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The Journal of Neuroscience, January 15, 2000, 20(2):798-805
Fos Protein Expression and Cocaine-Seeking Behavior in Rats after
Exposure to a Cocaine Self-Administration Environment
Janet L.
Neisewander1,
David A.
Baker1,
Rita A.
Fuchs1,
Ly T. L.
Tran-Nguyen1,
Art
Palmer1, and
John F.
Marshall2
1 Department of Psychology, Arizona State University,
Tempe, Arizona 85287-1104, and 2 Department of
Psychobiology, University of California, Irvine, California
92697-4550
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ABSTRACT |
To examine neuronal activation associated with incentive motivation
for cocaine, cocaine-seeking behavior (operant responding without
cocaine reinforcement) and Fos expression were examined in rats exposed
to saline and cocaine priming injections and/or a self-administration
environment. Rats were first trained to self-administer cocaine or
received yoked saline administration ("control"). They then
received 21 daily exposures to either the self-administration
environment ("extinction") or a different environment ("no
extinction") without cocaine available. Extinction training, used to
decrease incentive motivation for cocaine elicited by the
self-administration environment, decreased cocaine-seeking behavior
elicited by both the environment and the cocaine priming injection.
Exposure to the self-administration environment enhanced Fos expression
in the no extinction group relative to control and extinction groups in
the anterior cingulate, basolateral amygdala, hippocampal CA1 region,
dentate gyrus, nucleus accumbens shell and core, and central gray area,
regardless of whether or not priming injections were given. The priming
injections enhanced Fos expression in the ventral tegmental area,
caudate putamen, substantia nigra pars reticulata, entorhinal cortex,
central amygdala, lateral amygdala, arcuate nucleus, and central gray
area, regardless of group. Thus, these changes likely reflect an
unconditioned effect from either cocaine or injection stress. The
priming injections also enhanced Fos expression in the anterior
cingulate, but only in cocaine-experienced groups, suggesting that this
enhancement reflects an experience-dependent motivational effect of the
priming injections. The results suggest that different neural circuits may be involved in the incentive motivational effects of cocaine-paired environmental stimuli versus priming injections and that the anterior cingulate may be part of a common pathway for both.
Key words:
cocaine; cocaine-seeking behavior; incentive motivation; self-administration; reinstatement; priming injections; cocaine
conditioning; cocaine-paired stimuli; limbic system; basal ganglia; amygdala; anterior cingulate; Fos protein expression; neuronal
activation; immediate early genes
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INTRODUCTION |
Cocaine and cocaine-paired
environmental stimuli produce incentive motivational effects that are
thought to contribute to craving and relapse (Stewart, 1983 ). This
phenomenon can be studied in animals using the
extinction-reinstatement model (Stewart, 1983; Markou et al., 1993;
Fuchs et al., 1998). In this model, animals are first trained to press
a lever for cocaine reinforcement. Subsequently, they are tested for
cocaine-seeking behavior (i.e., lever pressing without cocaine
reinforcement) elicited by environmental stimuli or priming injections
of cocaine.
Theories suggest that incentive motivational effects of cocaine and
cocaine-paired stimuli involve the same neural pathways (Stewart, 1983;
Robinson and Berridge, 1993); however, recent studies suggest this may
not be the case. First, the ability of cocaine-paired stimuli to
reinstate cocaine-seeking behavior or to serve as cocaine-conditioned
secondary reinforcers is disrupted by lesions of the basolateral
amygdala (BlA), whereas these lesions fail to alter cocaine
self-administration (Whitelaw et al., 1996; Meil and See, 1997). These
findings suggest that the BlA is involved in cocaine-seeking behavior
elicited by cocaine-paired stimuli but not cocaine itself. Second, it
is unclear whether dopamine plays a similar role in cocaine-seeking
behavior elicited by cocaine versus cocaine-paired stimuli.
Reinstatement of cocaine-seeking behavior by cocaine priming injections
is mimicked by administration of dopamine agonists and attenuated by
dopamine antagonists (Self et al., 1996; Weissenborn et al., 1996). The
latter suggests that dopamine neurotransmission is necessary for
cocaine-reinstated cocaine-seeking behavior. Furthermore,
cocaine-seeking behavior is reinstated by morphine infusions into the
ventral tegmental area (VTA) which, similar to cocaine priming
injections, enhance dopamine neurotransmission in the nucleus accumbens
(NAc) (Stewart, 1984). Also, changes in cocaine-reinstated
cocaine-seeking behavior during the course of withdrawal from a
self-administration regimen correspond to changes in extracellular
dopamine in the amygdala (Tran-Nguyen et al., 1998). However,
cocaine-seeking behavior elicited by cocaine-paired environmental
stimuli is sometimes (Gratton and Wise, 1994; Kiyatkin and Stein, 1994;
Di Ciano et al., 1998), but not always (Neisewander et al., 1996;
Bradberry and Rubino, 1998; Tran-Nguyen et al., 1998), accompanied by
an increase in extracellular dopamine in mesolimbic terminals. Thus, enhanced extracellular dopamine in these regions may not be necessary for cocaine-seeking behavior elicited by cocaine-paired stimuli.
