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THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics
JPET 303:1216–1226, 2002
Vol. 303, No. 3
38950/1026542
Printed in U.S.A.
Cocaine Is Self-Administered into the Shell but Not the Core of
the Nucleus Accumbens of Wistar Rats
ZACHARY A. RODD-HENRICKS, DAVID L. MCKINZIE, TING-KAI LI, JAMES M. MURPHY, and WILLIAM J. MCBRIDE
Institute of Psychiatric Research and Department of Psychiatry (Z.A.R.-H., D.L.M., J.M.M., W.J.M.), and Departments of Medicine (T.-K.L.) and
Biochemistry (W.J.M.), Indiana University School of Medicine, Indianapolis, Indiana; and Department of Psychology (J.M.M.), Purdue School of
Science, Indiana University-Purdue University at Indianapolis, Indianapolis, Indiana
Received May 15, 2002; accepted July 16, 2002
The intracranial self-administration (ICSA) technique has
been hypothesized to be a valid procedure to identify specific
brain regions involved in the initiation of response-contingent behaviors for the delivery of a reinforcer (Bozarth and
Wise, 1980; Goeders and Smith, 1987; McBride et al., 1999).
Studies using the ICSA procedure have successfully isolated
discrete brain regions where opioids (Bozarth and Wise,
1981; Devine and Wise, 1994), amphetamine (Hoebel et al.,
1983; Phillips et al., 1994a), acetaldehyde (Rodd-Henricks et
al., 2002), and ethanol (Gatto et al., 1994; Rodd-Henricks et
al., 2000) produce their reinforcing effects. Previous ICSA
research indicated that cocaine was self-administered into
the medial prefrontal cortex (mPFC; 50 –90 pmol), but not in
the nucleus accumbens (Acb) or the ventral tegmental area
(VTA) (Goeders and Smith, 1983). Additional research reported that cocaine self-administration in the mPFC was
This study was supported in part by National Institute on Alcohol Abuse
and Alcoholism Grants AA07462, AA00207, AA12262, and AA10721.
Article, publication date, and citation information can be found at
http://jpet.aspetjournals.org.
DOI: 10.1124/jpet.102.038950.
ister. The data indicate that rats with placements within the
AcbSh readily self-administered 800 to 1600 pmol of cocaine/
100 nl and responded significantly more on the active than
inactive lever. These subjects also decreased responding on
the active lever when aCSF was substituted for cocaine and
reinstated responding on the active lever when cocaine was
reintroduced. Coinfusion of the D2-like receptor antagonist
sulpiride inhibited cocaine self-infusion in the AcbSh. In contrast to the AcbSh data, rats failed to self-administer any tested
dose of cocaine into the AcbC or areas ventral to the AcbSh.
These findings suggest that the AcbSh is a neuroanatomical
substrate for the reinforcing effects of cocaine and that activation of D2-like receptors is involved.
blocked by presynaptic lesioning of dopamine (DA) neurons,
or coadministration of the D2 receptor antagonist sulpride
(Goeders and Smith, 1986), but not by coadministration of
D1, muscarinic-cholinergic, or ␤-noradrenergic receptor antagonists (Goeders et al., 1986). Thus, cocaine self-administration in the mPFC was dependent upon an intact DA system and activation of D2 receptors (Goeders and Smith,
1986).
In contrast to the cocaine ICSA reports, numerous studies
have shown that the Acb mediates i.v. cocaine self-administration. Nonspecific kainic acid lesions of the Acb decrease
i.v. cocaine self-administration (Zito et al., 1985). Lesioning
of DA projections to the Acb by 6-hydroxydopamine extinguished i.v. cocaine self-administration (Roberts et al., 1977,
1980; Pettit et al., 1984) and blocked cocaine-induced locomotor activation (Kelly et al., 1975; Le Moal and Simon,
1991). Direct microinjections of DA antagonists into the Acb
resulted in compensatory increases in i.v. cocaine self-administration (Maldonado et al., 1993; McGregor and Roberts,
1993; Phillips et al., 1994b). Self-administration (i.v.) of cocaine directly increases neuronal activity (Carelli and Dead-
ABBREVIATIONS: ICSA, intracranial self-administration; mPFC, medial prefrontal cortex; Acb, nucleus accumbens; VTA, ventral tegmental area;
DA, dopamine; AcbSh, nucleus accumbens shell; AcbC, nucleus accumbens core; aCSF, artificial cerebral spinal fluid; EMIT, electrolytic
microinfusion transducer; ANOVA, analysis of variance.
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ABSTRACT
The rewarding properties of cocaine have been postulated to
be regulated, in part, by the mesolimbic dopamine system.
