ABSTRACT
A previous study demonstrated that the development of behavioral sensitization
to repeated cocaine was associated with an increase in glutamate transmission
in the nucleus accumbens three weeks after discontinuing the daily injection
regimen. The present study extends these findings by examining changes in
glutamate transmission in the nucleus accumbens between 1 and 3 days after
discontinuing repeated daily cocaine or saline treatment. In all experiments,
rats were pretreated with cocaine (15 mg/kg, ip X 2 days, 30 mg/kg, ip X 5
days) or saline. The intra-accumbens administration of AMPA (0.1 µg) produced
a motor response that was significantly greater in cocaine- than in
saline-pretreated rats. The augmented behavioral response to AMPA occurred
only in rats that developed behavioral sensitization to repeated cocaine, and
not in the subpopulation of rats pretreated with daily cocaine that did not
develop behavioral sensitization. Using microdialysis, it was shown that the
augmented behavioral response to AMPA was not the result of enhanced dopamine
transmission since the administration of AMPA (0.1-100.0 µM) through a
microdialysis probe in the nucleus accumbens produced an equivalent increase
in extracellular dopamine in both the saline and cocaine treatment groups. In
vivo microdialysis also was used to measure extracellular glutamate in the
nucleus accumbens and it was shown that a cocaine injection (15 mg/kg, ip) did
not significantly alter extracellular glutamate levels in either the repeated
cocaine or saline groups. These results indicate that, compared to what was
observed three weeks after discontinuing daily cocaine, at early withdrawal
there are relatively smaller alterations in glutamate transmission in the
nucleus accumbens that are associated with the development of behavioral
sensitization.
INTRODUCTION
Repeated administration of amphetamine-like psychostimulants results in a
progressive and enduring augmentation in behavioral hyperactivity known as
behavioral sensitization (Segal and Schuckit, 1983; Robinson and Becker, 1986;
Post and Weiss, 1988; Kalivas and Stewart, 1991). A growing body of evidence
indicates that the nucleus accumbens plays an important role in the expression
of psychostimulant-induced behavioral sensitization (Robinson and Becker,
1986; Kalivas and Stewart, 1991; Nestler, 1992). After extended withdrawal
periods, many laboratories report an increase in the capacity of amphetamine
or cocaine to augment extracellular dopamine in the nucleus accumbens
following repeated treatment with psychostimulants (Robinson et al., 1988;
Akimoto et al., 1989; Pettit et al., 1990; Kalivas and Duffy, 1990, 1993;
Patrick et al., 1991; Wolf et al., 1993; Pierce and Kalivas, 1995). While
cocaine-induced behavioral sensitization becomes more robust following several
weeks of withdrawal from repeated drug administration, augmented behavior is
present during the first few days after the cessation of cocaine treatment (Hitzemann
et al., 1977; Kolta et al., 1985; Paulson et al., 1991; Kalivas and Duffy,
1993; Hooks et al., 1994). In contrast, the augmentation in the releasability
of dopamine in the nucleus accumbens is not consistently observed during early
withdrawal (Segal and Kuczenski, 1992a,b; Kalivas and Duffy, 1993; Pierce and
Kalivas, 1995). These latter results suggest that the behavioral augmentation
produced by repeated cocaine early in withdrawal may be independent of
augmented dopamine release in the nucleus accumbens.
Based upon the finding that systemic administration of
a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) antagonists
blocked the expression of behavioral sensitization to psychostimulants, Karler
et al. (1991, 1994) proposed that alterations in excitatory amino acid (EAA)
transmission may also contribute to the long-term expression of behavioral
sensitization. This postulate was supported by a recent study by Pierce et al.
(1996) who found that at two to three weeks after discontinuing daily cocaine
treatments, administration of the AMPA antagonist, CNQX, into the nucleus
accumbens inhibits the expression of behavioral sensitization. Moreover,
behavioral stimulation following intra-accumbens infusion of AMPA was
augmented among animals that develop behavioral sensitization to daily
cocaine. Finally, using microdialysis Pierce et al. (1996) demonstrated that a
systemic cocaine injection increased extracellular glutamate levels in the
nucleus accumbens only in rats that had developed behavioral sensitization to
repeated cocaine.