Studies thus far have used techniques that are limited to examining a
specific region. The purpose of the present study was to identify other
brain regions that may be involved in cocaine-seeking behavior using
Fos protein expression as a marker for neuronal activation (Sharp et
al., 1993; Herrera and Robertson, 1996). Fos is the product of
c-fos, an immediate early gene transiently induced by
various stimuli, including cocaine (Graybiel et al., 1990; Young et
al., 1991) and cocaine-associated stimuli (Brown et al., 1992; Crawford
et al., 1995). Because Fos is a transcription factor, it may play a
role in long-lasting neuronal changes involved in incentive
motivational learning. Thus, the present study examined the effects of
exposure to a cocaine self-administration environment on
cocaine-seeking behavior and Fos protein expression in various limbic
and motor brain regions. In addition, this study examined whether these
effects were further enhanced by saline and cocaine priming injections.
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MATERIALS AND METHODS |
Animals and surgery. Male Sprague Dawley rats,
weighing 250-300 gm at the start of the experiment, were housed
individually in a temperature-controlled colony room with a 12 hr
reverse light/dark cycle (lights off at 6:00 A.M.). The housing
conditions and care of the animals were consistent with those specified
in the Guide for the Care and Use of Laboratory Animals
(Institute of Laboratory Animal Resources on Life Science, National
Research Council, 1996). Animals were acclimated to handling for at
least 5 d before surgical implantation of intravenous catheters.
Catheters were constructed from SILASTIC tubing (10 cm; inner diameter
0.012 × outer diameter 0.025 inches; Dow Corning, Midland, MI)
connected to a bent 22 gauge metal cannula encased within a plastic
screw connector (Plastics One, Roanoke, VA) at one end and affixed with
a small ball of aquarium sealant ~4 cm from the other end. Before
surgery, the animals received atropine sulfate (10 mg/kg, i.p.; Sigma,
St. Louis, MO) to decrease bronchial secretions. Ten minutes later, the
animals were anesthetized with sodium pentobarbital (50 mg/kg, i.p.;
Sigma). Incisions were made in clean shaven areas on the neck to
expose the jugular vein and on the head to expose the skull. A burrow
was then made subcutaneously from the incision on the neck to the
incision on the head, and the catheter was pulled through the burrow. A
small incision was made in the jugular vein, and the catheter was
inserted into the vein until flush with the ball of aquarium sealant.
The catheter was then secured to the vein with sutures on both sides of
the ball. The metal end of the catheter was secured to the skull using
dental acrylic cement and small anchor screws drilled into the skull.
The incisions were then sutured and treated with a topical antibiotic.
Throughout the experiment, the catheters were flushed daily with a
solution of 0.1 ml of bacteriostatic saline containing heparin sodium
(10 U/ml; Elkins-Sinn, Cherry Hill, NJ), streptokinase (0.67 mg/ml; Astra Pharmaceutical Products, Westerborough, MA), and ticarcillin disodium (66.67 mg/ml; SmithKline Beecham Pharmaceuticals, West Chester, PA) to maintain patency. Catheter patency was verified periodically throughout the experiment by administering 0.8 mg of
methohexital sodium (Eli Lilly & Co., Indianapolis, IN), a dose that
anesthetizes the animals briefly only when administered intravenously.
Self-administration training. Cocaine self-administration
training began 5 d after surgery and took place during the
animals' dark cycle. Animals were randomly assigned to groups that
received either response-contingent cocaine administration or an equal volume of saline contingent upon schedule completions made by an animal
in the cocaine group. During the initial phase of training, animals in
the cocaine group were placed on a fixed ratio (FR) 1 schedule of
cocaine reinforcement (0.5 mg/kg per 0.1 ml, i.v.) until they received
at least 10 cocaine infusions in 1 hr. Session length during this phase
varied between 2 and 6 hr depending on the animals' performance. After
reaching the criterion of 10 infusions/hr, the animals received 15 daily 2 hr sessions during which the schedule of reinforcement was
increased every 5 d from an FR 1 to a variable ratio (VR)
2, and then to a VR 5.
Training sessions took place in operant chambers that were housed
within ventilated sound-attenuating chambers. The operant chambers were
equipped with a lever, a cue light located 4 cm above the lever, a tone
generator (500 Hz, 10 dB above background), and a house light located
in the center of the back (Med Associates, St. Albans, VT). The
infusion pumps were connected via Tygon tubing to liquid swivels
(Instech, Plymouth Meeting, PA) above the chamber. The swivels were
connected to the screw cap of the catheter via Tygon tubing that ran
through a metal spring leash. Schedule completions by a cocaine animal
resulted in simultaneous activation of the house light, cue light, and
tone generator, followed 1 sec later by activation of the infusion
pump. The infusion was delivered over a 6 sec period, after which the
stimulus light, tone, and pump were inactivated simultaneously. The
house light remained activated for a 20 sec timeout period.
