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The Journal of Neuroscience, October 15, 2000, 20(20):7737-7742
Coincident Activation of NMDA and Dopamine D1
Receptors within the Nucleus Accumbens Core Is Required for Appetitive
Instrumental Learning
Stephanie L.
Smith-Roe and
Ann E.
Kelley
Department of Psychiatry, University of Wisconsin-Madison, Madison,
Wisconsin 53719
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ABSTRACT |
The nucleus accumbens, a brain structure ideally situated to act as
an interface between corticolimbic information-processing regions and
motor output systems, is well known to subserve behaviors governed by
natural reinforcers. In the accumbens core, glutamatergic input from
its corticolimbic afferents and dopaminergic input from the ventral
tegmental area converge onto common dendrites of the medium spiny
neurons that populate the accumbens. We have previously found that
blockade of NMDA receptors in the core with the antagonist
2-amino-5-phosphonopentanoic acid (AP-5; 5 nmol) abolishes acquisition
but not performance of an appetitive instrumental learning task (Kelley
et al., 1997 ). Because it is currently hypothesized that concurrent
dopamine D1 and glutamate receptor activation is required
for long-term changes associated with plasticity, we wished to examine
whether the dopamine system in the accumbens core modulates learning
via NMDA receptors. Co-infusion of low doses of the D1
receptor antagonist SCH-23390 (0.3 nmol) and AP-5 (0.5 nmol)
into the accumbens core strongly impaired acquisition of instrumental
learning (lever pressing for food), whereas when infused separately,
these low doses had no effect. Infusion of the combined low doses had
no effect on indices of feeding and motor activity, suggesting a
specific effect on learning. We hypothesize that co-activation of NMDA
and D1 receptors in the nucleus accumbens core is a key
process for acquisition of appetitive instrumental learning. Such an
interaction is likely to promote intracellular events and gene
regulation necessary for synaptic plasticity and is supported by a
number of cellular models.
Key words:
glutamate; plasticity; striatum; intracellular signals; rat; reinforcement; reward
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INTRODUCTION |
The nucleus accumbens, a forebrain
structure known to subserve behaviors governed by natural reinforcers,
receives excitatory glutamatergic input from prefrontal cortex,
hippocampus, thalamus, and amygdala (McGeer et al., 1977; Walaas and
Fonnum, 1979; Young and Bradford, 1986; Fuller et al., 1987; Robinson
and Beart, 1988), as well as a major dopaminergic innervation from the
ventral tegmental area (Lindvall and Bjorklund, 1978). These
innervations converge on the dendritic spines of the medium spiny
neurons that populate the nucleus accumbens (Totterdell and Smith,
1989; Sesack and Pickel, 1990; Smith and Bolam, 1990). Therefore, these
neurons are in a unique position to recognize context-driven patterns of activation and to transfer this information to planning and motor
regions for appropriate behavioral responses (Houk et al., 1995).
Recently, there has been much interest in the neuromodulatory effects
of dopamine (DA) receptor activation on NMDA receptor state, as
well as the intracellular mechanisms that may govern their interaction.
For example, DA D1 receptor activation in
striatal slices potentiates responses mediated by NMDA receptor
activation (an effect that is blocked by the D1
receptor antagonist SCH-23390), whereas dopamine
D2 receptors have an attenuating effect (Cepeda et al., 1993; Cepeda and Levine, 1998). Moreover, DA receptor modulation of NMDA receptor-mediated responses is blunted in
D1A-deficient mutant mice (Levine et al., 1996).
When corticostriatal excitation and dopaminergic activation are
temporally coordinated, there is a long-lasting enhancement of synaptic
strength in medium spiny neurons (Wickens et al., 1996). In a
behavioral study, it was reported that impairment of learning of a
one-trial inhibitory avoidance task attributable to post-trial systemic
administration of NMDA antagonists is attenuated by systemic
administration of low doses of dopamine agonists (Adriani et al.,
1998). Taken together, these emerging findings suggest that
co-activation of dopamine D1 and glutamate NMDA
receptors is required for long-term changes associated with plasticity
and perhaps certain forms of learning.