Considering the fact that augmented dopamine transmission is more consistently
measured a few weeks after discontinuing daily cocaine treatments than after
only a few days (Kalivas and Duffy, 1993; Wolf et al., 1993; Heidbreder et
al., 1996), the present study was designed to determine if the changes in
glutamate transmission found by Pierce et al. (1996) at two to three wks after
discontinuing cocaine were also present during the first three days. All rats
were pretreated with daily injections of cocaine or saline, and three
experiments were conducted at one to three days after discontinuing the daily
injections. 1) AMPA was microinjected into the nucleus accumbens and motor
activity was monitored. 2) Since the response to AMPA was augmented in rats
developing behavioral sensitization to cocaine, it was determined if the
increased response to AMPA was associated with an enhanced capacity for AMPA
to elevate extracellular dopamine in the nucleus accumbens. 3) The effect of a
cocaine challenge on extracellular glutamate in the nucleus accumbens was
examined in cocaine- and saline-pretreated rats.
MATERIALS AND METHODS
Animal housing and surgery: Male Sprague-Dawley rats (Simmonsen
Laboratories, Gilroy, CA) were individually housed with food and water
available ad libitum. A 12/12 hr light/dark cycle was used with the lights on
at 7:00 a.m. All cocaine injections, behavioral testing and microdialysis were
performed during the light cycle.
Prior to surgery, rats weighing 250 to 350 g were anesthetized with Equithesin
(3.0 ml/kg) and mounted in a stereotaxic apparatus. For microdialysis and
behavioral experiments, cannulae (12 mm, 20 gauge stainless steel for
dialysis; 14 mm, 26 gauge for behavior) were implanted bilaterally 2 mm dorsal
to the nucleus accumbens core or shell (9.0 mm A/P; 0.8-1.8 mm M/L; 0.0 mm
relative to the interaural line, Pellegrino et al., 1979) and cemented in
place by affixing dental acrylic to three stainless steel screws tapped into
the skull.
Repeated cocaine or saline treatment: In both behavior and
microdialysis experiments, subjects were assigned to either the cocaine or
saline treatment groups following at least 7 days of post-operative recovery.
The day prior to the start of the experiment, all animals were habituated to
the photocell boxes (Omnitech Electronics, Columbus, OH) for 3 hours. On the
first treatment day, animals were habituated to the photocell boxes for 1
hour. Following habituation, the rats were injected with either cocaine (15
mg/kg, ip; donated by the National Institute of Drug Abuse) or saline (1.0
ml/kg, ip) and behavior was monitored for 2 hr. On days 2 through 6, cocaine
rats received daily injections of cocaine (30 mg/kg, ip) while control animals
received saline in their home cages. On the seventh day, all animals were
again habituated to the photocell boxes for 1 hr followed by the
administration of cocaine (15 mg/kg, ip) or saline and behavior was monitored
for 2 hr post-injection. Thus, half of the subjects received 7 administrations
of cocaine while the other half were injected daily with saline.
AMPA microinjection and behavior: One day after discontinuing
daily saline or cocaine, rats were microinjected with saline into the nucleus
accumbens. During the next two days, rats were given one of two doses of AMPA
(0.03 or 0.1 µg; RBI, Natick, MA) in random order and motor activity was
monitored for 2 hr. Following a one hr adaptation to the photocell cell
apparatus (Omnitech Electronics), the obturators were removed from the
microinjection guide cannulae and were replaced by an injection needle (33 ga
stainless steel) which extended 2 mm below the tip of the guide cannulae into
the nucleus accumbens. Bilateral infusions were made over 60 sec in a volume
of 0.5 microliter/side. Twenty sec later the injector was removed and the rat
was returned to the photocell cage.
Microdialysis and measurement of extracellular glutamate and dopamine:
The dialysis probes were constructed as described by Robinson and Wishaw
(1988), with approximately 2.0 mm of active dialysis membrane exposed at the
tip. The probes were inserted through the guide cannulae into the nucleus
accumbens the night prior to the experiment. The next day, dialysis buffer (5
mM KCl, 120 mM NaCl, 1.4 mM CaCl2, 1.2 mM MgCl2, 5.0 mM
glucose, plus 0.2 mM phosphate-buffered saline to give a pH value of 7.4 and a
final sodium concentration of 120.7 mM) was advanced through the probe at a
rate of 1.9 microliter/min via a syringe pump (Harvard Instruments, Boston,
MA) for 1 hr. Baseline samples were collected for 100 min prior to beginning
drug treatment.
