maleate] blocked not only the acquisition but
also the performance of a multiple chain schedule response for food in
rats (Cory-Slechta et al., 1999), suggesting that NMDA receptors may
also participate under certain conditions in ongoing complex behaviors.
NMDA and DA receptors have also been shown to interact in the
acquisition of goal-directed behaviors. When infused together into the
NAcc core, AP-5 and the D1 receptor antagonist SCH-23390 [R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride] blocked the acquisition of an instrumental response for
food at low doses of each of these drugs that were ineffective on their
own (Smith-Roe and Kelley, 2000), suggesting that these two receptors
may interact critically during learning (Berke and Hyman, 2000). The
functional importance of interactions between DA and glutamate
receptors has also been established in studies of locomotor activity.
For example, NMDA increased NAcc DA efflux, which was shown to be
associated with increased motor activity (Svensson et al., 1994),
whereas locomotor activity induced by intra-NAcc infusions of NMDA was
attenuated by DA receptor antagonists, suggesting that DA may mediate
glutamate-induced increases in motor activity (Wu et al., 1993). The
converse is also true in that AP-5 inhibited cocaine-induced increases
in DA when it was administered through a dialysis probe, with no
effects on basal levels of DA (Pap and Bradberry, 1995).
-Flupenthixol and LY293558 disrupt discriminated Pavlovian
approach to a CS
Infusion of the AMPA/KA receptor antagonist LY293558 into the core
disrupted the performance of an already acquired discriminated approach
by increasing the probability of approach to the CS only. This is
consistent with previous findings that AMPA/KA receptors have a greater
contribution to the performance, rather than the acquisition, of
learned behaviors (Cervo and Samanin, 1995; Kelley et al., 1997;
Roullet et al., 2001). For example, infusion of LY293558 into the core
decreased responding for cocaine under a second-order schedule of
reinforcement, whereas lever presses on an inactive lever increased (Di
Ciano and Everitt, 2001), implicating AMPA/KA receptors in the NAcc
core in the discriminated response to stimuli predictive of reward. In
contrast, intracore AP-5 was without effect on the performance of this
response, as in the present experiment. It is noteworthy that lesions
of the ACC also impaired autoshaping by increasing approaches to the
CS (Bussey et al., 1997). Given that the ACC projects to the core
(Groenewegen et al., 1987; Groenewegen et al., 1996, 1999) and that its
disconnection from the core also impaired the acquisition of
autoshaping (Parkinson et al., 2000b), the impaired discrimination
after LY293558 may depend on disruption of ACC-dependent processes
within the NAcc.
Infusion of the DA receptor antagonist into the NAcc core also blocked
discriminated approach to the CS+. Together with similar findings after
6-OHDA lesions of the NAcc (Parkinson et al., 2001), this suggests an
important role for DA in the NAcc in both the acquisition and
performance of responses under the control of a Pavlovian CS. Because
DA depletions from the NAcc do not affect consumption of food (Koob et
al., 1978; Parkinson et al., 2001) or the palatability or hedonics of
the primary reward (Berridge et al., 1989; Pecina et al., 1997), the
effect seems specific to conditioned responses to incentive stimuli.
Thus, DA receptor antagonism produced a selective attenuation of
approach to the appetitive CS+, suggesting that it may influence the
vigor of responding directed toward Pavlovian stimuli (Cador et al.,
1989; Parkinson et al., 2000b), and this may also underlie the effects seen in acquisition. Indeed, infusion of DA receptor agonists into the
NAcc increased the ability of a Pavlovian stimulus to enhance
instrumental responding without influence on the hedonic value of the
reward (Wyvell and Berridge, 2000), whereas infusion of DA receptor
agonists into the NAcc increased responding for a conditioned stimulus
(Wolterink et al., 1993). Together, these findings suggest an important
role for DA in the NAcc in approach elicited by Pavlovian stimuli,
which may be critical in both the establishment and expression of
conditioned approach and preparatory behaviors (Blackburn et al., 1987,
1989; Pfaus et al., 1990; Fiorino et al., 1997).
