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The Journal of Neuroscience, April 15, 2003, 23(8):3531
Prefrontal Glutamate Release into the Core of the Nucleus
Accumbens Mediates Cocaine-Induced Reinstatement of Drug-Seeking
Behavior
Krista
McFarland,
Christopher C.
Lapish, and
Peter W.
Kalivas
Department of Physiology ad Neuroscience, Medical University of
South Carolina, Charleston, South Carolina 29425
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ABSTRACT |
The relative contributions of glutamate and dopamine within the
nucleus accumbens to cocaine-induced reinstatement of drug-seeking behavior were assessed. When extinguished cocaine self-administration behavior was reinstated by a cocaine-priming injection, extracellular levels of both dopamine and glutamate were elevated in the nucleus accumbens. However, when yoked cocaine or saline control subjects were
administered a cocaine prime, only dopamine levels were elevated. Thus,
glutamate increased only when animals reinstated lever pressing, whereas dopamine increased regardless of behavior. The increase in
glutamate was not accounted for simply by the act of lever pressing
itself, because the cocaine self-administration group still
demonstrated elevated glutamate when the levers were withdrawn from the
operant chamber. Moreover, reinstatement of lever pressing for food did
not elevate extracellular glutamate, indicating that increased
glutamate initiated responding selectively for a drug reinforcement.
The source of glutamate was shown to be glutamatergic afferents from
the prefrontal cortex because inhibiting prefrontal cortical
glutamatergic neurons that project to the accumbens prevented the rise
in glutamate. Together, these data demonstrate that activation of a
glutamatergic projection from the prefrontal cortex to the nucleus
accumbens underlies cocaine-primed reinstatement of drug-seeking behavior.
Key words:
dopamine; glutamate; reinstatement; nucleus
accumbens; medial prefrontal cortex; self-administration; cocaine
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Introduction |
One of the defining characteristics
of cocaine (COC) addiction is repeated cycles of drug use
followed by abstinence. Thus, the biggest challenge to successful
treatment of cocaine addiction is preventing craving and relapse.
Neuroimaging studies in addicts demonstrate that metabolic activation
of the prefrontal cortex is associated with craving for cocaine (Volkow
et al., 1999 ; Kilts et al., 2001). Despite this well documented
involvement of the prefrontal cortex in human craving, most animal
studies have centered on the nucleus accumbens because it receives a
major dopamine projection from the ventral tegmental area (Fallon and
Moore, 1978) that is critical for the learning and maintenance of
goal-directed responding, including drug-seeking behavior (Koob and
Swerdlow, 1988; Ettenberg, 1989).
Notably, many long-term adaptations resulting from repeated drug
exposure manifest as presynaptic and postsynaptic changes in dopamine
and glutamate transmission within the nucleus accumbens. For example,
there is an enduring electrophysiological supersensitivity of
D1 dopamine receptors (Henry and White,
1991) and accompanying increases in protein kinase A signaling (Zhang
et al., 2002), as well as increased releasability of presynaptic
dopamine that depends on calcium/calmodulin-dependent protein kinase
II signaling (Pierce and Kalivas, 1997; Gnegy, 2000).
Additionally, basal extracellular levels of accumbens glutamate are
decreased (Pierce et al., 1996), whereas there is increased glutamate
in response to a cocaine challenge (Pierce et al., 1996; Reid and
Berger, 1996). Furthermore, electrophysiological and neurochemical
experiments find long-term decreases in signaling through AMPA (Thomas
et al., 2001; Beurrier and Malenka, 2002) and metabotropic glutamate
receptors (mGluRs) (Swanson et al., 2001; Xi et al., 2002) after
repeated cocaine administration. Together, these data demonstrate that
enduring changes in either glutamate or dopamine transmission in the
nucleus accumbens produced by repeated cocaine administration could
contribute to the enduring expression of craving and relapse in addicts.