Saline-yoked controls received presentation of the same stimulus
complex contingent upon schedule completions by an animal in the
cocaine group, except that saline was infused rather than cocaine.
Responses by saline-yoked controls had no scheduled consequences. No
priming infusions were given during training. To facilitate acquisition
of cocaine self-administration (Carroll et al., 1981; de la Garza and
Johanson, 1987), access to food was restricted to 1 hr/d until the rats
received at least 10 infusions per day for 3 consecutive days. All
animals reached this criterion within 8 d of training and were
then given food ad libitum throughout the remainder of the
experiment, including the test day.
Extinction training. During self-administration training, an
association is presumably formed between the environmental stimuli and
the unconditioned effects of cocaine, such that exposure to the
environmental stimuli alone can elicit incentive motivation for
cocaine. Extensive extinction training, which refers to repeated presentation of the cocaine-paired environmental stimuli in the absence
of cocaine reinforcement, has been shown to decrease incentive salience
of cocaine-paired stimuli as reflected by a decrease in
stimuli-elicited self-reports of craving in humans (Childress et al.,
1988) and drug-seeking behavior in animals (Meil and See, 1997). Thus,
to manipulate incentive salience of the cocaine-paired environmental
stimuli in this study, animals were further assigned to groups that
either did or did not receive extinction training. Assignment to these
groups was counterbalanced for number of cocaine infusions received
during self-administration training. Extinction training began the day
after self-administration training was completed and consisted of 2 hr
exposures to the self-administration environment across 21 consecutive
days. The stimulus complex paired previously with cocaine infusions was
presented once every 5 min during the entire 2 hr period. Animals that
did not receive extinction training were transported to a room
different from the self-administration room and were placed into
Plexiglas holding cages. The holding cages were the same size as the
operant chambers, but the bedding and visual cues around the cages were
different from that of the operant chambers. Saline-yoked controls
received the same training as their paired experimental animal. All
animals were connected to a liquid swivel while they were confined to
their respective environments; however, the swivels were not connected
to a pump and no infusions were delivered.
Test for cocaine-seeking behavior. The day after extinction
training was completed, all animals were reintroduced to the
self-administration chambers and were tested for cocaine-seeking
behavior, defined as lever presses in the absence of cocaine
reinforcement. Animals within each group were randomly assigned to
groups tested for cocaine-seeking behavior and Fos protein expression
after exposure to the self-administration environment only or
after exposure to the self-administration environment and priming
injections. To examine whether changes in Fos protein expression were
caused by the act of lever pressing, an additional cocaine group
was included that did not receive extinction training and was exposed to the self-administration environment but without levers present. Thus, the design of this experiment yielded seven groups
(n = 5-7), as shown in Table
1.
Testing began by placing the animals into the operant chambers for a 90 min extinction test phase. Animals that were tested after exposure to
the self-administration environment only were then removed from the
chambers and killed within 30 min, with the exception of one
animal in the "no extinction" group that was killed 90 min after
testing. The remaining animals received an injection of saline (1 ml/kg, i.p.) to examine the effects of an injection on reinstatement of
cocaine-seeking behavior. One hour later, the animals received an
injection of cocaine hydrochloride (15 mg/kg, i.p.) to examine the
effects of a cocaine priming injection on reinstatement of
cocaine-seeking behavior. Ninety minutes later, the animals were
removed from the chambers and killed within 30 min. Every 5 min
throughout testing, the stimulus complex paired previously with
infusions was presented, except that the infusion pump was disconnected
from the swivel. The noncontingent presentation of the stimulus complex
was used to model craving and relapse that occurs in humans after
inadvertent exposure to cocaine-paired stimuli. Responses on the levers
were recorded but had no scheduled consequences.