However, the possibility that the rewarding properties of cocaine are mediated by direct activation of this system has
yielded contradictory findings. The intracranial self-administration technique is used to identify specific brain regions involved
in the initiation of response-contingent behaviors for the delivery of a reinforcer. The present study assessed whether adult
Wistar rats would self-administer cocaine directly into the nucleus accumbens shell (AcbSh) and core (AcbC). For each
subregion, subjects were placed in standard two-lever operant
chambers and randomly assigned to one of five groups for each
site that were given either artificial cerebrospinal fluid (aCSF), or
400, 800, 1200, or 1600 pmol of cocaine/100 nl to self-admin-
Self-Infusion of Cocaine into Accumbens
Materials and Methods
Animals
Experimentally naive female Wistar rats (Harlan, Indianapolis,
IN), weighing 250 to 320 g at time of surgery, were used. Rats were
double-housed upon arrival and maintained on a 12-h reverse light/
dark cycle (lights off at 9:00 AM). Female rats were used because
they maintain their body size better than males, which allows for
more accurate cannula placements. Although not systematically
studied, the estrus cycle did not seem to have a significant effect on
ICSA behavior in the present study or in previous studies (Gatto et
al., 1994; Ikemoto et al., 1997; Rodd-Henricks et al., 2000, 2002), as
indicated by no obvious fluctuations in ICSA behavior in rats given
similar doses of the same agent for two or more sessions conducted
every other day. Food and water were freely available except in the
test chamber. Protocols were approved by the institutional animal
care and use committee and are in accordance with the guidelines of
the Institutional Care and Use Committee of the National Institute
on Drug Abuse, National Institutes of Health, and the Guide for the
Care and Use of Laboratory Animals (National Research Council,
1996).
Data for rats that did not complete all experimental test sessions
were eliminated from the analyses. The number of animals indicated
for each experiment represents approximately 95% of the total number that underwent surgery; about 5% of the animals were not
included for analyses mainly due to the loss of the guide cannula
before completion of all experimental sessions. The data for these
animals were not used because their injection sites could not be
verified due to the loss of the guide cannula.
Drug and Vehicle
The artificial cerebrospinal fluid (aCSF) consisted of 120.0 mM
NaCl, 4.8 mM KCl, 1.2 mM KH2PO4, 1.2 mM Mg SO4, 25.0 mM
NaHCO3, 2.5 mM CaCl2, and 10.0 mM d-glucose. Cocaine hydrochloride (National Institute on Drug Abuse) and the D2/D3 DA receptor
antagonist sulpiride (Sigma-Aldrich, St. Louis, MO) were dissolved
in the aCSF solution. When necessary, 0.1 M HCl or 0.1 M NaOH
was added to the solutions to adjust pH levels to 7.4 ⫾ 0.1.
Apparatus
The test chambers (30 ⫻ 30 ⫻ 26 cm; width ⫻ height ⫻ depth)
were situated in a sound-attenuating cubicle (64 ⫻ 60 ⫻ 50 cm;
Coulbourn Instruments, Allentown, PA) and illuminated by a dim
house light during testing. Two identical levers (3.5 ⫻ 1.8 cm) were
mounted on the same wall of the test chamber, 15 cm above a grid
floor, and separated by 12 cm. Levers were raised to this level to
avoid inadvertent bar pressing and to reduce responses as a result of
general locomotor activation. Directly above each lever was a row of
three different-colored cue lights. The light (red) to the far right over
the active bar was illuminated during resting conditions and was
extinguished when the active lever was pressed. A desktop computer
equipped with an operant control system (L2T2 system; Coulbourn
Instruments) recorded the data and controlled the delivery of infusate in relation to lever response.
An electrolytic microinfusion transducer (EMIT) system (Bozarth
and Wise, 1980) was used to control microinfusions of drug or vehicle. Briefly, two platinum electrodes were placed in an infusate-filled
cylinder container (28 mm in length ⫻ 6 mm in diameter) equipped
with a 28-gauge injection cannula (Plastics One, Roanoke, VA). The
electrodes were connected by a spring-coated cable (Plastics One)
and a swivel (model 205; Mercotac, Carlsbad, CA) to a constant
current generator (MNC, Shreveport, LA), which delivered 6 ␮A of
quiescent current and 200 ␮A of infusion current between the electrodes. Depression of the active lever delivered the infusion current
for 5 s, which led to the rapid generation of H2 gas (increasing the
pressure inside the airtight cylinder), and, in turn, forcing 100 nl of
the infusate through the injection cannula. EMIT units were calibrated weekly by sampling after a 60- and 5-s infusion test. During,
the 5-s infusion and additional 5-s time-out period, the house light
and right cue light (red) were extinguished and the left cue light
(green) over the active lever flashed on and off at 0.5-s intervals. A
55-s time-out period was used in one experiment to provide evidence
that responding on the active lever was not solely a result of reflexive
responding (Goeders and Smith, 1987). The conditions for the 55-s
time-out were the same as the 5-s time-out period, except for the
duration.
Animal Preparation
While under halothane anesthesia, a unilateral 22-gauge guide
cannula (Plastics One) was stereotaxically implanted in the right
hemisphere of each subject, aimed 1.0 mm above the target region.