We have previously found that blockade of NMDA receptors in the
accumbens core with the antagonist 2-amino-5-phosphonopentanoic acid (AP-5) completely abolishes acquisition but not performance of an
appetitive instrumental learning task (acquisition of lever pressing
for food; Kelley et al., 1997) and also disrupts spatial learning in
the radial arm maze (Smith-Roe et al., 1999). Considering the
substantial evidence for DA-NMDA receptor interactions at the
physiological and molecular level, we hypothesized that such interactions may play a key role in learning subserved by the nucleus
accumbens. Our first objective was to assess the effects of
intra-accumbens core infusion of the D1 dopamine
receptor antagonist SCH-23390 in an appetitive instrumental learning
task. However, a major obstacle to investigating the role of DA
receptors in learning and to interpreting effects on behavior is the
considerable motor impairment that often results with DA receptor
antagonist treatment. Because we indeed found evidence of a motor
impairment, we also examined the effects of very low doses of the
D1 antagonist as well as combinations of low
doses of AP-5 and SCH-23390. We report here that co-activation of
D1 and NMDA receptors is necessary for appetitive
instrumental learning.
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MATERIALS AND METHODS |
Animals and surgery. A total of 48 male Sprague
Dawley rats (Harlan Sprague Dawley, Madison, WI) weighing 275-300 gm
were used for these experiments. Care of animals was in accordance with
institutional guidelines. Rats were housed two per cage in a
temperature-controlled (21°C) and light-controlled (12 hr light/dark cycle) animal colony. For cannula implantation, rats were anesthetized with a ketamine-xylazine mixture (100 and 10 mg/kg, respectively; Research Biochemicals, Natick, MA). Standard stereotaxic procedures were used to implant bilateral 23 gauge stainless steel guide cannulas,
with coordinates based on flat-skull stereotaxic orientation. Cannulas
were secured with dental acrylic and stainless steel screws, and a wire
stylet occluded the guide to maintain patency. For all experiments,
rats were implanted with cannulas placed 2.5 mm above the nucleus
accumbens core at the following coordinates: anteroposterior, +1.4 mm;
lateromedial, ±1.7 mm from midline; and dorsoventral,  5.5 mm from
skull. After several days of recovery from surgery, all rats were put
on a restricted diet that maintained body weight at 85% of
free-feeding weight. Water was available ad libitum at all
times in the home cage.
Drugs and microinfusions. The selective, competitive NMDA
receptor antagonist AP-5 and the D1 receptor
antagonist SCH-23390 HCl were obtained from Research Biochemicals. All
drugs were dissolved in isotonic sterile saline and kept at 4°C in
200 µl aliquots. Intracerebral microinfusions were bilateral in a
volume of 0.5 µl/side. AP-5 was administered in a dose per side of
0.5 nmol (0.1 µg), and SCH-23390 was administered in two doses: 3 nmol (1 µg) and 0.3 nmol (0.1 µg). Infusions of drug or vehicle
were given by lowering 30 gauge injector cannulas to the site of
infusion (8.0 mm from skull). A Harvard Apparatus microdrive pump was used to administer drug infusions with an infusion time of 1 min 33 sec, followed by 1 min of diffusion time. The injectors were then
removed, the stylets were replaced, and the rats were placed into the
test apparatus immediately. For all experiments, rats were given two
preliminary sham injections, in which a dummy injector was lowered
through the guide to adapt them to the procedure.
Behavioral training. All rats (except those in the feeding
and locomotion study described below) were trained in operant chambers (Coulbourn Instruments, Allentown, PA) equipped with two levers, a
house light, and a red signal light. All stimulus events and data
acquisition were controlled with a computer (Paul Fray, Cambridge, UK).
Before training, rats were adapted to the food pellets (45 mg sucrose
pellets). Additionally, the rats had preexposure for two 10 min
sessions to the operant test cages with several pellets available
ad libitum in the food tray (with no levers present). On the
first test day and all days thereafter, rats were placed in the operant
chamber for a 15 min session. Responding on one lever resulted in
delivery of a food pellet on a variable ratio 2 schedule of
reinforcement, rewarding an average of every two responses. The other
lever was not distinguishable from the first lever but did not deliver
a food pellet or alter house lighting. The correct lever was randomized
among animals but was always the same for an individual animal. When a
correct response was made, a food pellet was delivered into a food tray
located in between the two levers. A photocell located in the food tray
recorded nose pokes. Pellet delivery was accompanied by house light
offset and illumination of a red stimulus light on the response panel (3 sec), as well as a light in the food tray. Dependent variables recorded included correct responses, incorrect responses, and nose
pokes. Animals were tested between 9 A.M. and 2 P.M.