Fos protein immunoreactivity. After behavioral testing,
animals were deeply anesthetized using sodium pentobarbital (50 mg/kg, i.p.) and transcardially perfused with ice-cold 0.1 M PBS, pH 7.4, followed by ice-cold 4%
paraformaldehyde in 0.1 M PBS, pH 7.4. The brains
were removed, post-fixed for 60 min, and then stored in 30% sucrose at
4°C. Coronal sections (40 µm) were collected at levels
corresponding to 1.6,  0.26, 2.56, and 5.6 mm from bregma (Paxinos
and Watson, 1986) using a freezing microtome. All of the tissue
sections used in this experiment were processed for Fos protein
expression at the same time. The tissue was rinsed in 0.1 M PBS (three times for 10 min each) and
incubated in 0.1 M PBS containing 5% normal goat
serum (NGS) (Vector Laboratories, Burlingame, CA) and 0.2% Triton
X-100 (Sigma) for 1 hr. Sections were then incubated for 48 hr at 4°C
in 0.1 M PBS containing anti-Fos rabbit
polyclonal antibody (1:20,000; Oncogene Science, Cambridge, MA) and
0.1% Triton X-100. The sections were then rinsed in 0.1 M PBS (six times for 5 min each) and incubated in
0.1 M PBS containing biotinylated goat
anti-rabbit IgG (1:200; Vector Laboratories) and 1% NGS for 1 hr. The
sections were rinsed again using 0.1 M PBS (three
times for 10 min each) and incubated with avidin-biotinylated peroxidase complex (ABC Elite kit; Vector Laboratories) for 1 hr. The
reaction was terminated by rinsing the tissue first in 0.1 M PBS (two times for 10 min each) and then in
stable peroxide substrate buffer (10 min; Pierce, Rockford, IL). The
tissue was then incubated in metal-enhanced 3,3'- diaminobenzidine
tetrahydrochloride (Pierce) for 3-6 min. This reaction was terminated
by rinsing the tissue in 0.1 M PBS (two times for
10 min each) and then 0.1 M Tris buffer (10 min).
Sections were then mounted onto gelatin-coated slides, dried, and
dehydrated before coverslipping. Fos immunoreactivity was quantified
using an Olympus Opticals (Tokyo, Japan) microscope (40×
magnification) attached to an image analysis system (Imaging Research
Inc., St. Catherines, Ontario, Canada). The shape of the
sampling area (rectangular or oval) was varied to best conform to the
structure being measured with the sampling area ranging between
0.05-0.135 mm2 (see Fig. 3 caption for
specific area used for each region). Objects within the sampling area
of a neuronal region that met size and optical density criteria set by
an observer blind to group assignments were counted as Fos-positive nuclei.
Statistical analyses. To examine the effect of extinction
training on cocaine-seeking behavior, a repeated measures ANOVA of
lever presses was conducted with self-administration history as a
between subjects factor and extinction training day as a repeated
measure. In addition, lever presses during extinction on the test day
were analyzed using a 2 × 2 factorial ANOVA with self-administration history and extinction training as between subjects
factors. There were no significant differences between saline-yoked
controls that received exposure to the operant chambers during
extinction training versus those that were placed into the alternate
environment on any of the dependent measures. Thus, the data from these
groups have been combined to comprise a single saline-yoked control
group. To examine the effects of the saline and cocaine priming
injections on lever presses, a repeated measures ANOVA was performed
with conditioning group (i.e., "controls," "extinction," and
"no extinction") as a between subjects factor and 30 min interval
as a repeated measure. To examine the effects of exposure to the
environment and the priming injections on Fos protein expression (i.e.,
Fos-positive nuclei/0.1 mm2) a 3 × 2 factorial ANOVA was performed for each region with conditioning group
(i.e., controls, extinction, and no extinction) and type of stimuli
exposure (i.e., exposure to the environment only vs exposure to the
environment and priming injections) as between subjects factors. In the
anterior cingulate and central gray area, the analyses indicated trends
(p < 0.166) toward an interaction that may have
been obscured by low power and strong main effects. Thus, to further
investigate possible group differences in these regions, a one-way
ANOVA was performed with each group as a level. Significant effects
were further analyzed using Fisher's LSD tests. To examine the
influence of lever pressing on Fos protein expression in regions
exhibiting a conditioning group effect, planned t tests were
performed comparing the no extinction-no lever group with the
extinction and no extinction groups.
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RESULTS |
Acquisition of cocaine self-administration
The number of self-administration training sessions varied
from 16 to 28 depending on the animals' performance during the initial
training phase. The mean ± SEM total amount of cocaine intake was
251.5 ± 14 mg/kg. The rats exhibited stable self-administration rates during the last 15 d of self-administration training that varied by <10% with a mean ± SEM daily intake of 13.9 ± 0.85 mg/kg.
Cocaine-seeking behavior
Extinction training abolished cocaine-seeking behavior (Fig.
1). The repeated measures ANOVA indicated
a significant group by time interaction
(F(1,340) = 8.78; p < 0.0001). Animals with a history of cocaine self-administration
exhibited significantly more lever presses than controls on days 1, 2, 4, 5, and 10 of extinction training (Fisher's LSD test;
p < 0.05). Thus, cocaine-seeking behavior extinguished
within 10 d of training because there were no significant
differences between the groups on days 11-21. Furthermore, the ANOVA
of lever presses on the test day indicated a significant cocaine
history by extinction training interaction
(F(1,33) = 18.23; p < 0.001). The cocaine-no extinction group exhibited significantly more
lever presses than all other groups (Fisher's LSD test;
p < 0.001), and there were no differences among the
other three groups.