Consistent with the notion that the nucleus accumbens plays a central
role in mediating renewed responding after drug abstinence is the
finding that reversible inactivation of the core of the nucleus
accumbens (NAcore) blocks cocaine-induced reinstatement (McFarland and
Kalivas, 2001). Studies implicating dopamine transmission in
reinstatement include demonstrations that systemic pretreatment with
dopamine receptor antagonists block, whereas direct and indirect dopamine agonists facilitate reinstatement of cocaine-seeking behavior
(De Vries et al., 1999, 2002). Also, infusion of dopamine or cocaine
directly into the nucleus accumbens reinstates cocaine-seeking behavior
(Cornish and Kalivas, 2000; Park et al., 2002). However, infusion of
D1/D2 dopamine receptor
antagonist directly into the NAcore fails to block cocaine-primed
reinstatement (McFarland and Kalivas, 2001) Instead, infusion of AMPA
glutamate receptor antagonist prevents reinstatement by a cocaine prime
(Cornish and Kalivas, 2000), and AMPA receptor agonists elicit
reinstatement responding (Cornish et al., 1999).
The goal of the present study was to simultaneously assess the
involvement of dopaminergic and glutamatergic mechanisms within the
accumbens to cocaine-induced reinstatement of drug-seeking behavior.
Subjects with their cocaine self-administration (SA) behavior
extinguished were tested for their propensity to reinstate responding
after cocaine challenge. During tests for reinstatement in
vivo microdialysis was performed, and the levels of extracellular glutamate and dopamine were measured.
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Materials and Methods |
Animal housing and surgery. All experiments were
conducted in accordance with the National Institutes of Health
Guidelines for the Care and Use of Laboratory Animals, and
the Institutional Animal Care and Use Committee at the Medical
University of South Carolina approved all procedures. The subjects were
62 male Sprague Dawley rats, purchased from Charles River
Laboratories (Indianapolis, IN). They were housed in an
Association for the Assessment and Accreditation of Laboratory Animal
Care-approved facility, in a temperature-controlled room (23°C),
maintained on a 12 hr reverse light/dark cycle (lights on 7:00 P.M.).
On arrival, subjects were weighed and handled daily for 1 week
to assess their health and allow them to acclimate to handling
procedures. Animals were given ad libitum access to food
(Purina Rat Chow; Purina Mills, St. Louis, MO) until 7 d
after surgery, when they received a 20 gm daily ration of food for the
remainder of the experiment. This regimen aided in the acquisition of
the lever-press response while allowing them to gain weight throughout
the course of the experiment.
One week after arrival, rats were anesthetized with ketamine HCl (87.5 mg/kg Ketaset; Fort Dodge Animal Health, Fort Dodge, IA)
and xylazine (5 mg/kg Rompum; Bayer, Shawnee Mission, KS) and implanted with intravenous catheters, microdialysis guide cannulas
(26 gauge, cut to 11 mm below the pedestal; Plastics One,
Roanoak, VA) aimed at the NAcore, and bilateral microinfusion guide
cannulas (30 gauge, cut to 14 mm; Small Parts, Logansport, IN) aimed at the dorsal prefrontal cortex (PFCd) (corresponding to the
transition between the prelimbic and anterior cingulated cortices).
Coordinates were determined according to the atlas of Paxinos and
Watson (1998): NAcore (anteroposterior, +1.2 mm; mediolateral, ±2.5 mm
at and angle of 6° from vertical; dorsoventral,  4.7 mm relative to
bregma) and PFCd (anteroposterior, +3.0 mm; mediolateral, ±0.7 mm;
dorsoventral, 2.2 mm relative to bregma). For cannula implantation,
the skull was exposed, and holes were drilled at the target locations.
Additional holes were drilled peripheral to the target locations, and
jewelers screws were inserted to serve as anchors. The cannulas were
lowered to the desired location, and then cannulas and screws were
embedded in dental acrylic to fasten them to the skull. Metal
obdurators (33 gauge; Small Parts) were inserted to extend
0.5 mm beyond the tip of the injection cannulas to prevent their
obstruction by debris.
For catheter implantation, a guide cannula (C313G; Plastics
One) attached to SILASTIC tubing (0.025 inner diameter;
0.047 outer diameter; VWR Scientific, West Chester, PA) and Marlex mesh (Allegiance, McGaw Park, IL) via dental cement was inserted
subcutaneously between the shoulder blades, with the guide cannula
externalized through a dermal biopsy hole (3 mm). The other end of the
SILASTIC tubing was threaded subcutaneously to the jugular vein. After the vein was isolated, the tubing was inserted 2.7-3.0 cm and secured
in place with sutures to the underlying muscle tissue. Subjects
remained on a heating pad, closely monitored, until they were fully
conscious. The catheter was flushed daily with (1) heparinized saline
(0.2 ml of 100 IU) to help maintain catheter patency and (2) cefazolin
antibiotic (0.2 ml of 0.1 gm/ml) to help protect against infection.