Conclusions
Consistent with an originally suggested role for the NAcc as a
limbic-motor interface (Mogenson et al., 1980), recent neuroanatomical and neurochemical evidence supports the existence of a limbic cortical-ventral striatal neural circuit subserving Pavlovian approach
behavior that converges on the NAcc core. For example, bilateral
lesions of the core (Parkinson et al., 1999), central amygdala
(Parkinson et al., 2000a), or ACC (Bussey et al., 1997) abolished the
acquisition of autoshaping, whereas the core and ACC have been shown to
interact critically in the acquisition of autoshaping (Parkinson et
al., 2000b). In the present study, we supported and extended these
findings by demonstrating that antagonism of DA, NMDA, or AMPA/KA
receptors in the NAcc core differentially disrupted the acquisition and
performance of discriminated approach, which indicates that these
receptor types have differential control over the learning and
performance of this Pavlovian conditioned response. In support of a
role for DA in anticipatory behaviors directed selectively at a
stimulus predictive of reward, antagonism of DA receptors disrupted
both the acquisition and performance of approach to the CS+.
Furthermore, AMPA/KA receptor antagonism disrupted discrimination of
the two stimuli during performance only, and we suggest that this
receptor may mediate the impact of ACC processes on approach behavior
through its glutamatergic projections to the NAcc core. In support of a
wealth of evidence implicating NMDA receptors in learning, AP-5 infused
into the NAcc core impaired the acquisition, but not performance, of
this approach response. Together, these results suggest that the NAcc core mediates the acquisition and expression of Pavlovian conditioned responses toward drug-paired stimuli by acting as an interface between
limbic-cortical processes and downstream response mechanisms.
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FOOTNOTES |
Received July 13, 2001; revised Sept. 10, 2001; accepted Sept. 14, 2001.
This work was supported by Medical Research Council (MRC) Program Grant
G9537855 to B.J.E. and an MRC Cooperative in Brain, Behavior, and
Neuropsychiatry. P.D.C. was supported by a Postdoctoral Fellowship from
the Natural Sciences and Engineering Research Council of Canada. We
thank Dr. H. C. Fibiger and Eli Lilly for generously donating the LY293558.
Correspondence should be addressed to Patricia Di Ciano, Department of
Experimental Psychology, University of Cambridge, Downing Street,
Cambridge, CB2 3EB, UK. E-mail: pd241{at}cus.cam.ac.uk.
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REFERENCES |
-
Baldwin AE,
Holahan MR,
Sadeghian K,
Kelley AE
(2000)
N-methyl-D-aspartate receptor-dependent plasticity within a distributed corticostriatal network mediates appetitive instrumental learning.
Behav Neurosci
114:84-98[Web of Science][Medline].
-
Bannerman DM,
Good MA,
Butcher SP,
Ramsay M,
Morris RG
(1995)
Distinct components of spatial learning revealed by prior training and NMDA receptor blockade.
Nature
378:182-186[Medline].
-
Beninger RJ,
Hahn BL
(1983)
Pimozide blocks the establishment but not the expression of amphetamine-produced environment-specific conditioning.
Science
220:1304-1306[Abstract/Free Full Text].
-
Berke JD,
Hyman SE
(2000)
Addiction, dopamine, and the molecular mechanisms of memory.
Neuron
25:515-532[Web of Science][Medline].
-
Berridge KC,
Venier IL,
Robinson TE
(1989)
Taste reactivity analysis of 6-hydroxydopamine-induced aphagia: implications for arousal and anhedonia hypotheses of dopamine function.
Behav Neurosci
103:36-45[Web of Science][Medline].
-
Blackburn JR,
Phillips AG,
Fibiger HC
(1987)
Dopamine and preparatory behavior. I. Effects of pimozide.
Behav Neurosci
101:352-360[Web of Science][Medline].
-
Blackburn JR,
Phillips AG,
Jakubovic A,
Fibiger HC
(1989)
Dopamine and preparatory behavior. II. A neurochemical analysis.
Behav Neurosci
103:15-23[Web of Science][Medline].
-
Blaha CD,
Yang CR,
Floresco SB,
Barr AM,
Phillips AG
(1997)
Stimulation of the ventral subiculum of the hippocampus evokes glutamate receptor-mediated changes in dopamine efflux in the rat nucleus accumbens.
Eur J Neurosci
9:902-911[Web of Science][Medline].
-
Brown PL,
Jenkins HM
(1968)
Auto-shaping of the pigeon's key-peck.
J Exp Anal Behav
11:1-8[Web of Science][Medline].
-
Bussey TJ,
Everitt BJ,
Robbins TW
(1997)
Dissociable effects of cingulate and medial frontal cortex lesions on stimulus-reward learning using a novel Pavlovian autoshaping procedure for the rat: implications for the neurobiology of emotion.
Behav Neurosci
111:908-919[Web of Science][Medline].
-
Cador M,
Robbins TW,
Everitt BJ
(1989)
Involvement of the amygdala in stimulus-reward associations: interaction with the ventral striatum.
Neuroscience
30:77-86[Web of Science][Medline].