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Figure 1.
Effect of extinction training on cocaine-seeking
behavior. Cocaine-seeking behavior is illustrated as nonreinforced
lever presses (±SEM) during the first 90 min on extinction training
days and on the test day. *p < 0.05, represents a
difference from other groups tested; Fisher's LSD test.
+p < 0.05, represents a difference from the
cocaine-extinction group tested on day 1; t test.
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Cocaine-seeking behavior was more robust after a 21 d withdrawal
period relative to a 1 d withdrawal period (Fig. 1), consistent with previous research (Tran-Nguyen et al., 1998). Animals with a
history of cocaine self-administration tested for the first time after
a 21 d withdrawal period exhibited significantly more lever
presses than animals tested after a 1 d withdrawal period, (t(23) = 2.42; p < 0.05).
The cocaine priming injection reinstated extinguished cocaine-seeking
behavior, and extinction training attenuated the effectiveness of the
priming injection on reinstatement. Figure
2 illustrates cocaine-seeking behavior
across all three test phases in animals that received the priming
injections. An ANOVA of lever presses during the extinction test phase
indicated a significant main effect of conditioning group
(F(2,15) = 20.6; p < 0.0001). The no extinction group was significantly different from both
the control and extinction groups (Fisher's LSD test;
p < 0.001). The saline primer did not alter
lever presses in any of the groups. In contrast, the cocaine priming
injection reinstated cocaine-seeking behavior in all groups, although
the effect was most robust in the no extinction group. A repeated
measures ANOVA of lever presses during the 30 min intervals before and
after the cocaine priming injection indicated a significant main effect
of time (F(1,15) = 7.6;
p < 0.05), suggesting that the cocaine primer
increased lever presses regardless of conditioning group. However,
planned comparisons of individual conditioning groups indicated that
only the no extinction group exhibited a significant increase in lever presses during the 30 min interval after the cocaine priming injection relative to the 30 min interval preceding the injection,
(t(5) = 2.47; p < 0.05). Furthermore, an ANOVA of lever presses during the 30 min
intervals after the cocaine priming injection indicated a significant
main effect of conditioning group
(F(2,15) = 4.0; p < 0.05). Post hoc comparisons indicated that the no extinction group was significantly different from the control group (Fisher's LSD
test; p < 0.05) but not different from the extinction
group.
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Figure 2.
Effect of saline and cocaine priming injections on
reinstatement of cocaine-seeking behavior in animals tested in all
three phases. Cocaine-seeking behavior is illustrated as nonreinforced
lever presses (±SEM) across 30 min intervals. *p < 0.05, represents a difference from all other groups; Fisher's LSD
test. +p < 0.05, represents a difference from
controls; Fisher's LSD test.  p < 0.05, represents a difference from previous 30 min interval; ANOVA main
effect.
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Fos protein immunoreactivity
Figure 3 illustrates the regions
analyzed, and Table 1 summarizes the results for each group in each
region. The priming injections enhanced Fos protein expression (Fig.
4), evident as a main effect in the VTA
(F(1,29) = 8.11; p < 0.01), dorsal caudate putamen (F(1,29) = 13.25; p < 0.001), substantia nigra pars reticulata (SNr) (F(1,29) = 34.13;
p < 0.001), entorhinal cortex
(F(1,29) = 8.64; p < 0.01), central amygdala (F(1,29) = 27.72; p < 0.001), lateral amygdala
(F(1,29) = 15.98; p < 0.001), arcuate nucleus (F(1,29) = 7.01; p < 0.05), and central gray area
(F(1,29) = 9.33; p < 0.005). In all of these regions, the priming injections enhanced Fos
protein expression, regardless of conditioning group.
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Figure 3.
Schematic representation of regions analyzed.
Numbers at the top left of each section
represent the distance (in millimeters) from bregma.
Numbers in the sections represent the regions (area in
square millimeters) analyzed as follows: 1, dorsal
caudate putamen, 0.135; 2, anterior cingulate, 0.135;
3, NAc core, 0.135; 4, NAc shell, 0.1;
5, ventral pallidum, 0.09; 6, lateral
septal nucleus, 0.09; 7, motor cortex, 0.125;
8, lateral amygdala, 0.09; 9, central
amygdala, 0.134; 10, basolateral amygdala, 0.134;
11, cortical amygdala, 0.09; 12, medial
amygdala, 0.09; 13, lateral hypothalamus, 0.09; 14,
arcuate nucleus, 0.05; 15, dentate gyrus, 0.1;
16, central gray area, 0.07; 17,
hippocampal CA3 region, 0.1; 18, hippocampal CA1 region,
19, entorhinal cortex, 0.125; 20, ventral
subiculum, 0.1; 21, substantia nigra pars compacta, 0.6;
22, substantia nigra pars reticulata, 0.07;
23, VTA, 0.07. Drawings were adapted from the Paxinos
and Watson atlas (1986).