Coordinates (Paxinos and Watson, 1986) for placements into the
AcbSh were 1.7 mm anterior to bregma, 2.4 mm lateral to the
midline, and 7.5 mm ventral from the surface of the skull at a 10°
angle to the vertical. Coordinates for placements into the AcbC were
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wyler, 1994) and DA levels in the Acb (Wise et al., 1995;
Hemby et al., 1997). Additionally, the initiation of cocaine
self-infusions is predicated upon the extracellular DA level in
the Acb (Wise et al., 1995; Peoples and West, 1996). Moreover, neural firing of Acb cells may reflect changes in cocaine
levels and contribute to the temporal spacing of cocaine selfadministration (Nicola and Deadwyler, 2000). Furthermore,
research has indicated that cells within the Acb display distinct, independent firing patterns in response to i.v. cocaine
administration compared with water and food reinforcements (Carelli et al., 2000).
In the initial cocaine ICSA study (Goeders and Smith,
1983), placements seemed to be mainly within the AcbC.
However, since the publication of the Goeders and Smith
(1983) study, several reports have demonstrated functional
differences between the two subregions of the Acb with respect to DA neurotransmission, psychostimulant-induced DA
transmission, and behavioral effects of local application of
psychostimulants. For example, cocaine-induced locomotor
activity is reduced by microinjections of NMDA antagonists
directly into the AcbC, but not into the AcbSh (Pulvirenti et
al., 1994), whereas i.v. administration of cocaine, morphine,
and amphetamine preferentially increase extracellular DA in
the AcbSh compared with the AcbC (Pontieri et al., 1995).
Similarly, i.p.-administered cocaine significantly increased
DA levels in the AcbSh, whereas only a slight increase was
observed in the AcbC (Hedou et al., 1999). Additionally, cocaine-induced increases of extracellular DA levels within the
AcbSh were associated with an increase in locomotor activity
(Hedou et al., 1999), and the AcbSh is also more responsive to
systemically administered D1 dopamine receptor agonists
and antagonists than the AcbC when observing acetylcholine
output (Consolo et al., 1999). Last, evidence for an important
difference between the accumbens subregions in the ability
to support self-administration behavior emerges from a study
reporting that the ICSA of nomifensine, a DA uptake inhibitor, occurred in the AcbSh, but not in the AcbC (Carlezon et
al., 1995).
The present study was undertaken to examine the ICSA of
cocaine into the AcbSh and AcbC and to determine the effects
of a D2/D3 receptor antagonist on this ICSA behavior. The
hypothesis to be tested is that the AcbSh is a site supporting
the reinforcing effects of cocaine and these effects are mediated in part by D2/D3 receptors.
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1.7 mm anterior to bregma, 2.7 mm lateral to the midline, and 6.5
mm ventral from the surface of the skull at a 10° angle to the
vertical. Between experimental sessions, a 28-gauge stylet was
placed into the guide cannula and extended 0.5 mm beyond the tip of
the guide. After surgery, all rats were individually housed and allowed to recover for 7 to 10 days. Animals were handled for at least
5 min daily after the fourth recovery day. Subjects were not acclimated to the test chamber before the commencement of data collection nor were they trained on any other operant paradigm.
General Test Condition
Treatment Procedures
Dose Response. Animals were randomly assigned to one of five
groups per injection site (shell, n ⫽ 10 –12/group; core, n ⫽ 6 –7/
group). A vehicle group received infusions of 100 nl of aCSF for all
seven sessions. The other groups received infusions of 400, 800, 1200,
or 1600 pmol of cocaine/100 nl (4, 8, 12, or 16 mM cocaine) for the
first four sessions, followed by infusions of 100 nl of aCSF during the
fifth and sixth sessions; in the seventh session, rats were allowed to
respond for their originally assigned infusate. A total of 110 rats
completed the training procedure. Thirteen rats from various groups
(aCSF, n ⫽ 2; for cocaine: 400 pmol, n ⫽ 3; 800 pmol, n ⫽ 3; 1200
pmol, n ⫽ 2; and 1600 pmol, n ⫽ 3) had placements ventral to the
AcbSh. For the rats with placements ventral to the AcbSh, data from
the 400 to 1600 pmol of cocaine/100 nl of aCSF groups were collapsed
across infusate groups and served as neuroanatomical controls.
Sulpiride Coadministration. A separate group of rats with
guide cannulae aimed at the AcbSh, self-administered 1200 pmol of
cocaine/100 nl for the initial four sessions (n ⫽ 9). During the fifth
and sixth sessions, 400 pmol of sulpiride/100 nl was added to the
cocaine solution, and the rats were allowed to self-administer the
combined solution. On the seventh and eighth sessions, rats were
given only the 1200 pmol of cocaine/100 nl. Another group of rats
(n ⫽ 8) was given 400 pmol/100 nl of sulpiride alone for the entire
eight sessions.
Extended Time-Out. An additional control experiment was conducted to determine whether extending the time-out period between
infusions would alter self-administration of cocaine into the AcbSh.