-
Cervo L,
Samanin R
(1995)
Effects of dopaminergic and glutamatergic receptor antagonists on the acquisition and expression of cocaine conditioning place preference.
Brain Res
673:242-250[Web of Science][Medline].
-
Cervo L,
Samanin R
(1996)
Effects of dopaminergic and glutamatergic receptor antagonists on the establishment and expression of conditioned locomotion to cocaine in rats.
Brain Res
731:31-38[Web of Science][Medline].
-
Chen G,
Steinmetz JE
(2000)
Intra-cerebellar infusion of NMDA receptor antagonist AP5 disrupts classical eyeblink conditioning in rabbits.
Brain Res
887:144-156[Web of Science][Medline].
-
Cory-Slechta DA,
O'Mara DJ,
Brockel BJ
(1999)
Learning versus performance impairments following regional administration of MK-801 into nucleus accumbens and dorsomedial striatum.
Behav Brain Res
102:181-194[Medline].
-
Davis S,
Butcher SP,
Morris RG
(1992)
The NMDA receptor antagonist D-2-amino-5-phosphonopentanoate (D-AP5) impairs spatial learning and LTP in vivo at intracerebral concentrations comparable to those that block LTP in vitro.
J Neurosci
12:21-34[Abstract].
-
Di Ciano P,
Everitt BJ
(2001)
Dissociable effect of antagonism of NMDA and AMPA/KA receptors in the nucleus accumbens core and shell on cocaine-seeking behaviour.
Neuropsychopharmacology
25:341-360[Web of Science][Medline].
-
Fiorino D,
Coury A,
Phillips AG
(1997)
Dynamic changes in nucleus accumbens dopamine efflux during the Coolidge effect in male rats.
J Neurosci
17:4849-4855[Abstract/Free Full Text].
-
Floresco SB,
Yang CR,
Phillips AG,
Blaha CD
(1998)
Basolateral amygdala stimulation evokes glutamate receptor-dependent dopamine efflux in the nucleus accumbens of the anaesthetized rat.
Eur J Neurosci
10:1241-1251[Web of Science][Medline].
-
Groenewegen HJ,
Vermeulen-Van der Zee E,
te Kortschot A,
Witter MP
(1987)
Organization of the projections from the subiculum to the ventral striatum in the rat. A study using anterograde transport of Phaseolus vulgaris leucoagglutinin.
Neuroscience
23:103-120[Web of Science][Medline].
-
Groenewegen HJ,
Wright CI,
Beijer AVJ
(1996)
The nucleus accumbens: gateway for limbic structures to reach the motor system.
In: Progress in brain research, Ed 12547 (Holstege G,
Bandler R,
Saper CB,
eds), pp 485-511. Amsterdam: Elsevier Science.
-
Groenewegen HJ,
Wright CI,
Beijer AV,
Voorn P
(1999)
Convergence and segregation of ventral striatal inputs and outputs.
Ann NY Acad Sci
877:49-63[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].
-
Keppel G
(1991)
In: Design and analysis: a researcher's handbook (Finnemore S, Riker, E, Nassauer C, eds). Upper Saddle River, NJ: Prentice Hall.
-
Koob GF,
Riley SJ,
Smith SC,
Robbins TW
(1978)
Effects of 6-hydroxydopamine lesions of the nucleus accumbens septi and olfactory tubercle on feeding, locomotor activity, and amphetamine anorexia in the rat.
J Comp Physiol Psychol
92:917-927[Web of Science][Medline].
-
Ljungberg,
Apicella P,
Schultz W
(1992)
Responses of monkey dopamine neurons during learning of behavioral reactions.
J Neurophysiol
67:145-163[Abstract/Free Full Text].
-
Locurto C,
Terrace HS,
Gibbon J
(1976)
Autoshaping, random control, and omission training in the rat.
J Exp Anal Behav
26:451-462[Medline].
-
Mogenson GJ,
Jones DL,
Yim CY
(1980)
From motivation to action: functional interface between the limbic system and motor system.
Prog Neurobiol
14:69-97[Web of Science][Medline].
-
Pap A,
Bradberry CW
(1995)
Excitatory amino acid antagonists attenuate the effects of cocaine on extracellular dopamine in the nucleus accumbens.
J Pharmacol Exp Ther
274:127-133[Abstract/Free Full Text].
-
Parkinson JA,
Olmstead MC,
Burns LH,
Robbins TW,
Everitt BJ
(1999)
Dissociation in effects of lesions of the nucleus accumbens core and shell on 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,
Robbins TW,
Everitt BJ
(2000a)
Dissociable roles of the central and basolateral amygdala in appetitive emotional learning.