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Figure 4.
Fos-positive nuclei/0.1 mm2
(±SEM) in brain regions that exhibited enhanced Fos protein expression
by the priming injections. The data are collapsed across conditioning
groups. *p < 0.05, represents a difference from
the respective group receiving exposure to the environment only;
Fisher's LSD test. Cpu, Caudate putamen;
EC, entorhinal cortex; CeA, central
amygdala; LA, lateral amygdala; Arc,
arcuate nucleus; CG, central gray area.
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In the substantia nigra pars reticulata, there was also enhanced Fos
protein expression attributable to previous cocaine experience and/or
withdrawal (Fig. 5). There was a main
effect of conditioning group in this region
(F(2,29) = 5.00; p < 0.05), and post hoc comparisons indicated that both the
extinction and no extinction groups exhibited a significant increase in
Fos-positive nuclei relative to the control group (Fisher's LSD test;
p < 0.05), regardless of whether they were exposed to
the environment only or to the environment and priming injections.
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Figure 5.
Fos-positive nuclei/0.1 mm2
(±SEM) in the substantia nigra pars reticulata demonstrating enhanced
Fos protein expression in rats with a history of cocaine
self-administration. The data are collapsed across groups receiving
exposure to the environment versus the environment and priming
injections. *p < 0.05, represents a difference
from controls; Fisher's LSD test.
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Exposure to the cocaine self-administration environment enhanced Fos
protein expression (Fig. 6), evident from
a main effect of conditioning group in the NAc core
(F(2,29) = 4.53; p < 0.05), NAc shell (F(2,29) = 4.05;
p < 0.05), BlA
(F(2,29) = 5.58; p < 0.01), dentate gyrus (F(2,29) = 3.23;
p < 0.05), hippocampal CA1 region
(F(2,29) = 3.20; p < 0.05), and anterior cingulate (F(2,29) = 4.29; p < 0.05) (Figure
7). In all of these regions, the no extinction group exhibited significantly more Fos-positive nuclei than
both the control and extinction groups (Fisher's LSD test; p < 0.05), and there were no significant differences
between the latter two groups. Also in the central gray area,
post hoc analysis of a one-way ANOVA with each group as a
separate level (F(5,34) = 3.73;
p < 0.01) indicated that, within the groups exposed to the cocaine self-administration environment only, the no extinction group exhibited significantly more Fos-positive nuclei than both the
control and extinction groups (Fisher's LSD test; p < 0.05), and there were no significant differences between the latter two groups. However, planned comparisons indicated no significant difference between the no extinction-no lever group and either the
extinction or no extinction groups in the central gray area and NAc
core, suggesting that some of the Fos protein expression in the no
extinction group may have been caused by the act of lever pressing. In
contrast, planned comparisons indicated a significant difference
between the extinction and the no extinction-no lever groups in the
NAc shell (t(17) = 2.20;
p < 0.05), BlA (t(17) = 1.71; p < 0.055), dentate gyrus
(t(17) = 2.02; p < 0.05), and hippocampal CA1 region
(t(17) = 2.09; p < 0.05) but no significant difference between the no extinction group and
the no extinction-no lever group. These findings suggest that the
increase in Fos protein expression in the no extinction group in these
regions was not simply caused by lever pressing behavior. Furthermore,
this pattern of changes across groups is consistent with a conditioned
enhancement of Fos protein expression elicited by the
self-administration environment.
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Figure 6.
Fos-positive nuclei/0.1 mm2
(±SEM) in brain regions that exhibited a pattern of changes consistent
with conditioned Fos protein expression by the self-administration
environment. The data are collapsed across groups receiving exposure to
the environment versus the environment and priming injections, except
in the central gray area, which illustrates the groups receiving
exposure to the environment only. *p < 0.05, represents a difference from all other groups; Fisher's LSD
test.
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Figure 7.
Fos-positive nuclei/0.1 mm2
(±SEM) in the anterior cingulate. *p < 0.05, represents a significant difference from other groups shown; Fisher's
LSD test.
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In the anterior cingulate, there was conditioned enhancement of Fos
protein expression, as well as enhancement by the priming injections,
but only in animals with a history of cocaine self-administration (Fig.
7). A one-way ANOVA performed with each group as a separate level that
indicated a significant main effect of group
(F(5,34) = 2.99; p < 0.05). Within the groups receiving exposure to the environment only,
Fos protein expression was greater in the no extinction group relative
to both the controls and extinction groups, consistent with conditioned
Fos protein expression described above. Furthermore, planned
comparisons indicated a marginally significant difference between the
extinction and the no extinction-no lever groups
(t(11) = 1.73; p < 0.056) but no significant difference between the no extinction group
and the no extinction-no lever group, suggesting that the increase in
Fos protein expression in the no extinction group was not simply caused
by lever pressing behavior. Within the groups receiving the priming
injections, Fos protein expression was greater in both the extinction
and no extinction groups relative to the control group (Fisher's LSD test; p < 0.05). It should also be noted that, within
the no extinction groups, there was no difference between the group
exposed to the environment only versus the group exposed to the
environment and priming injections, suggesting that exposure to either
the environment or the priming injections produced a maximal increase
in Fos protein expression.