Reflexive responding, particularly with psychostimulants, may underlie the self-infusion of cocaine into the AcbSh (Goeders and Smith,
1987). Therefore, a recommended control experiment is to extend the
interinfusion interval by increasing the time-out period (Goeders and
Smith, 1987). Thus, during this experiment, depression of the active
lever (fixed ratio 1 schedule of reinforcement) caused the delivery of
a 100-nl bolus of infusate over a 5-s period followed by a 55-s time-out
period. During both the 5-s infusion period and 55-s time-out period,
responses on the active lever were recorded but did not produce
Results
Placements. Cannula placements in and around the AcbC
and AcbSh are depicted in Fig. 1. Cannula placements outside the Acb were ventral to the AcbSh. Primary locations of
the cannula tips were between ⫹1.0 and ⫹1.6 mm relative to
bregma. Additionally, approximately 95% of all subjects successfully completed the experimental paradigms and had
cannula tip locations within the AcbC, AcbSh, or area immediately ventral to the AcbSh. Photomicrographic images represent the cannula tract and angle of descent for placements
in the AcbC, AcbSh, and ventral to the AcbSh (Fig. 1, left).
The right side of Fig. 1 shows the distribution of placements.
Dose Response. A select range of cocaine concentrations
supported response-contingent behaviors in the AcbSh. For
rats receiving infusions into the AcbSh, an ANOVA on the
average number of infusions (Fig. 2) received during the
initial four test days (acquisition) revealed a significant effect
of dose (F4,48 ⫽ 3.53; p ⫽ 0.013). Post hoc comparisons
(Tukey’s b; p ⬍ 0.05) indicated that the 400-, 800-, 1200-, and
1600-pmol groups received significantly more infusions than
the aCSF controls. Additionally, the post hoc comparisons
revealed that the 1200-pmol group received significantly
more infusions than the 400-pmol group. In contrast, an
ANOVA performed on the average number of infusions received during acquisition by rats self-administering into the
AcbC (Fig. 2) revealed no significant effect of dose (F4,29 ⫽
1.65; p ⫽ 0.19). Although not included in any of the analyses,
rats with cannulae implanted ventral to the AcbSh (Fig. 2)
received a comparable amount of infusions as those administering aCSF into either the AcbSh or AcbC.
Extinction and Reinstatement. For subjects receiving
infusions into the AcbSh, a repeated measures ANOVA performed on the number of infusions across the seven sessions
revealed that there was a significant effect of dose (F4,48 ⫽
4.5; p ⫽ 0.004), an effect of session (F6,288 ⫽ 6.3; p ⬍ 0.001),
and a session ⫻ dose interaction (F24,288 ⫽ 3.9; p ⬍ 0.001).
Decomposing the interaction term by holding sessions constant resulted in individual ANOVAs for each acquisition
session being performed. The analysis revealed a significant
effect of dose for each session in which cocaine was selfadministered (sessions 1– 4 and 7; F4,48 values ⬎ 2.65; p
values ⬍ 0.045). Post hoc comparisons revealed that during
session 4, all four cocaine groups received significantly more
infusions than the aCSF group, and the 800- and 1200-pmol
cocaine groups received significantly more infusions than the
400-pmol group (Fig. 3). In contrast, when aCSF was substituted for cocaine in sessions 5 and 6, there were no significant differences between the dose groups on the amount of
infusions administered (F4,48 values ⬍ 2.19; p values ⬎ 0.09).
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For testing, subjects were brought to the testing room, the stylet
was removed, and the injection cannula was screwed into place. Rats
were then placed in the operant chamber. To avoid trapping air at
the tip of the injection cannula, the infusion current was delivered
for 5 s during insertion of the injector, which extended 1.0 mm
beyond the tip of the guide. Depression of the “active lever” on a fixed
ratio 1 schedule of reinforcement caused the delivery of a 100-nl
bolus of infusate over a 5-s period followed by a 5-s time-out period.
During both the 5-s infusion period and 5-s time-out period, responses on the active lever did not produce further infusions, but
were recorded. Responses on the “inactive lever” were recorded, but
did not result in infusions. The assignment of active and inactive
lever with respect to the left or right position was counterbalanced
among subjects. However, the active and inactive levers remained
the same for each rat throughout the experiment. No shaping technique was used to facilitate the acquisition of lever responses. The
number of infusions and responses on the active and inactive bar
were recorded throughout each session. The duration of each operant
session was 4 h and sessions occurred every 48 h.
further infusions. Responses on the inactive lever were recorded but
did not result in infusions. Under these conditions, a group of rats
(n ⫽ 8) received infusions of 1200 pmol of cocaine/100 nl of aCSF for
11 consecutive sessions.
Histology. At the termination of the experiment, 1% bromphenol
blue (0.5 ␮l) was injected into the infusion site. Subsequently, the
animals were given a fatal dose of Nembutal and then decapitated.
Brains were removed and immediately frozen at ⫺70°C. Frozen
brains were equilibrated at ⫺15°C in a cryostat microtome and then
sliced into 40-␮m sections. Sections were then stained with cresyl
violet and examined under a light microscope for verification of the
injector site using the rat brain atlas of Paxinos and Watson (1986).