Eur J Neurosci
12:405-413[Web of Science][Medline].
-
Parkinson JA,
Willoughby PJ,
Robbins TW,
Everitt BJ
(2000b)
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].
-
Parkinson J, Dalley J, Cardinal R, Bamford A, Fehnert B, Lachenal G,
Rudarakanchana N, Halkerston K, Robbins T, Everitt
B (2001) Nucleus accumbens dopamine depletion impairs both
acquisition and performance of appetitive Pavlovian approach behaviour:
implications for mesoaccumbens dopamine function. Behav Brain Res, in
press.
-
Paxinos G,
Watson C
(1986)
In: The rat brain in stereotaxic coordinates. Sydney: Academic.
-
Pecina S,
Berridge KC,
Parker LA
(1997)
Pimozide does not shift palatibility: separation of anhedonia from sensorimotor suppression by taste reactivity.
Pharmacol Biochem Behav
58:801-811[Web of Science][Medline].
-
Pfaus JG,
Damsma G,
Nomikos GG,
Wenkstern DG,
Blaha CD,
Phillips AG,
Fibiger HC
(1990)
Sexual behavior enhances central dopamine transmission in the male rat.
Brain Res
530:345-348[Web of Science][Medline].
-
Roullet P,
Sargolini F,
Oliverio A,
Mele A
(2001)
NMDA and AMPA antagonist infusions into the ventral striatum impair different steps of spatial information processing in a nonassociative task in mice.
J Neurosci
21:2143-2149[Abstract/Free Full Text].
-
Schoepp DD,
Lodge D,
Bleakman D,
Leander JD,
Tizzano JP,
Wright RA,
Palmer AJ,
Salhoff CR,
Ornstein PL
(1995)
In vitro and in vivo antagonism of AMPA receptor activation by (3S, 4aR, 6R, 8aR)-6-[2-(1(2)H-tetrazole-5-yl) ethyl] decahydroisoquinoline-3-carboxylic acid.
Neuropharmacology
34:1159-1168[Medline].
-
Shimizu E,
Tang YP,
Rampon C,
Tsien JZ
(2000)
NMDA receptor-dependent synaptic reinforcement as a crucial process for memory consolidation.
Science
290:1170-1174[Abstract/Free Full Text].
-
Smith-Roe SL,
Kelley AE
(2000)
Coincident activation of NMDA and dopamine D1 receptors within the nucleus accumbens core is required for appetitive instrumental learning.
J Neurosci
20:7737-7742[Abstract/Free Full Text].
-
Smith-Roe SL,
Sadeghian K,
Kelley AE
(1999)
Spatial learning and performance in the radial arm maze is impaired after N-methyl-D-aspartate (NMDA) receptor blockade in striatal subregions.
Behav Neurosci
113:703-717[Web of Science][Medline].
-
Svensson L,
Zhang J,
Johannessen K,
Engel JA
(1994)
Effect of local infusion of glutamate analogues into the nucleus accumbens of rats: an electrochemical and behavioural study.
Brain Res
643:155-161[Medline].
-
Taepavarapruk P,
Floresco SB,
Phillips AG
(2000)
Hyperlocomotion and increased dopamine efflux in the rat nucleus accumbens evoked by electrical stimulation of the ventral subiculum: role of ionotropic glutamate and dopamine D1 receptors.
Psychopharmacology
151:242-251[Medline].
-
Williams DR,
Williams H
(1969)
Auto-maintenance in the pigeon: sustained pecking despite contingent non-reinforcement.
J Exp Anal Behav
12:511-520[Medline].
-
Wolterink G,
Phillips G,
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].
-
Wu M,
Brudzynski SM
(1995)
Mesolimbic dopamine terminals and locomotor activity induced from the subiculum.
NeuroReport
6:1601-1604[Web of Science][Medline].
-
Wu M,
Brudzynski SM,
Mogenson GJ
(1993)
Functional interaction of dopamine and glutamate in the nucleus accumbens in the regulation of locomotion.
Can J Physiol Pharmacol
71:407-413[Web of Science][Medline].
-
Wyvell CL,
Berridge KC
(2000)
Intra-accumbens amphetamine increases the conditioned incentive salience of sucrose reward: enhancement of reward "wanting" without enhanced "liking" or response reinforcement.
J Neurosci
20:8122-8130[Abstract/Free Full Text].
Copyright © 2001 Society for Neuroscience 0270-6474/01/21239471-07$05.00/0
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ABSTRACT
INTRODUCTION
Compound via MeSH