There were no significant group differences in Fos protein expression
in the ventral pallidum, substantia nigra pars compacta, motor cortex,
lateral septal nucleus, lateral hypothalamus, medial amygdala,
cortical amygdala, hippocampal CA3 region, or ventral subiculum,
although there was a trend toward a significant conditioning group
effect in the latter region (F(2,29) = 2.99; p < 0.07).
| |
DISCUSSION |
Extinction training abolished cocaine-seeking behavior elicited by
the self-administration environment, because responding in animals with
a history of cocaine self-administration declined to saline-yoked
control levels by day 11 of extinction training (Fig. 1). This finding
suggests that extinction training decreased the incentive salience of
the self-administration environment. The cocaine priming injection
reinstated responding in all groups initially, but maintained
responding throughout the cocaine reinstatement test phase only in
animals with a history of cocaine self-administration that did not
undergo extinction training (no extinction group). Extinction training
attenuated reinstatement of cocaine-seeking behavior by the cocaine
primer because animals with a history of cocaine self-administration
and extinction training (extinction group) exhibited an intermediate
level of responding after the cocaine priming injection that did not
differ from the controls or the no extinction groups (Fig. 2). The
finding that responding was less robust in the extinction group
relative to the no extinction group during this test phase suggests
that some of the reinstatement of responding in the no extinction group
may have been attributable to cocaine-induced recovery of incentive
motivational effects of the environmental stimuli. Thus, the cocaine
priming injection may reinstate incentive motivational effects of the
self-administration environment.
Regarding possible neural substrates of these behavioral effects, four
different patterns of Fos protein expression were observed. First, the
priming injections enhanced Fos protein expression, regardless of
conditioning group in the VTA, caudate putamen, SNr, entorhinal cortex,
central amygdala, lateral amygdala, arcuate nucleus, and central gray
area (Fig. 4). The magnitude of Fos protein expression did not differ
across conditioning groups, suggesting that the effect was likely
caused by unconditioned effects of cocaine or stress associated with
the injection procedure. Because many of these regions are innervated
by dopamine neurons, Fos protein expression in these regions may be
caused by increased dopamine receptor stimulation. In any case, it is
unclear whether these changes are involved in cocaine-seeking behavior
because the effects were observed in the control and extinction groups.
A second distinct pattern of Fos protein expression occurred in the
SNr. In addition to the effect of priming injections mentioned above,
there was also an effect of conditioning group, indicating that animals
with a history of cocaine self-administration exhibited enhanced Fos
protein expression relative to controls, regardless of whether they
received extinction training (Fig. 5). This effect is not likely
related to cocaine-seeking behavior because it was observed in the
extinction group exposed to the environment only that did not engage in
cocaine-seeking behavior. Thus, the effect likely reflects enhanced
reactivity resulting from cocaine experience and/or cocaine withdrawal.
A third pattern of Fos protein expression consistent with conditioned
enhancement by the cocaine self-administration environment was observed
in the NAc core, NAc shell, BlA, hippocampal CA1 region, dentate gyrus,
and central gray area (Fig. 6). In all of these regions, enhanced Fos
protein expression was observed in the no extinction group relative to
controls and extinction groups, regardless of whether the animals
received priming injections. This pattern of changes in Fos protein
expression corresponds to the pattern of cocaine-seeking behavior in
these groups, suggesting that these regions play some role in the
behavior. Furthermore, Fos protein expression in the no extinction-no
lever group was significantly higher than the extinction group, but not
different from the no extinction group, in the anterior cingulate, NAc
shell, BlA, hippocampal CA1 region, and dentate gyrus. This suggests that enhanced Fos protein expression in these regions was not caused by
lever pressing per se.
A fourth distinct pattern of Fos protein expression was observed in the
anterior cingulate in which, in addition to conditioned enhancement by
the self-administration environment, there was also enhancement by the
priming injections but only in groups with a history of cocaine
self-administration (Fig. 7). Thus, all groups exhibiting
cocaine-seeking behavior on the test day also exhibited enhanced Fos
protein expression in the anterior cingulate. The magnitude of the
enhanced Fos protein expression was similar in the no extinction
groups, regardless of priming injections, and was also similar in
groups receiving the priming injections, regardless of extinction
training; this suggests that a maximal effect on Fos protein expression
occurred after exposure to either type of stimuli. Importantly,
enhanced Fos protein expression in the anterior cingulate by the
priming injections was not likely caused by stress associated with the
injection procedure because it was not observed in the controls given
priming injections. Furthermore, this effect was not simply caused by
lever pressing because the no extinction-no lever group also exhibited
enhanced Fos protein expression relative to the extinction group.