Self-Infusion of Cocaine into Accumbens
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When cocaine was restored in session 7, the 400-, 800-, and
1200-pmol cocaine groups showed an increase (Fig. 3) in the
number of infusions during session 7 compared with session
6 (F1,9 values ⬎ 11.51; p values ⬍ 0.008), whereas the 1600pmol cocaine group did not. Additionally, an ANOVA performed on the number of infusions received during session 7
revealed a significant effect of dose (F4,48 ⫽ 2.92; p ⫽ 0.03).
Post hoc comparisons indicated that all cocaine infusate
groups were significantly higher than the aCSF group and
that the 1200-pmol group received significantly more infusions than the 1600-pmol group (Tukey’s b; p ⬍ 0.05). Of
particular interest, the 400-pmol group displayed a more
than 3-fold increase (F3,27 ⫽ 7.93; p ⬍ 0.001) in the number
of infusions received during session 7 (43 ⫾ 6) than during
session 4 (14 ⫾ 3).
Patterns of Infusions. The temporal patterns of infusions (in 30-min blocks) by rats given aCSF, 400 or 1200 pmol
of cocaine into the AcbSh or 1200 pmol of cocaine into the
AcbC are depicted in Fig. 4. Throughout all sessions, rats
self-administering aCSF into the AcbSh closely resembled
the infusion pattern for rats that were self-administering
1200 pmol of cocaine into the AcbC. For the group selfinfusing 1200 pmol of cocaine into the AcbSh, approximately
2 h into the first session, this group diverged from the other
groups and displayed signs of acquiring self-administration
(Fig. 4, top). During session 4, rats readily administered 1200
pmol of cocaine/100 nl within the first 30-min block maintained a higher level of responding throughout the session
and displayed an increase in responding during the last
30-min block. During the second aCSF substitution session
(session 6), the number of infusions was low and most were
administered during the initial two 30-min periods. When
1200 pmol of cocaine was restored in session 7, rats rapidly
reinstated self-administration behavior and exhibited an infusion pattern similar to acquisition session 4, except for the
high number of infusions in the last 30-min period. With
regard to the group that was self-infusing 400 pmol of cocaine/100 nl into the AcbSh, the pattern of self-administration during session 1 and 4 only slightly deviated from that
observed with aCSF self-administration with higher infu-
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Fig. 1. Left, photomicrograph for a representative rat with an injection site in either the AcbC (top), AcbSh (middle), or ventral to the AcbSh (bottom).
Right, injection sites for all ICSA of cocaine experiments. Circles represent placements for animals in the present experiment according to the atlas
of Paxinos and Watson (1986). Placements are from representative subjects with overlapping placements not illustrated.
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Rodd-Henricks et al.
Fig. 2. Depicted is the average number of infusions (mean ⫾ S.E.M.)
across the initial four sessions (acquisition) as a function of infusate concentration (aCSF, or 400, 800, 1200, or
1600 pmol of cocaine/100 nl of aCSF)
and cannula placement (ventral to
AcbSh, AcbSh, and AchC). ⴱ, p ⬍ 0.05,
Tukey’s test versus aCSF. ⫹, p ⬍ 0.05,
Tukey’s test versus aCSF and 400
pmol of cocaine/100 nl of aCSF.
sions occurring mainly during the first six 30-min blocks.
When cocaine was restored in session 7, rats in the 400-pmol
group displayed higher levels of infusions compared with
session 4 throughout the course of the session (Fig. 4, middle).
Lever Discrimination. Lever discrimination was determined by performing a separate analysis on each infusate
group (Figs. 5 and 6). Throughout the sessions, the number of
responses on the active and inactive lever did not differ in
rats self-administering aCSF into the AcbSh (p ⫽ 0.67). Rats
self-administering either 800 or 1200 pmol of cocaine into the
AcbSh discriminated between the active and inactive lever
during sessions 2, 3, 4, and 7 (F1,9 values ⬎ 42.5; p values ⬍
0.0001), whereas the 400- and 1600-pmol groups discrimi-
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Fig. 3. Depicted is the number of infusions (⫾S.E.M.) received during
sessions 4 through 7 for rats self-administering cocaine into the AcbSh.
During the fourth session (acquisition), the 400-, 800-, 1200-, and 1600pmol/100-nl infusate groups showed elevated levels of infusions compared with aCSF controls, and the 1200-pmol group self-infused at a
significantly higher level than the 400- and 1600-pmol group, and the
800-pmol group received significantly more infusions than the 400-pmol
group (all factors represented by an asterisk). During sessions 5 and 6
(extinction), aCSF was substituted for cocaine. In sessions 7 (reinstatement of cocaine), all cocaine groups self-infused at a higher rate than
aCSF controls, and the amount of infusions received by the 1200-pmol
group was higher than the 1600-pmol group (all factors represented by
plus symbol).
nated between the active and inactive lever only during session 7 (F1,9 values ⬎ 21.3; p values ⬍ 0.001).