Self-administration and extinction procedures. Behavioral
training began 7 d after surgery. All training and testing was
conducted in standard operant chambers fitted with two retractable
levers (ENV-008; Med Associates, Georgia, VT). The first
step in behavioral training was acquisition of the lever-press
response, in which subjects were trained in a single 15 hr training
session to press a lever on a fixed ratio 1 (FR-1) schedule of
reinforcement for one 45 mg food pellet (Noyes, Lancaster, NH). The
next day, the reinforcer was switched to a cocaine-HCl solution (0.25 mg/kg). Presses on the active lever now resulted in an intravenous
infusion of cocaine (over 4 sec), whereas presses on the inactive lever had no programmed consequences. Cocaine reinforcement was delivered on
a modified FR-1 schedule such that each infusion of cocaine was
accompanied by illumination of a stimulus over the lever and a 20 sec
timeout when active lever presses were counted but did not result in
reinforcer delivery. After 20 sec, the stimulus light was extinguished
and the first lever press again resulted in cocaine delivery. Daily
training sessions lasted 2 hr or until a subject earned 200 cocaine
infusions, whichever came first. Subjects remained in cocaine
self-administration training until they met an acquisition criterion
that required the average presses on the active lever over 3 consecutive training days to vary by <10%.
Once subjects met the acquisition criterion, extinction procedures were
instituted on the following day. During extinction training, presses on
the active lever resulted in infusions of saline (SAL) (0.9% saline
over 4 sec) instead of cocaine. All other aspects of training remained
the same. Subjects remained in behavioral extinction until responding
on the active lever averaged 10% or less of active lever pressing
during maintenance for 3 consecutive days. The day after meeting this
criterion, subjects were returned to the operant chambers for probing
and reinstatement testing, as described below.
Yoked control subjects. Some rats served as yoked control
subjects for the self-administering rats. Each yoked subject was paired
with a rat that self-administered cocaine and received either
intravenous infusions of cocaine (cocaine-yoked rats, 0.25 mg/kg over 4 sec) or saline (saline-yoked rats, 0.9%) in the same temporal pattern
as that self-administered by their paired rat. Yoked rats received the
same number of training sessions as paired rats, but because lever
presses did not result in reinforcer delivery, they occurred only
infrequently. Similarly, yoked rats received the same number of
"extinction" sessions as their paired rats, in which both cocaine-
and saline-yoked subjects received saline infusions in the same pattern
as their paired self-administering subjects. The self-administering
rats to which others were cocaine yoked were chosen so that the mean
cocaine intake of cocaine-yoked rats would be the same as the mean
cocaine intake of all of the self-administering rats (20.5 vs 20.25 mg/kg per 2 hr session).
Reinstatement testing and microdialysis procedure.
Microdialysis probes were constructed with inlet and outlet tubing
(made of fused silica) inserted into a semipermeable membrane with 2 mm
of active length. On the night before reinstatement testing, microdialysis probes were inserted into the NAcore, with the active membrane beginning 2 mm beyond the end of the guide cannula. Subjects were then housed in the operant chambers, in which they were given their daily ration of food and ad libitum access to water.
On the following morning, dialysis buffer (5 mM
glucose, 2.5 mM KCl, 140 mM
NaCl, 1.4 mM CaCl2, 1.2 mM MgCl2, and 0.15%
PBS, pH 7.4) was perfused through the probe (2 µl/min) for 2 hr, after which, 2 hr of baseline samples were collected at 10 min
intervals. All samples were collected into 10 µl of mobile phase (150 mM sodium dihydrogen phosphate monobasic, 4.76 mM citric acid, 3 mM sodium dodecyl sulfate, 50 µM EDTA, 10% methanol v/v,
and 15% acetonitirle v/v, pH 5.6) to prevent oxidation of dopamine.
Samples were then stored at 80 C for later analysis of dopamine and
glutamate content.
After the 2 hr baseline sampling, subjects were tested for their
propensity to reinstate drug-seeking behavior after a challenge injection of cocaine (10 mg/kg, i.p., in a volume of 1 ml/kg
bodyweight) or saline (0.9% in a volume of 1 ml/kg bodyweight).