Experimental procedure. Rats were given the appropriate
microinfusion immediately before the session for the first 4 test days.
They were then tested without any infusion for days 5-9. On day 10, all animals received their initial treatment to test for performance
effects once learning had occurred. Five groups of rats were given one
of five different treatments: a high dose of SCH-23390 (3 nmol),
n = 7; a low dose of SCH-23390 (0.3 nmol), n = 8; a low dose of AP-5 (0.5 nmol), n = 8; a combined infusion of the low doses of AP-5 and SCH-23390,
n = 7, and saline vehicle, n = 10. Previous work in our laboratory has demonstrated that microinfusion of
a 5 nmol dose of AP-5 completely blocks learning (Kelley et al., 1997),
and the high dose of SCH-23390 effectively blocks DA receptors (Delfs
and Kelley, 1990).
Feeding and locomotion in food-deprived rats. To examine the
possibility of motor and motivational effects of these treatments on
behavior, feeding and locomotion were observed in rats with the
combined treatment of AP-5 and SCH-23390 and vehicle (n = 8) or with the 3 nmol dose of SCH-23390 and vehicle
(n = 8) infused into the nucleus accumbens core. Rats
were food-deprived in a manner similar to that described above. After
infusion, the animals were placed immediately in a cage similar to
their home cage and observed for 15 min using an event recorder.
Behaviors recorded were locomotion (crossing center of cage) counts,
rearing (counts and duration), feeding (bouts, total duration, and mean
duration of a bout), food intake (grams), and latency to eat. A Latin
square design was used to randomize drug and vehicle infusions. Rats were given two acclimation sessions of 15 min, during which they were
given mock infusions. Test sessions were several days apart.
Histological analysis. At the completion of testing, all
rats were deeply anesthetized with sodium pentobarbital and perfused transcardially with 0.9% saline followed by 10% formalin. The brains
were stored in a 10% sucrose-formalin mixture for several days before
sectioning. Brains were cut into 60 µm sections and stained for Nissl
substance with cresyl violet. The sections were examined with light
microscopy, and estimated locations of infusion sites were recorded on
atlas sections. All infusion sites fell within the boundaries of the
accumbens core (histology results are shown in Fig. 4).
Statistical analysis. Learning data were analyzed using
one-, two-, or three-factor ANOVA, with treatment as the
between-subjects factor and days and lever as the within-subjects
(repeated measures) factors in the multifactorial analyses. For each
experiment, three separate analyses were performed: days 1-4
(acquisition during treatment), days 5-9 (acquisition/performance with
no treatment), and days 9-10 (comparison of performance on treatment
day 10 with performance on previous day of no treatment). The locomotor
and feeding data were analyzed by a one-factor ANOVA.
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RESULTS |
Infusion of a high dose of SCH-23390 impairs instrumental learning
and performance
As shown in Figure
1A, the 3 nmol dose of
SCH-23390 infused into the nucleus accumbens impaired acquisition of
lever pressing. Analysis of data from days 1-4 revealed a significant
treatment effect [F(1,15) = 36.12;
p < 0.0001] as well as day × treatment [F(3, 45) = 11.25; p < 0.0001], lever × treatment [F(1,
15) = 9.69; p < 0.007], and day × lever × treatment [F(1,3) = 7.99; p < 0.0002] interactions. There were no
significant effects on days 5-9. Readministration of this dose
strongly impaired performance on day 10, because comparison of days 9 and 10 revealed a treatment effect
[F(1,15) = 12.09; p < 0.003] as well as day × treatment [F(1,15) = 25.16; p < 0.0002], lever × treatment
[F(1,15) = 13.73; p < 0.002], and day × lever × treatment
[F(1,15) = 22.17; p < 0.0003] interactions.
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Figure 1.
Influence of the high dose (3 nmol) of
D1 receptor antagonist infusion into the nucleus accumbens
core on acquisition of lever pressing for sucrose pellets: correct and
incorrect lever responses. Animals received intra-accumbens infusion of
SCH-23390 (3 nmol) or vehicle (saline) on the first 4 test days; on the
remaining training days, no infusion was given except on day 10, when
animals received their initial treatments (underscored
days indicate infusion days). A, Lever presses.
**p < 0.01, treatment effect;
 p < 0.01, interactions.
B, Nose pokes into the food tray during learning.
**p < 0.01, treatment effect;
p < 0.01, interactions. See
Materials and Methods for statistical details.