Examining the number of active lever presses in the five
groups (aCSF and 400 to 1600 pmol of cocaine/100 nl) with
cannula placements in the AcbC revealed no significant effects of session (F6,174 ⫽ 1.0; p ⫽ 0.44), group (F4,29 ⫽ 1.61;
p ⫽ 0.39), or interaction (all p values ⬎ 0.05), indicating that
responses on the active lever were the same for aCSF and
cocaine infusions across all sessions (Figs. 5 and 6, right
columns).
Rats with guide cannulae placements ventral to the AcbSh
(data not shown) responded similarly to animals self-administering aCSF into either the AcbSh or AcbC. During the
seven sessions, active lever presses ranged from 13 ⫾ 2 to
20 ⫾ 4, declined across sessions, and were not different from
the responses on the inactive lever.
Effects of Sulpiride on Cocaine Self-Infusions. Replicating the initial finding, rats allowed to self-administer 1200
pmol of cocaine/100 nl directly into the AcbSh readily acquired response-contingent behavior (Fig. 7). During the second through fourth sessions, rats discriminated between the
active and inactive lever (F1,8 values ⬎ 13.0; p values ⬍
0.007). When 400 pmol/100 nl of sulpiride was coadministered with cocaine, responding on the active lever was reduced in sessions 5 and 6 compared with session 4 (F2,16 ⫽
9.1; p ⫽ 0.002) and lever discrimination was no longer apparent (F1,8 values ⬍ 1.7; p values ⬎ 0.23). As a measure of
the overall effects of sulpiride on general locomotor activity,
an analysis preformed on the number of inactive lever response during sessions 4 to 6 indicated no alterations in
number of responses (F2,16 ⫽ 2.6; p ⫽ 0.11). In addition, a
general comparison of the number of active lever responses in
rats self-administering 1200 pmol of cocaine within the initial 30 min of the first sulpiride coadministration or aCSF
substitution session (data not shown) indicated that the effect of sulpiride coadministration was not different from
aCSF substitution (22.2 ⫾ 8.6 and 31.6 ⫾ 10.4, respectively).
Giving 1200 pmol/100 nl of cocaine alone in sessions 7 and 8
resulted in the recovery of responding on the active lever
(F2,16 ⫽ 9.1; p ⫽ 0.002) and the re-establishment of lever
discrimination (F1,8 values ⬎ 9.3; p values ⬍ 0.016). Rats
Self-Infusion of Cocaine into Accumbens
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Fig. 4. Depicted is the number of infusions (separated
into 30-min time blocks)
self-administered (mean ⫾
S.E.M.) by rats given aCSF,
400 or 1200 pmol of cocaine/
100 nl into the AcbSh, or
1200 pmol of cocaine/100 nl
into the AcbC during sessions 1, 4, 6, and 7.
Discussion
The results of the current study indicate that Wistar rats
will initiate and maintain self-administration of cocaine directly into the AcbSh, but not the AcbC or areas ventral to
the AcbSh (Fig. 2), suggesting that the AcbSh is a site supporting the reinforcing actions of cocaine. The self-infusion of
cocaine into the AcbSh does not seem to be a result of a
general increase in behavioral activity because rats learned
to discriminate the active from the inactive lever during
acquisition for the self-infusion of 800 to 1200 pmol of cocaine
(Figs. 5 and 6), and self-administration was still evident with
an increase in the interval between reinforcements (Fig. 8).
Additionally, the 800- and 1200-pmol cocaine groups decreased responding on the active lever when aCSF was substituted for cocaine and reinstated responding on the active
lever when cocaine was restored (Figs. 5 and 6). Furthermore, the coadministration of the D2-like receptor antagonist
sulpiride reversibly reduced cocaine self-administration,
which was reinstated when sulpiride was removed from the
infusate (Fig. 7), suggesting that the reinforcing properties of
cocaine in the AcbSh involves activation of D2-like receptors.
The behavioral effects of cocaine have been linked to an
indirect increase of DA levels that activates both D1 and D2
receptors postsynaptically (Spealman et al., 1992). Subsequently, cocaine self-administration (i.v.) is altered by either
systemic (Haile and Kosten, 2001) or intra-accumbens
(McGregor and Roberts, 1993; Caine and Koob, 1994; Phillips
et al., 1994b) administration of D1 and D2 receptor agents.
Self-administration of the DA-reuptake inhibitor nomifensine into the AcbSh is reduced by coadministration of the
D2 receptor antagonist sulpiride (Carlezon et al., 1995). Similarly, amphetamine ICSA into the Acb (shell-core boundary)
is reduced by coadministration of either D1 or D2 receptor
antagonists (Phillips et al., 1994a). In agreement with these
results, Ikemoto et al. (1997) reported that coadministration
of D1 and D2 receptor agonists into the AcbSh was effective at
maintaining response-contingent behaviors, whereas administration of either agonist alone did not support ICSA, suggesting that activation of both the D1 and D2 receptors in the
Acb is required to produce reinforcing effects within the
AcbSh. In the current study, only a D2/3 receptor antagonist
was used to reduce cocaine ICSA into the AcbSh, a D1 receptor antagonist may have also reduced cocaine ICSA into the
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self-administering sulpiride alone throughout all eight sessions (data not shown) had low levels of responding on both
levers (⬍20 responses/session) and did not discriminate between active and inactive levers during any session (F1,7
values ⬍ 0.07; p values ⬎ 0.79).