Immediately preceding systemic cocaine or saline challenge, some
subjects also received bilateral microinfusion of saline or a
combination of the GABAB agonist baclofen and the
GABAA agonist muscimol (B/M) (0.3 and 0.03 nmol,
respectively) into the dorsal prefrontal cortex. The GABA agonist drugs
were used to hyperpolarize the PFCd and produce a reversible
inactivation of the area. For microinjections, obdurators were removed
and bilateral infusion cannulas were inserted to extend 1 mm beyond the
tip of the guide cannula. All infusions were made in a volume of 0.3 µl over 60 sec. Microinfusion cannulas were left in place for 90 sec
after injection to allow time for diffusion. Obdurators were then
replaced, an intraperitoneal injection of cocaine or saline was given,
and animals were returned to the self-administration chambers for a 2 hr reinstatement test. During reinstatement testing, active lever
presses were counted but resulted in saline, not cocaine, delivery. Ten
minute microdialysis samples were collected across the 2 hr test
session, and then subjects were disconnected and returned to their home cages.
Motor control. Subjects in the motor control experiment were
trained using the same procedures described above for
self-administering animals. However, during reinstatement testing, the
levers were not extended into the chambers, thus no lever pressing occurred.
Food reinstatement. Food reinstatement subjects were trained
in a manner parallel to cocaine self-administering rats. They were
trained to lever press on an FR-1 schedule of reinforcement (each
reinforcement consisting of a single 45 mg Noyes food pellet) in daily
2 hr sessions. Once stable responding was achieved, the schedule of
reinforcement was increased to FR-2 and then to FR-5. Subjects remained
in maintenance until lever pressing stabilized (<10% variation across
3 consecutive days). Subjects then entered behavioral extinction, in
which lever pressing no longer resulted in food delivery. Once lever
presses fell to <10% of maintenance levels across 3 consecutive days,
rats were tested for their propensity to reinstate responding for
noncontingent food delivery. The session started when the levers
extended into the chamber and the house light illuminated. Subjects
received two pellets immediately on the initiation and an additional 10 pellets at 2 min intervals for the first 20 min of the reinstatement
session. Lever presses never resulted in food delivery.
Quantification of dopamine and glutamate. Before analysis,
samples were thawed and divided, so they could be used to measure levels of both dopamine and glutamate. Of the 30 µl in each sample (20 µl of diastylate and 10 µl mobile phase), 10 µl was used for quantification of glutamate and 20 µl was used for quantification of
dopamine. For dopamine analysis, samples were placed in an ESA (Chelmsford, MA) model 540 autosampler connected to an
HPLC system with electrochemical detection. Separation was achieved by
pumping the samples through a 15 cm C18
reversed-phase column (ESA), and then samples were
reduced-oxidized using coulometric detection. Three electrodes were
used: a guard cell (+400 mV), a reduction analytical electrode (150
mV), and an oxidation analytical electrode (+250 mV). Peaks were
recorded, and the area under the curve was measured by a computer
running ESA Chromatography Data System. These values were
normalized by comparison with an internal standard curve for
isoproteronol and quantified by comparison with an external standard curve.
Concentration of glutamate in the samples was determined using HPLC
with fluorometric detection. Samples were loaded by an autosampler
(Gilson Medical Electric, Middleton, WI) that performed a
precolumn derivitization with o-pthalaldehyde. Amino acids
were then separated with a reversed-phase C18 (15 cm) column. Glutamate was detected using a fluorescence
spectrophotometer (Linear Fluor LC 305; ESA) using an
excitation wavelength of 336 nm and an emission wavelength of 440 nm. A
chart recorder recorded peaks, and peak heights were measured. These
values were normalized by comparison with an internal standard curve
for homoserine and quantified by comparison with an external standard curve.
Histology and statistics. After reinstatement testing,
subjects were overdosed with pentobarbital anesthesia (100 mg/kg, i.p.) and then perfused transcardially with 0.9% physiological saline, followed by 10% Formalin. Brains were stored in Formalin for at least
24 hr before being sectioned. Brains were blocked and sliced in coronal
sections (50 µm thick) through the prefrontal cortex and nucleus
accumbens to examine placement of both dialysis and microinfusion
cannulas. Sections were mounted on gel-coated slides, stained with
cresyl violet, and examined for cannula placement by an individual
unaware of each subject's behavior. The data were statistically
evaluated using a one-way or two-way ANOVA with repeated
measures across time and between-subjects analyses across conditions.