The changes in Fos protein expression in the anterior cingulate, NAc
shell, BlA, hippocampal CA1 region, and dentate gyrus described above
suggest that these regions likely play a role in cocaine-seeking
behavior elicited by the self-administration environment apart from the
act of lever pressing. Indeed, these brain regions have been implicated
in various functions (e.g., motivation, emotion, memory, attention, and
expectancy) (for review, see Aggleton, 1992; Kalivas and Barnes, 1993;
Devinsky et al., 1995; Schultz, 1998) that contribute to
cocaine-seeking behavior. Furthermore, previous research offers
converging lines of evidence to support the hypothesis that the
amygdala and anterior cingulate are involved in the incentive
motivational effects of cocaine-paired stimuli. For instance,
cocaine-paired stimuli elicit conditioned locomotion and conditioned
place preference, as well as enhanced Fos protein expression in the
anterior cingulate and amygdala in rats (Brown et al., 1992; Crawford
et al., 1995). Furthermore, imaging studies in human cocaine abusers
have demonstrated that cocaine-paired stimuli increase self-reports of
cocaine craving and metabolic activity in the anterior cingulate and
amygdala (Grant et al., 1996; Maas et al., 1998; Childress et al.,
1999). It is unlikely that these effects are attributable to
performance of a particular behavior or to cognitive processes involved
in response-contingent procurement of drug because these factors vary
across studies. Common to all of these studies, however, are incentive
motivational effects of cocaine-paired stimuli, as reflected by
cocaine-seeking behavior, cocaine-conditioned place preference, and
cocaine craving. Furthermore, previous research suggests that the BlA
is necessary for the ability of cocaine-paired stimuli to reinstate
cocaine-seeking behavior or to serve as cocaine-conditioned secondary
reinforcers (Whitelaw et al., 1996; Meil and See, 1997).
The lack of a change in Fos protein expression in some of the brain
regions examined must be interpreted with caution because it does not
preclude the possibility that these regions are involved in
cocaine-seeking behavior. Furthermore, the present study failed to
observe changes in Fos protein expression by cocaine and cocaine-paired stimuli that have been observed previously. For instance, previous studies examining Fos protein expression by cocaine-paired stimuli have
found enhanced Fos protein expression in the lateral septal nucleus but
have not found changes in the NAc or hippocampus (Brown et al., 1992;
Crawford et al., 1995). Furthermore, previous studies have reported
increased Fos protein expression in the NAc after acute cocaine
administration that exhibits tolerance after repeated administration
(Graybiel et al., 1990; Brown et al., 1992; Hope et al., 1992;
Moratalla et al., 1996). These discrepancies may be attributable to
differences in previous cocaine experience, cocaine challenge dose,
amount of handling, length of drug-free period before testing, and/or
anatomical subregion analyzed.
The overall pattern of Fos protein expression was different in animals
exhibiting cocaine-seeking behavior elicited by the self-administration
environment versus priming injections, suggesting that these stimuli
activate different neural substrates. Based on this finding, we
hypothesize that different neural circuits may be involved in the
incentive motivational effects of these stimuli for cocaine.
Importantly, this hypothesis is contrary to some of the leading
theories of incentive motivation for drug that suggest the same
mechanisms are involved for both types of stimuli (Stewart, 1983;
Robinson and Berridge, 1993). We further hypothesize that a limbic
circuitry is involved in incentive motivation for cocaine elicited by
cocaine-paired stimuli. Moreover, the anterior cingulate may be part of
a final common pathway for cocaine-seeking behavior elicited by
cocaine-paired stimuli and priming injections given that Fos protein
expression in this region was associated with cocaine-seeking behavior
elicited by either type of stimuli. Further research using procedures
that directly manipulate these brain regions is needed to examine these
hypotheses. This line of research is important because understanding
the neural mechanisms involved in incentive motivation for cocaine has
implications for developing and evaluating treatments for cocaine dependence.
| |
FOOTNOTES |
Received June 23, 1999; revised Oct. 4, 1999; accepted Oct. 28, 1999.
This work was supported by National Institute on Drug Abuse Grants
DA11064 (J.L.N.), DA05816 (L.T.L.T.), and DA10249 (J.F.M.). We thank
Ron McPherson for his expert technical assistance and Dr. Miles
Orchinik for the use of his image analysis system.
Correspondence should be addressed to Dr. Janet Neisewander, Department
of Psychology, Arizona State University, P.O. Box 871104, Tempe, AZ
85287-1104. E-mail: janet.neisewander{at}asu.edu.
| |
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TOP
ABSTRACT
INTRODUCTION