Extended Time-Out. Extending the time-out period from
5 to 55 s retarded the acquisition of 1200 pmol of cocaine/
100-nl self-administration into the AcbSh (Fig. 8), as indicated by the finding that responses on the active lever were
not greater than responses on the inactive lever until the
fourth session (F1,8 values ⬎ 15.3; p values ⬍ 0.004). There
was a significant effect of session on the number of infusions
administered (F10,80 ⫽ 23.8; p ⬍ 0.0001) and the number of
active lever responses (F10,80 ⫽ 19.2; p ⬍ 0.0001). Post hoc
comparisons (Tukey’s) revealed that both the number of infusions administered and the number of active lever responses were greater during the last three sessions (sessions
9 –11) than after the initial signs of acquisition of self-administration (sessions 4 –7) and had reached asymptotic levels.
1222
Rodd-Henricks et al.
AcbSh. It is possible that the coadministration of sulpiride
reduced cocaine self-administration through a nonspecific
reduction in activity or a general negative effect of the drug.
However, this explanation seems unlikely because the initial
level of responding was comparable after coadministration of
sulpiride and aCSF substitution (Figs. 6 and 7), and sulpiride
was self-administered at a slightly higher rate than aCSF.
In general, local administration of a drug can produce very
different effects compared with systemic administration of the
same drug. For example, there is a marked contrast between
the effects of systemic (Haile and Kosten, 2001) or intra-accumbens (McGregor and Roberts, 1993; Caine and Koob, 1994;
Phillips et al., 1994b) administration of D1 and D2 receptor
agents on i.v. self-administration of cocaine and cocaine ICSA.
Under i.v. self-administration paradigms, administration of D1
and D2 receptor antagonists typically increases the amount of
responding, and number of infusions received for cocaine
(McGregor and Roberts, 1993; Caine and Koob, 1994; Phillips et
al., 1994b; Haile and Kosten, 2002). The increase in responding
and number of infusions has been asserted as a compensatory
reaction so that the organism maintains the previously established level of reinforcement (Caine and Koob, 1994; Phillips et
al., 1994b). Under ICSA conditions, coadministration of D2/3
receptor antagonists reduced cocaine self-administration in the
mPFC (Goeders and Smith, 1986; Goeders et al., 1986) and in
the AcbSh. Additionally, increasing the concentration of cocaine/infusion did not alleviate the reduction of self-administration after coadministration of sulpiride with cocaine in the
mPFC (Goeders et al., 1986). Conceptually, the likelihood of a
compensatory increase in self-administration under ICSA conditions is less than under i.v. self-administration because the
ICSA paradigm results in a local administration of both drug
and neurotransmitter agent. Therefore, the animal cannot
“overcome” the effects of the agent on the reinforcing properties
of the reinforcer by increasing self-administration of the reinforcer because an equal amount of agent will also be directly
administered into the neuroanatomically specific location after
each operant response.
Behaviorally, the rapid acquisition of self-administration
of reinforcers directly into specific neuroanatomical loci has
previously been shown for the self-administration of ethanol
(Gatto et al., 1994; Rodd-Henricks et al., 2000), acetaldehyde
(Rodd-Henricks et al., 2002), morphine (Bozarth and Wise,
1981), and other opioid agonists (Devine and Wise, 1994) into
the VTA. Goeders and Smith (1983) reported that cocaine
self-administration into the mPFC occurred within the first
8-h session. Additionally, self-administration of the DA up-
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Fig. 5. Depicted is the number of active and inactive
lever responses (mean ⫾ S.E.M.) for rats self-administering aCSF, or 400 or 800 pmol of cocaine/100 nl
of aCSF into the AcbSh or AcbC. Asterisks (p ⬍ 0.05;
Tukey’s test) represent significant difference in responses on the active lever versus responses on the
inactive lever and responding observed for rats selfadministering aCSF (p values ⬍ 0.05; determined by
one-way ANOVAs performed on individual sessions).
Self-Infusion of Cocaine into Accumbens
1223
Fig. 7. Depicted is the number of
active and inactive lever responses (mean ⫾ S.E.M.) for
rats self-administering 1200
pmol/100 nl alone (sessions 1– 4
and 7–8) or coadministering 400
pmol/100 nl of sulpiride and
1200 pmol of cocaine/100 nl (sessions 5–6) into the AcbSh. Asterisks represent significant (p ⬍
0.05; Tukey’s test) difference in
responses on the active versus
inactive lever and from responding observed for rats self-administering sulpiride alone (p values ⬍ 0.05).
take inhibitor nomifensine into the AcbSh was apparent
within the second 3-h session (Carlezon et al., 1995).