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Rats treated with the high dose of SCH-23390 demonstrated a nose poking
profile quite different from that of vehicle-treated rats (Fig.
1B). In vehicle-treated rats, this unconditioned
behavior parallels the lever-pressing curve, increasing markedly as
animals begin to learn and gradually leveling off. Analysis of days
1-4 showed a treatment effect
[F(1,15) = 23.16; p < 0.0002] and day × treatment interaction
[F(1,3) = 9.46; p < 0.0001]. The day × treatment interaction
[F(1,3) = 3.82; p < 0.008] persisted for days 5-9. A dramatic decrease in nose poking was
observed in SCH-23390-treated rats between days 9 and 10, revealing a
treatment effect [F(1,15) = 6.14;
p < 0.03] and a day × treatment interaction
[F(1,1) = 12.16; p < 0.003].
Low doses of SCH-23390 and AP-5 administered separately have no
effect on learning
It can be observed from Figure
2A that intra-accumbens
infusion of either the 0.3 nmol dose of the D1
antagonist or the 0.5 nmol dose of the NMDA antagonist, administered
separately, had no effect on response learning. The learning curve of
drug-treated animals was similar to that of controls. There was also no
effect of reinfusion on day 10. A similar profile was noted for nose pokes (Fig. 2B).
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Figure 2.
Influence of D1 receptor antagonist
SCH-23390 (0.3 nmol) or NMDA receptor antagonist AP-5 (0.5 nmol)
infusion into the nucleus accumbens core on acquisition of lever
pressing for sucrose pellets. See legend of Figure 1 for further
details. A, Lever presses. B, Nose pokes.
See Materials and Methods for statistical details.
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Co-infusion of low doses of SCH-23390 and AP-5
inhibits learning
In contrast to the lack of effect of low doses of SCH-23390 and
AP-5 when infused separately into the nucleus accumbens core, co-infusion of these drugs clearly inhibited learning (Fig.
3A). Analysis of days 1-4
revealed a significant treatment effect
[F(1,15) = 12.5; p < 0.003] as well as day × treatment
[F(3,45) = 11.35; p < 0.0001], lever × treatment
[F(1,1) = 9.438; p < 0.008], and day × lever × treatment
[F(3,45) = 9.21; p < 0.0001] interactions. Drug-treated animals sampled the levers but did
not begin to discriminate between them until day 4. The lever × treatment effect [F(1,15) = 5.15;
p < 0.04] persisted on days 5-9, indicating a
residual effect on learning. Comparison of days 9 and 10 revealed
significant day × treatment
[F(1,15) = 6.90; p < 0.02], lever × treatment [F(1,15) = 4.90; p < 0.04], and day × lever × treatment
[F(1,15) = 5.38; p < 0.03] interactions. It can be observed in Figure 3A that
performance declined somewhat after readministration of the combined
drug treatment, whereas the performance of vehicle-treated rats
continued to increase.
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Figure 3.
Influence of the co-infusion of D1
receptor antagonist SCH-23390 (0.3 nmol) and NMDA receptor antagonist
AP-5 (0.5 nmol) into the nucleus accumbens core on acquisition of lever
pressing for sucrose pellets. See legend of Figure 1 for further
details. A, Lever presses. **p < 0.01, treatment effect; p < 0.01, interactions. B, Nose pokes. *p < 0.05, treatment effect; p < 0.01, interactions. See Materials and Methods for statistical
details.
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Analysis of days 1-4 revealed a significant treatment effect
[F(1,15) = 15.74; p < 0.001] and a day × treatment interaction [F(3,45) = 9.37; p < 0.0001] for nose poking behavior (Fig. 3B). Although a
significant reduction in lever pressing occurred on day 10, nose poking
in combined dose animals did not change significantly from day 9 to 10.
Combined infusion of AP-5 and SCH-23390 does not affect food intake
or motor activity
Combined infusion of AP-5 (0.5 nmol) and SCH-23390 (0.3 nmol) into
the nucleus accumbens core had no effect on locomotor or feeding
behavior in hungry rats (Table 1).
However, animals infused with the higher dose of SCH-23390 (3 nmol) had
significantly fewer counts of locomotion
[F(1,7) = 18.03; p < 0.004] and engaged in longer bouts of feeding
[F(1,7) = 7.56; p < 0.03] yet did not differ in total food intake. Thus, the high dose of
SCH-23390 infused into the accumbens core did not alter motivation to
feed but did cause motor inhibition and prolonged bout length,
eliciting a classic neuroleptic profile.