In order to assess the effects of AMPA on extracellular dopamine levels in the
nucleus accumbens, 24 to 48 hrs after discontinuing repeated cocaine or saline
injections four concentrations of AMPA (0.1, 1.0, 10.0 and 100.0 micromolar)
were administered sequentially in ascending order through the dialysis probe
for 100 min each. Both prior to and during AMPA administration, samples were
taken every 20 min.
For the measurement of extracellular dopamine, samples were collected into
microfuge tubes containing 20 µl of mobile phase (0.1 M citric acid, 75mM Na2HPO4,
1.5 mM heptane sulfonic acid, 0.1 mM EDTA, 15 % methanol, v/v, pH=4.2) plus
2.0 pmol of dihydroxybenzylamine as the internal standard. Following
collection, all samples were frozen at -80o C until analyzed. The
samples were subsequently thawed and placed in an autosampler (Gilson Medical
supplies, Middleton, WI) connected to an HPLC system with electrochemical
detection. The dopamine was separated using a 25 cm C-18 reversed phase column
(Bioanalytical Systems, West LaFayette, IN) and oxidized/reduced using
coulometric detection (ESA Inc., Bedford, MA). Three electrodes were used: a
preinjection port guard cell (+0.4 V) to oxidize the mobile phase, an
oxidation analytical electrode (+0.3 V) and a reduction analytical electrode
(-0.14 V). Peaks were recorded on a chart recorder and compared to an external
standard curve (10-1000 fmol).
In a separate group of animals, microdialysis was conducted in the nucleus
accumbens to measure the levels of extracellular glutamate on the first day
after discontinuing repeated cocaine or saline. After collecting 100 min of
baseline data, rats were challenged with saline (1.0 ml/kg, ip) followed 80
min later by cocaine (15 mg/kg, ip). Samples were collected for 180 min (once
every 20 min) after cocaine administration before terminating the experiment.
For the measurement of extracellular glutamate, samples were collected into 10
µl of mobile phase (0.1 M Na2HPO4, 0.13 mM Na2EDTA,
25% methanol, v/v, pH = 6.2) plus 2.0 pmol homoserine as an internal standard.
Precolumn derivatization with o-pthaldehyde was performed by an autosampler,
and the chromatography was conducted as described above for dopamine, except a
10 cm column was used and the electrode currents were set as follows:
preinjection port guard cell=+0.7 V; reduction analytical electrode=-0.25 V;
oxidation analytical electrode=+0.65 V.
Histology: Following dialysis and behavioral experiments, rats
were given an overdose of pentobarbital (>100 mg/kg, ip) and perfused
intracardially with phosphate-buffered saline followed by 10% formalin. The
brain was removed and stored in 10% formalin for at least 1 week. The brains
were blocked and coronal sections (100 µm) were taken at the level of the
nucleus accumbens with a vibratome. The sections were mounted on
gelatin-coated slides and stained with Cresyl violet. Probe and cannula
placements were determined according to the atlas of Paxinos and Watson (1986)
by an individual unaware of the rats' behavioral or neurochemical response.
Data analysis: Mixed factors analyses of variance (ANOVAs) were
performed on the totals (horizontal counts summed across 120 min) of the
behavioral data (see figure legends for specific statistical information). For
time course analysis of behavioral data, a two-way ANOVA with repeated
measures over time was conducted. For neurochemistry, the dopamine or
glutamate content was expressed as both the raw values (pmol/sample) and
percent change from baseline. Based on the average of the last two dialysis
samples at each AMPA concentration, dopamine data were evaluated using a
two-way ANOVA with repeated measures over dose. For the glutamate data, a
two-way ANOVA with repeated measures over time was performed. In all cases,
pairwise comparisons were made using a least significant difference test for
repeated measures ANOVAs.
Based upon the study by Pierce et al. (1996), rats receiving daily cocaine
were divided into two groups. Animals in the sensitized group demonstrated a
>20% increase in horizontal photocell counts on the last day of daily
cocaine administration compared with the first day. The remaining animals were
grouped as nonsensitized. Separating rats into these two groups was found by
Pierce et al. (1996) to clearly distinguish animals in which repeated cocaine
elevated glutamate transmission in the nucleus accumbens at three weeks of
withdrawal. The majority of rats fall into the sensitized group, and in
experiments 2 and 3 the nonsensitized group included less than 3 animals (see
Table 1). Therefore, for experiments 2 and 3 the data from the nonsensitized
group were excluded from the statistical analyses.