Post hoc comparisons between individual treatments were made
using a Tukey's test.
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Results |
Cocaine-induced reinstatement is associated with elevations in
nucleus accumbens glutamate but not dopamine
Figure 1 depicts levels of
extracellular glutamate (A) and dopamine
(B) measured in the nucleus accumbens during
reinstatement testing for three groups of animals: those with previous
experience self-administering cocaine or those that received passive
infusions of cocaine (yoked cocaine) or saline (yoked saline) in the
same pattern as self-administering animals. Only animals that had
previously self-administered cocaine showed behavioral reinstatement
(Fig. 1C) after cocaine challenge and were the only subjects
to display increased extracellular glutamate within the accumbens (Fig.
1A). In contrast, all animals showed an increase in
extracellular dopamine after cocaine challenge (Fig.
1B). These data suggest that increased levels of
accumbens glutamate are specifically associated with reinstatement,
whereas extracellular dopamine is not.
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Figure 1.
Cocaine-induced reinstatement responding is
associated with a rise in accumbal glutamate rather than dopamine.
A and B depict extracellular levels of
glutamate (A) and dopamine
(B) within the nucleus accumbens during
cocaine-induced reinstatement testing. This figure depicts data from
rats that passively received either cocaine (Yoke COC;
n = 7) or saline (Yoke SAL; n = 7) in the same temporal pattern that self-administering subjects (SA;
n = 6) lever pressed to receive cocaine infusions.
Animals that received chronic cocaine displayed decreased basal levels
of glutamate (A; SA and Yoke COC) and increased
responsivity of dopamine after cocaine challenge (B;
time 0 min). All groups showed a reliable increase in extracellular
dopamine after COC challenge; however, only SA subjects showed a
reliable increase in glutamate. Thus, glutamate levels are most closely
related to lever pressing (C). Extinction
responding (EXT) is shown for comparison. *p < 0.05 indicates a significant difference from baseline (before COC
challenge) or EXT; +p < 0.05 indicates a
significant difference from yoked SAL control subjects.
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Consistent with previous studies, subjects that had received either
self-administered or yoked cocaine infusions (Fig. 1, SA and Yoke COC)
showed reduced basal glutamate levels (Fig. 1A) and
sensitized dopamine increases after cocaine challenge (Fig. 1B) compared with yoked saline controls.
Inactivation of the dorsal prefrontal cortex blocks cocaine-induced
reinstatement and rise in extracellular glutamate but does not affect
dopamine
To assess the contribution of prefrontal cortical glutamatergic
inputs to the accumbens in the reinstatement-associated rise in
extracellular glutamate, the PFCd (for anterior cingulate and prelimbic
cortex, see Fig. 6B) was reversibly inactivated with GABA agonists immediately preceding reinstatement testing. Rats received microinfusions of the GABAB agonist
baclofen and the GABAA agonist muscimol (0.3 and
0.03 nmol, respectively) or SAL into the PFCd before systemic challenge
with COC or SAL. Thus, there were four treatment conditions: SAL-COC,
B/M-COC, SAL-SAL, and B/M-SAL. As seen in Figure
2C, systemic COC (SAL-COC),
but not SAL (SAL-SAL and B/M-SAL), elicited robust reinstatement
responding on the previously drug-paired lever, and this responding was
blocked by inactivating the PFCd with baclofen and muscimol (B/M-COC). Figure 2A shows that the extracellular levels of
glutamate within the NAcore paralleled behavioral responding because
the increase in glutamate associated with behavioral responding
in the SAL-COC group was abolished after inactivation of the PFCd
(B/M-COC group). In contrast, the extracellular levels of dopamine did
not correspond with behavior. COC challenge produced increases in
extracellular dopamine that were resistant to inactivation of the PFCd
(Fig. 2B).
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Figure 2.