Figure 4 shows examples of representative
histology from both an experimental (AP5- and SCH-23390-infused) rat
and a control (saline-infused) rat. Cannula tracks from all rats were
well localized in the nucleus accumbens core. Damage from
microinjections was generally minimal, and there were no observable
differences between drug- and saline-infused brains.
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Figure 4.
Representative histology from a rat infused with
the co-treatment (SCH-23390, 0.3 nmol; AP-5, 0.5 nmol) as shown in
A and from a rat infused with saline, as shown in
B.
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DISCUSSION |
The results reported here suggest that coincident activation of
dopamine D1 receptors and glutamatergic NMDA
receptors within the nucleus accumbens core may be an important
mechanism for appetitive response learning. Previous work has shown a
nearly complete inhibition of such learning after infusion of an
effective dose of the selective NMDA antagonist AP-5 into the accumbens
core (Kelley et al., 1997; Baldwin et al., 2000). Given the convincing
evidence for DA-NMDA interactions in cellular and molecular models of
plasticity, it seemed logical to propose that such an interaction may
participate in accumbens-mediated response learning. Although dopamine
has been implicated in many theories of learning (Beninger, 1983; Ettenberg, 1989; Schultz et al., 1997; Berridge and Robinson, 1998), to
our knowledge there has been no direct test of intra-accumbens selective DA antagonists on acquisition of instrumental learning. Data
resulting from such an approach are quite difficult to interpret, because instrumental behavior is often very sensitive to the
motor-inhibitory effects of DA antagonists (Fibiger et al., 1976;
Salamone, 1987). Indeed, in the paradigm described here, learning
appeared to be severely impaired with infusion of the higher dose of
SCH-23390. However, once the task was learned, performance was also
drastically reduced by the treatment, rendering interpretation of the
initial "learning" effect more complex.
To circumvent this problem, we infused a dose of the
D1 antagonist one order of magnitude lower than
the performance-impairing dose. A 10-fold lower dose of AP-5 than that
necessary to inhibit learning was also tested. Neither of these
treatments by itself was found to affect acquisition of the
lever-pressing task. However, co-infusion of both the NMDA and
D1 antagonists together strongly impaired
learning, suggesting that a critical level of co-activation of
D1 and NMDA receptors is necessary for learning.
Because this treatment had no effect in control tests of motor
behavior, it is unlikely that motor impairment could account for the
learning deficit. Moreover, although the combined treatment lowered
performance somewhat once the task was learned, this was a very small
effect compared with that of the high dose of SCH-23390. This profile suggests a preferential role for DA-NMDA interaction in the early stages of motor learning, rather than in performance of learned motor
behavior. It is important to note further that neither the combined
dosage nor even the high dose of SCH-23390 had any effect on food
intake, demonstrating that motivation for primary reward is not
affected by blockade of DA D1 receptors within
the accumbens. This result supports previous work showing that
treatment with low doses of SCH-23390 reduces lever pressing for food
but actually increases food intake (Cousins et al., 1994).
It is also very interesting that nose poking behavior was impaired by
the combined treatment of AP-5 and SCH-23390, an effect that appears to
recover more quickly than the impairment of instrumental learning, from
close inspection of Figure 3. Thus, although no overt inhibition of
locomotor or feeding behavior was found, the combined treatment
nevertheless appears to inhibit this form of behavioral activation.
Combined activation of NMDA receptors and DA D1
receptors may also be necessary for enhancing arousal and promotion of
behaviors that would serve to bring the animal in contact with
potentially important environmental stimuli.
The present results provide additional evidence for emerging theories
of DA D1-NMDA receptor interactions in the
control of activity of striatal medium spiny neurons (Cepeda and
Levine, 1998). In anatomical terms, these two classes of receptors are localized on the same dendritic spines, providing a locus of close interaction. In rat striatal slices, a number of studies show that
dopamine can enhance glutamate- and particularly NMDA receptor-mediated excitation (Cepeda et al., 1993, 1998; Galarraga et al., 1997; Harvey
and Lacey, 1997; Hernandez-Lopez et al., 1997; Hu and White, 1997). For
example, neuronal excitation evoked by NMDA was markedly potentiated by
iontophoretic application of dopamine; the potentiation was mimicked by
a D1 agonist and blocked by co-application of SCH-23390 (Cepeda et al., 1993). Although DA has often been found to
inhibit postsynaptic currents (Uchimura et al., 1986; Calabresi et al.,
1987), in vivo models often report the opposite effect under
particular conditions (Pierce and Rebec, 1995; Kiyatkin and Rebec,
1996). For example, Hernandez-Lopez et al. (1997) found that
D1 agonists or cAMP analogs enhanced evoked
activation in medium spiny neurons when membranes were relatively
depolarized, an effect that was dependent on L-type
Ca2+ channels.