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| Table 1: Effect of seven daily
administrations of cocaine or saline on horizontal activity in the rat.
Day 1 corresponds to the first, and day 7 the last, daily injection.
Saline refers to rats receiving 7 daily saline administrations;
sensitized to the subpopulation of cocaine rats showing a greater than
20% increase in photocell counts between day 1 and day 7; nonsensitized
corresponds to cocaine animals demonstrating a less than 20% increase.
Data are presented as the mean (standard error) horizontal photocell
counts over the first 120 min after cocaine injection. |
RESULTS
Sensitization to repeated cocaine: Table 1 shows the behavioral
response to cocaine or saline on the first and last days of daily
administration. As described by Pierce et al. (1996), the daily cocaine
treated group was divided into a sensitized and a nonsensitized subgroup. The
criterion used to define a rat as sensitized was an increase of at least a 20%
in the number of horizontal photocell counts on the last cocaine injection
(day 7) compared to the first (day 1). Between 63 and 100% of all rats
developed behavioral sensitization by this criterion. The response to repeated
saline, in contrast, was not significantly augmented after 7 daily injections.
Experiment 1: Microinjection of AMPA. Figure
1A shows that following microinjection of 0.1 µg AMPA into the nucleus
accumbens there was a significant increase in horizontal photocell counts in
all three groups of animals. However, the sensitized animals showed an
enhanced behavioral response to AMPA relative to the saline and nonsensitized
groups. There was no statistical difference in the response to AMPA between
the nonsensitized and saline pretreated rats. This effect is more readily seen
in the time course of the behavioral response to AMPA shown in figure
1B. The behavioral response to 0.1 µg AMPA was significantly greater in
sensitized, relative to saline pretreated and nonsensitized animals at the 45
and 60 min time points after microinjection. At no time point did the
behavioral response of the nonsensitized animals differ from the saline group.
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| Figure 1: Behavioral effect of AMPA
microinjection into the nucleus accumbens of saline, sensitized and
nonsensitized groups one to three days after discontinuing daily
treatments with saline or cocaine. The data are represented as mean (±
standard error) horizontal photocell counts. The upper panel shows total
photocell counts (over the 120 min recording period after saline or AMPA
microinjection); these data were evaluated with a 2-way ANOVA (treatment
X AMPA dose) with repeated measures over dose. This analysis revealed
significant main effects of treatment [F(2,72)=2.97, p=0.056] and AMPA
dose [F(2,72)=20.98, p=0.0001]. The lower panel shows the time course of
the effect of 0.1 µg AMPA in the three treatment groups. These data
were evaluated with a 2-way ANOVA (treatment X time) with repeated
measures over time. This analysis revealed a significant main effect of
time [F(7,168)=41.43, p=0.0001] and a significant interaction between
treatment and time [F(14,168)=2.3, p=0.0065]. *p < 0.05, comparing
treatments to saline-saline using a least significant difference test
(Milliken and Johnson, 1984). +p < 0.05, comparing sensitized and
nonsensitized to saline-0.1 µg AMPA. |
Experiment 2: AMPA-induced dopamine release. In this experiment
only two rats failed to meet the criterion for the development of
sensitization (see
Table 1). Thus, the nonsensitized animals were excluded from the data
analysis. The perfusion of AMPA through a microdialysis probe in the nucleus
accumbens produced a dose-dependent increase in extracellular dopamine in the
nucleus accumbens of saline and sensitized animals (see
figure 2). However, there were no significant differences in the dopamine
responses between the sensitized and saline groups when the data were
expressed as either percent baseline (figure
2A) or as the raw data (figure
2B). The baseline values for dopamine did not differ significantly among
the treatment groups (F(1,14)=0.037, p=0.8498; saline=0.071±0.02 pmol/sample,
sensitized=0.076±0.018).