Inactivation of the dorsal prefrontal cortex
blocks cocaine-induced reinstatement and the associated rise in
extracellular glutamate. Extracellular levels of glutamate
(A) and dopamine (B) were
measured during reinstatement testing. Subjects received microinfusions
of either SAL or B/M into the dorsal prefrontal cortex, followed
by systemic (intraperitoneal) infusions of either COC or SAL at time 0 min. Thus, there were four treatment conditions (SAL-COC,
n = 6; B/M-COC, n = 6; SAL-SAL,
n = 5; B/M-SAL, n = 5), with
the intracranial treatment indicated first and the systemic treatment
second. C shows responding on the active lever during
the 2 hr test for reinstatement and, for comparison, shows responding
during extinction conditions (EXT). Challenge with systemic SAL
(SAL-SAL or B/M-SAL) did not elicit reinstatement or a rise in
extracellular levels of glutamate or dopamine within the NAcore. In
contrast, challenge with systemic COC elicited both renewed responding
on the active lever as well as increases in extracellular levels of
glutamate and dopamine within the NAcore. Inactivation of the PFCd with
baclofen and muscimol before COC challenge blocked both the rise in
extracellular glutamate and behavioral reinstatement but left the rise
in NAcore dopamine unaffected (compare SAL-COC with B/M-COC).
*p < 0.05 indicates a significant difference from
baseline (before COC challenge) or EXT; +p < 0.05 indicates a significant difference from SAL control subjects.
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Elevations in extracellular glutamate that underlie cocaine-induced
reinstatement depend on neuronal activation
Because the basal levels of extracellular glutamate levels depend
primarily on nonsynaptic mechanisms (Baker et al., 2002), the
contribution of action potential-dependent glutamate release to the
reinstatement-associated rise in glutamate within the NAcore was
assessed by perfusing the voltage-gated sodium channel antagonist tetrodotoxin (TTX) through the dialysis probe before cocaine challenge. Figure 3 shows that blocking
voltage-gated sodium channels prevented the cocaine-induced rise in
glutamate levels. As was reported previously (Timmerman and Westerink,
1997), TTX had no significant effect on basal levels of extracellular
glutamate. Blockade of the cocaine-primed rise in extracellular
glutamate by both TTX and inactivation of the PFCd strongly indicates
that the elevation in glutamate underlying cocaine-induced
reinstatement arises from activation of the glutamatergic projection
from the PFCd to the NAcore.
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Figure 3.
The reinstatement-associated increase in accumbal
glutamate is activity dependent. One hour before cocaine challenge, TTX
(0 or 1 µM; n = 6 per group) was
advanced through the dialysis probe. Subjects pretreated with 0 µM TTX showed a reliable increase in extracellular
glutamate after COC challenge. This increase was blocked by 1 µM TTX. *p < 0.05 indicates a reliable
increase from pre-cocaine baseline.
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Elevated glutamate is not caused by operant responding
It was possible that the observed glutamate release could be the
result of, rather than the cause of, reinstatement (i.e., it was
possible lever pressing caused the glutamate release instead of
glutamate release leading to responding). To evaluate this possibility,
animals were trained to self-administer cocaine and then underwent
behavioral extinction. However, during reinstatement testing, the
levers were not extended after the cocaine-priming injection. Thus, no
lever pressing was permitted. As Figure 4 shows, there was no difference in the rise in extracellular glutamate between animals exhibiting lever pressing (SA, from Fig.
1A) and those not exhibiting lever pressing.
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Figure 4.
Cocaine-induced glutamate is not a byproduct of
lever pressing. This figure shows extracellular glutamate levels
measured from the NA of rats that were trained to lever press for
cocaine and had their lever pressing extinguished (just like other
self-administering subjects). However, the levers were not extended
during reinstatement testing. After COC challenge, these subjects
(Motor; n = 7) displayed increased levels of
glutamate within the NAcore comparable with increases shown by animals
allowed to lever press during reinstatement (SA, from Fig. 1),
suggesting that the rise in glutamate is not a consequence of
behavioral responding.
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Food-induced reinstatement does not depend on nucleus
accumbens glutamate
To assess the selectivity of the rise in glutamate for
cocaine-primed reinstatement, a separate group of animals was trained to lever press for food reinforcement, and extracellular glutamate was
measured in the nucleus accumbens during food-induced reinstatement. In
animals trained to lever press for food reinforcement, noncontingent food delivery produced levels of lever pressing comparable with that
elicited by the cocaine-priming injection (Fig.
5B). However, food-induced
reinstatement did not provoke a rise in extracellular glutamate (Fig.