Molecular approaches also support a general convergence or
interdependence between NMDA receptor- and
D1-mediated intracellular signal transduction.
Studies using primary striatal cell cultures showed that dopamine
D1-induced immediate early gene (IEG) expression is dependent on NMDA receptor activation (Konradi et al., 1996). These
studies also showed that blockade with NMDA antagonists reduced the
ability of dopamine to induce phosphorylation of the cAMP response
element-binding protein (CREB), a transcription factor activated in
many forms of learning. Similar results were reported by Das et al.
(1997), who found that NMDA- induced CREB phosphorylation was dependent
on calcium/calmodulin-dependent protein kinase and that
D1-induced IEG expression and CREB
phosphorylation was dependent on protein kinase A (PKA) activity.
Another potential site of interaction is phosphorylation of NMDA
receptors, which can occur via both PKA and
calcium/calmodulin-dependent protein kinase (Leonard and Hell, 1997;
Leonard et al., 1999). Thus, one can imagine a scenario in which
temporal coordination of specific glutamate inputs with enhanced DA
release would result in molecular integration of postsynaptic signals.
Such resultant integration within the dendrites of medium spiny neurons
could be a basis for the synaptic modification necessary for motor
learning (Kotter, 1994; Kelley, 1999). In support of this hypothesis,
we have recently found that PKA inhibitors also selectively impair
response learning when infused into the accumbens core (Baldwin et al.,
1999).
This hypothesis is further supported by evidence of neuronal plasticity
within striatum in physiological models. Both long-term potentiation
and long-term depression, phenomena hypothesized to underlie
associative processes in learning, have been demonstrated in striatum
and nucleus accumbens (Boeijinga et al., 1993; Lovinger et al., 1993;
Pennartz et al., 1993; Kombian and Malenka, 1994; Calabresi et al.,
1996; Charpier and Deniau, 1997). Most relevant to the present study is
the demonstration of long-term enhancement of synaptic strength when
corticostriatal excitation and dopaminergic activation are temporally
coordinated (Wickens et al., 1996). For appetitive instrumental
learning to occur, an animal must make an association between a motor
response and the positive outcome of that response. It is possible that
glutamate-coded afferent information arising from key corticolimbic
structures, such as amygdala and prefrontal and cingulate cortex, may
provide the sensorimotor and motivational information to medium spiny dendrites, whereas the primary reward of food (and/or motivational state of hunger) enhances DA release. The probability of temporal and
spatial convergence of glutamate- and dopamine-coded signals may
increase as the animal begins to gain experience in the chamber. For
example, Pavlovian cues (association of the environment with food)
would activate the amygdalostriatal pathway, preliminary and initially
random contact with the food would activate dopamine, and experience
with a positive outcome would promote bias toward correct response
selection, which may be the domain of the prefrontostriatal pathway.
Thus, a critical level of convergence may be reached to trigger
intracellular gene expression that enables motor learning. In support
of this hypothesis, parallel work has shown that NMDA receptor-dependent plasticity in amygdala and prefrontal cortex is also
necessary for instrumental learning (Baldwin et al., 2000).
In summary, these findings suggest that coincident activation of
dopamine D1 and NMDA receptors in the nucleus
accumbens core contributes to a process whereby animals acquire a new
motor response that results in a positive outcome. Further work is
required to know more precisely what intracellular signals and
transcriptional alterations mediate the synaptic modifications
necessary for such learning.
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FOOTNOTES |
Received April 20, 2000; revised July 20, 2000; accepted July 25, 2000.
This research was supported by National Institute on Drug Abuse Grant
DA04788 to A.E.K.
Correspondence should be addressed to Dr. Ann E. Kelley, Department of
Psychiatry, University of Wisconsin-Madison Medical School, 6001 Research Park Boulevard, Madison, WI 53719. E-mail: aekelley{at}macc.wisc.edu.
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ABSTRACT
INTRODUCTION
Compound via MeSH