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| Figure 2: Effect of AMPA administration
through the dialysis probe in the nucleus accumbens on extracellular
dopamine content. The experiment was conducted at 1 or 2 days after
discontinuing repeated cocaine or saline. These data were calculated by
averaging the last two samples taken at baseline and each AMPA
concentration and were analyzed via a 2-way ANOVA (treatment X dose)
with repeated measures over dose. When the data were expressed as
percent baseline (panel A) this analysis revealed a significant main
effect of AMPA dose [F(4,40)=16.33, p<0.0001]. Similarly, the
analysis of the raw data resulted only in a significant effect of dose
[F(4,40)=9.32, p<0.0001]. |
Experiment 3: Extracellular glutamate after a cocaine challenge.
In this experiment all of the animals assigned to the repeated cocaine group
met the criterion for sensitization. Figure
3A shows that although the average basal levels of glutamate did not
differ significantly between the treatment groups, the levels in the
sensitized animals tended to be lower than the saline pretreated rats
(t(12)=2.09, p=0.058; saline=32.6±7.3 pmol/sample, sensitized=13.4±3.9).
Following the challenge injections of saline and cocaine (15 mg/kg, ip), the
analysis of the absolute levels of extracellular glutamate revealed a
significant main effect of time. Likewise, when the data were examined as
percent change from baseline (figure
3B) there was significant effect over time However, in neither data format
was there a significant difference between the saline and sensitized groups.
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| Figure 3: Effect of saline and cocaine (15
mg/kg, ip) injections on extracellular glutamate in the nucleus
accumbens of saline- and cocaine-pretreated rats one day after
discontinuing daily injections. The data are presented as the mean (±
standard error) percent change from baseline glutamate. The data were
evaluated with a 2-way ANOVA (treatment X time) with repeated measures
over time. The analysis of the percent baseline transformation (panel A)
and the raw data (panel B) revealed significant main effects of
treatment [panel A: F(15,180)=2.02, p=0.016; panel B: F(15,180)=2.63,
p=0.001]. The open arrow indicates the administration of saline (after
100 min) and the closed arrow indicates the injection of cocaine (after
180 min). |
Histology: Figure
4 (top panel) is a micrograph showing the location of the ventral tip of
the microinjection cannulae in the nucleus accumbens for the behavioral
experiments from experiment 1. For this experiment, the cannulae were
distributed between the core and shell regions of the nucleus accumbens. Figure
4 (bottom panel) depicts a micrograph of dialysis probe placements in the
nucleus accumbens core from an animal used in experiment 3 (all placements
from experiments 2 and 3 were similarly located in the core). In some cases
the microdialysis probe placement included portions of the ventral nucleus
accumbens shell or the neostriatum. Note in both micrographs that there was no
neurotoxicity produced by AMPA beyond the mechanical tissue destruction
resulting from insertion of the injectors or dialysis probes.
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| Figure 4: The upper photomicrograph is
representative of an animal microinjected with AMPA in experiment 1. The
arrows point to the injection sites. The lower micrograph is from an
animal used in experiment 3 and shows the placement of the dialysis
probe in the core region of the nucleus accumbens. The arrows point to
the extreme ends of the active region of the dialysis probe. In both
micrographs, note the lack of neurotoxicity outside of the mechanical
damage produced by the injection cannulae or probe following perfusion
of AMPA through the dialysis probe. Bars= 1 mm. ac=anterior commisure. |
DISCUSSION
The expression of behavioral sensitization to psychostimulants is associated
with enhanced extracellular dopamine levels in the nucleus accumbens beginning
at least one week after discontinuing repeated psychostimulant administration
(Kalivas and Duffy, 1993; Wolf et al., 1993; Hooks et al., 1994; Heidebreder
et al., 1996). However, while the sensitized behavioral response is observed
early in the withdrawal period, the enhanced releasability of dopamine in the
nucleus accumbens is reduced or absent during the first week after
discontinuing repeated drug treatments (Hurd et al., 1989; Kalivas and
Stewart, 1991; Segal and Kuczenski, 1992a,b; Wolf et al., 1993; Kalivas and
Duffy, 1993; Hooks et al., 1994; Pierce and Kalivas, 1995). Similar to
extracellular dopamine in the nucleus accumbens, Pierce et al. (1996) recently
reported that three weeks after discontinuing daily cocaine, glutamate
transmission is enhanced in the nucleus accumbens of rats developing
behavioral sensitization and the present report indicates that this
augmentation in extracellular glutamate in cocaine-sensitized rats is absent
during the first three days after discontinuing daily cocaine.