5A), suggesting that accumbens glutamate does not underlie
renewed responding for natural reinforcement.
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Figure 5.
Food reinstatement is not associated with an
increase in accumbal glutamate. Some subjects were trained to lever
press for food reinforcement (45 mg food pellet) and then had their
lever pressing extinguished. A shows extracellular
glutamate levels measured in the NAcore during reinstatement elicited
by noncontingent food delivery. B shows active lever
presses during extinction (EXT) and reinstatement (FOOD;
n = 7). Note that, despite responding on the active
lever at rates comparable with COC subjects, food animals show no
increase in glutamate levels during reinstatement. Data from cocaine
animals (SA, from Fig. 1) is shown for comparison.
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Histology
Figure 6 shows the placement of
dialysis membranes in the nucleus accumbens (A) and
microinjection sites in the prefrontal cortex (B).
Dialysis membranes tended to span the length of the NAcore, clustered
around the anterior commissure, but avoided the ventromedial aspects of
the nucleus accumbens (i.e., the shell of the nucleus accumbens).
Microinjection sites in the PFCd clustered at the border between the
anterior cingulate and prelimbic cortices. All placements were
determined using the atlas of Paxinos and Watson (1998).
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Figure 6.
Histology. This figure depicts the placement of
microdialysis membranes (A) within the nucleus
accumbens core and microinfusion sites within the dorsal prefrontal
cortex (B) based on the atlas of Paxinos and
Watson (1998). For clarity, placements are only shown for subjects
whose data are shown in Figures 1 and 2, but placements for all other
subjects fall within the depicted range. Numbers indicate distance from
bregma in the anteroposterior plane.
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Discussion |
The present study demonstrates that cocaine-induced reinstatement
of drug-seeking behavior is initiated by increased glutamate transmission in the projection from the prefrontal cortex. Animals that
had previously self-administered cocaine (SA) showed a rise in
extracellular glutamate during cocaine-induced reinstatement responding
that was blocked by inactivation of the dorsal prefrontal cortex. In
contrast, there was no clear association between increased dopamine
transmission and whether or not a subject engaged in renewed
drug-seeking behavior (i.e., lever pressing). The fact that the cocaine
prime did not alter glutamate in either yoked control group
demonstrates that the increase in glutamate, unlike increased dopamine,
is not an obligatory pharmacological effect of acute or repeated
cocaine administration. Similarly, the fact that food-induced
reinstatement of food-seeking behavior is not accompanied by an
increase in extracellular glutamate within the accumbens suggests that
the rise is not common to renewed responding for natural reinforcers.
Moreover, the release of glutamate in response to a cocaine prime does
not depend on execution of lever pressing, because when the levers were
removed, the cocaine prime still elevated glutamate transmission in the
subjects trained to self-administer cocaine.
Given the treatment conditions outlined above in which a
cocaine-priming injection elicits reinstatement and a concurrent increase in extracellular glutamate, it appears that the glutamate may
be involved in initiating the behavioral response. The relative importance of glutamate transmission is also indicated by the fact that
the administration of AMPA glutamate receptor antagonists into the
NAcore blocked cocaine-primed reinstatement, whereas antagonizing
D1/D2 dopamine receptors
was without effect (Cornish and Kalivas, 2000; McFarland and Kalivas,
2001). Similarly, cued drug seeking maintained by a second-order
schedule of cocaine reinforcement has been shown to be blocked by AMPA
receptor antagonist administration into the core (not the shell) of the
nucleus accumbens (Di Ciano and Everitt, 2001), raising the possibility
that nucleus accumbens glutamate transmission might also be important
for the behavioral effects of drug-paired cues. Such a notion is
consistent with the finding that exposure to cocaine-paired cues
elicits an increase in extracellular glutamate within the nucleus
accumbens that is associated with the expression of conditioned
locomotion (Hotsenpiller et al., 2001).
The fact that the prefrontal cortex is the source of the cocaine-primed
increase in glutamate is consistent with imaging studies showing
increased metabolic activity in the prefrontal cortex, especially the
anterior cingulate cortex, during cue-primed craving in addicts (Grant
et al., 1996; Childress et al., 1999; Kilts et al., 2001). Moreover,
the activation of the anterior cingulate by cocaine or a
cocaine-associated cue precedes the awareness of craving and may be
more closely associated with mood states that initiate craving (Breiter
et al., 1997; Volkow et al., 1999; Wexler et al., 2001). Analogous to
studies in humans, animal studies demonstrate that there is an increase
in immediate early gene expression in the anterior cingulate cortex
associated with cocaine- or cue-primed reinstatement (Neisewander et
al., 2000; Ciccocioppo et al., 2001; Thomas and Everitt, 2001).