Pierce et al. (1996) also reported that three weeks after discontinuing daily
cocaine injections, the behavioral response elicited by microinjection of AMPA
into the nucleus accumbens was augmented. In contrast to the augmented levels
of extracellular glutamate and dopamine, the increased behavioral
responsiveness to AMPA was present at two and three days after discontinuing
repeated cocaine, albeit somewhat reduced compared with three weeks of
withdrawal (see Pierce et al., 1996). The presence of an augmented behavioral
response to AMPA may result, in part, from the lower levels of basal glutamate
measured at both 1 and 21 days after discontinuing daily cocaine injections.
Thus, lower levels of synaptic glutamate may result in an upregulation of AMPA
receptor density or transduction. The findings by Fitzgerald et al. (1996)
that neither the GluR1 nor GluR2 subunits are altered in the nucleus accumbens
after repeated cocaine argues that receptor density is not altered even though
GluR2 mRNA is increased after repeated cocaine (personal communication, Behnam
Ghasemzadeh, Ph.D., Washington State University). Likewise, the finding of
White et al. (1995) that the excitatory response to iontophoretic glutamate in
the nucleus accumbens is blunted after repeated cocaine treatment is difficult
to reconcile with upregulated AMPA receptor density or transduction.
Similar to Pierce et al. (1996), we found that the augmented behavioral
response to AMPA occurred only in rats that developed behavioral sensitization
to criterion (>20% increase in photocell counts on the last, compared to
the first day of daily cocaine administration). The predictability of this
criterion supports a causal association between the development of behaivoral
sensitization and enhanced responsiveness to AMPA receptor stimulation in the
nucleus accumbens. However, regression analysis between the percent difference
in photocell counts on the first and last cocaine injection and total
horizontal photocell counts following AMPA (0.1 nmol) microinjection into the
nucleus accumbens did not reveal a significant correlation (r= .207; p=
0.476). While the lack of correlation indicates that augmented AMPA receptor
responsiveness is not the primary variable regulating the expression of
behavioral sensitization, it may still contribute to the augmented behavioral
profile.
The fact that AMPA receptor responsivenes was not enhanced in rats that
received daily cocaine and did not develop behavioral sensitization (i.e. the
nonsensitized group) demonstrates that the effect on AMPA receptors does not
arise purely as a pharmacological effect of cocaine binding to the dopamine
transporter. Rather, the augmented AMPA response is regulated by a combination
of cocaine administration and other factors. One factor making a contribution
to the expression of behavioral sensitization is the development of learned
associations with cocaine administration (Tilson and Rech, 1973; Post et al.,
1981; Stewart and Vezina, 1988; Weiss et al., 1989; Pert et al., 1992; Badiani
et al., 1995). It is possible that the enhanced responsiveness of AMPA
receptor stimulation may arise in combination with learned associations the
animal makes with the daily cocaine injection. Consistent with this
hypothesis, rats repeatedly administered cocaine in a distinct environment
displayed a greater response to AMPA administration in that environment than
did rats given daily cocaine in the home cage (Bell and Kalivas, in press).
These results suggest that the contextually conditioned aspect of behavioral
sensitization to psychostimulants may be mediated in part by changes in AMPA
receptor sensitivity in the nucleus accumbens.
In summary, the current results, combined with those reported by Pierce et al.
(1996) indicate that, similar to changes in dopamine transmission associated
with behavioral sensitization, the changes in glutamate transmission are
blunted at early compared to late withdrawal times. Nonetheless, intra-accumbens
administration of either AMPA or D1 dopamine antagonists blocks the expression
of behavioral sensitization to cocaine (Pierce et al., 1996; unpublished
observations). Thus, while both dopamine and glutamate transmission in the
nucleus accumbens are necessary for the expression of behavioral sensitization
to repeated cocaine, other factors are also playing a critical role.
ACKNOWLEDGMENTS
This research was supported in part by the Washington State Alcohol and Drug
Abuse Program and U.S. Public Health Service grants MH-40817 and DA-03906,
Research Career Development Award DA-00158 (P.W.K.) and National Research
Service Award DA-05589 (R.C.P.).
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