Moreover, Neisewander et al. (2000) noted that the anterior cingulate
was the only brain region in which increased c-Fos expression
was associated with both a drug and cue prime.
Pharmacological studies further establish the initiating role of the
PFCd in precipitating drug-seeking behavior, because transient
inhibition of the PFCd with GABA agonists or TTX prevent cocaine-,
stress-, and cue-primed reinstatement (McFarland and Kalivas, 2001;
Capriles et al., 2002; McLaughlin and See, 2003), and the
microinjection of either cocaine or dopamine into the PFCd reinstates
drug-seeking behavior (McFarland and Kalivas, 2001; Park et al., 2002).
Moreover, reinstatement initiated by cocaine microinjection into the
PFCd was blocked by inhibiting AMPA receptors in the nucleus accumbens,
demonstrating involvement of the prefrontal-accumbens glutamatergic
projection (Park et al., 2002). Finally, although blockade of dopamine
receptors in the NAcore was ineffective, microinjection of the dopamine
antagonist into the PFCd abolished cocaine-primed reinstatement
(Cornish and Kalivas, 2000; McFarland and Kalivas, 2001).
Given the importance of increased glutamate release in the
nucleus accumbens for the initiation of cocaine-primed reinstatement, it is surprising that repeated cocaine administration causes an enduring reduction in glutamate transmission in the nucleus accumbens. Thus, after repeated cocaine administration, there is a decrease in
basal extracellular glutamate, especially when subjects have been
trained to associate cocaine with environmental stimuli (Pierce et al.,
1996; Bell et al., 2000; Hotsenpiller et al., 2001). In addition, after
repeated cocaine, there is a reduction in signaling through group I and
group II metabotropic glutamate receptors (Swanson et al., 2001; Xi et
al., 2002). Furthermore, there is a reduction in electrophysiological
sensitivity of AMPA glutamate receptors to electrical stimulation of
the prefrontal cortex (Thomas et al., 2001), and an enhanced inhibitory
effect of dopamine on excitatory AMPA currents (White et al., 1995;
Beurrier and Malenka, 2002). However, the apparent tonic downregulation
of presynaptic and postsynaptic glutamate transmission by repeated
cocaine may contribute to the enhanced release and detection of
glutamate after a cocaine-priming injection. For example, basal levels
of extracellular glutamate have been shown in vivo to
provide tone on group II mGluR autoreceptors (Baker et al., 2002; Xi et
al., 2002), and the cocaine-induced reduction in basal glutamate
combined with desensitization of group II mGluRs would be expected to
promote increased release of synaptic glutamate after activation of the prefrontal cortex.
In summary, the release of glutamate into the NAcore by a cocaine
priming injection initiates reinstatement of drug-seeking behavior in
rats trained to self-administer cocaine, and the glutamate arises from
PFCd afferents to the accumbens. The fact that a similar release of
glutamate was not elicited by a food prime in subjects trained to
self-administer food poses the possibility that the cocaine-induced
release of glutamate is indicative of a pathological change in
addiction rather than a physiological response initiating reinstatement
of behavior to obtain natural rewards. As such, pharmacological
modulation of glutamate release may prove an effective target for
selectively treating craving for drugs of abuse.
| |
FOOTNOTES |
Received Dec. 12, 2002; revised Jan. 29, 2003; accepted Feb. 5, 2003.
This research was supported in part by United States Public Health
Service Grants DA12513, MH40817, and DA03906 and Postdoctoral National
Research Service Award DA05978 (K.M.). We thank Susan Brie Davidge and
Russell Chapin for their outstanding technical assistance.
Correspondence should be addressed to Krista McFarland, Department of
Physiology and Neuroscience, 173 Ashley Avenue, Medical University of
South Carolina, Charleston, SC 29425. E-mail: mcfarlk{at}musc.edu.
| |
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TOP
ABSTRACT
Introduction
Compound via MeSH