The delay in the acquisition of self-administration when
the time-out period between infusions was extended (Fig. 8)
is predicted by most learning theories, which hold that prolonged separations between reinforcements should delay the
acquisition of learning, i.e., partial reinforcement and development of superstitious behaviors (Macintosh, 1977; c.f.
Domjan and Burkhard, 1982: discussion on probability learning theory, Pavlovian temporal contiguity, and instrumental
learning variables). Examination of the pattern of self-administration for 1200 pmol of cocaine (Fig. 4) indicates an
initial high period of drug delivery maintained a lower level
of self-infusion, followed by a return to a higher level of
self-administration at the conclusion of the session. Previously, we reported a similar pattern of self-administration for
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Fig. 6. Depicted is the number
of active and inactive lever responses (mean ⫾ S.E.M.) for
rats self-administering 1200 or
1600 pmol cocaine/100 nl of
aCSF into the AcbSh or AcbC.
Asterisks represent significant
(p ⬍ 0.05; Tukey’s test) difference in responses on the active
lever versus responses on the
inactive lever and responding
observed for rats self-administering aCSF (p values ⬍ 0.05;
determined by one-way ANOVAs performed on individual
sessions).
1224
Rodd-Henricks et al.
ethanol (Rodd-Henricks at al., 2000) and acetaldehyde
(Rodd-Henricks et al., 2002) into the posterior VTA. Additionally, Carlezon et al. (1995) reported that nomifensine
self-administration into the AcbSh was pronounced during
the initial 30-min period, but they did not observe the higher
self-administration near the end of the session.
Previous research attempting to determine whether cocaine would be self-administered into the Acb varied slightly
from the current study. In the initial study (Goeders and
Smith, 1983), it was reported that concentrations between 0
and 5000 pmol/100 nl of cocaine failed to support self-administration in the Acb. However, from the histological presentation of cannulae placements, it would seem that most of the
placements from that study were located in the AcbC, an area
that did not support self-administration of cocaine in the
current study. Yet, there are a number of methodological
distinctions, besides injector location, between the current
study and the reports of Goeders and Smith. Goeders and
Smith’s experiments used male Fisher-344 rats (Goeders and
Smith, 1983, 1986; Goeders et al., 1986), whereas the current
experiment used female Wistar rats. Fisher-344 rats are not
as responsive to cocaine as many other rat lines (i.e., Lewis
rats) and are less likely to acquire i.v. self-administration of
various drugs of abuse, including cocaine (Kosten et al., 1994,
1997; Ambrosio et al., 1995). Recently, Fisher-344 rats, which
were selected and highly trained to self-administer cocaine,
were found to differ from Lewis rats in response to D1 and D2
receptor agents on cocaine discrimination and i.v. self-administration (Haile and Kosten, 2001). Additionally, the initial
ICSA studies were conducted with older EMIT units, used
different environmental cues, and different temporal patterns than the current study (i.e., Goeders and Smith, 1983;
session every 3rd day, session length 8 h). Thus, injector
location, the use of a different rat line, and other experimental parameters may have contributed to different findings
regarding the self-administration of cocaine into the Acb.
In addition to examining nomifensine self-administration
in the AcbSh, Carlezon et al. (1995) reported some preliminary results examining cocaine self-administration into the
AcbSh. Using a within-subject design to gradually increase
the amount of cocaine/100 nl, during the 22nd to 24th session, Long-Evans rats reliably responded for 300 pmol/100 nl
of cocaine (Carlezon et al., 1995). However, the current study,
although using slightly higher concentrations of cocaine, established patterns of responding closely resembling cocaine
self-administration into the mPFC (Goeders and Smith,
1983) that were obtained within seven sessions, which would
lend greater assurance of injector site viability (Bozarth and
Wise, 1981).
The concentration of cocaine that supported self-administration in the current study is approximately 8 to 12 mM.
Cocaine self-administration in the mPFC was reported to
occur at concentrations ranging from 0.5 to 0.9 mM (Goeders
and Smith, 1983). Additionally, microinjection of cocaine directly into the nucleus accumbens, not delineated between
shell and core, can induce locomotor activation at concentrations ranging from 16 to 35 mM (Delfs et al., 1990; Hemby et
al., 1992) and condition a place preference between 40 and 65
mM (Liao et al., 2000). Thus, the concentrations used in the
current study seem to be higher than effective doses of cocaine in other brain areas but are lower than microinjected
concentrations of cocaine needed to induce locomotor activation and condition a place preference.
In addition to the reinforcing properties, cocaine can act as
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Fig. 8. For rats self-administering 1200 pmol of cocaine/100
nl into the AcbSh, depicted is the
number of infusions received after either a 5- or 55-s time-out
(top), and active and inactive lever responses (mean ⫾ S.E.M.)
given a 55-s time-out period between reinforcers (bottom). The
top graph provides additional
data from the 1200-pmol cocaine
group from the initial dose-response study; hence, infusion
data from only session 1 to 4 and
7 are presented. Asterisks represent significantly (p ⬍ 0.05;
Tukey’s test) higher responding
on the active lever versus the inactive lever. Pluses represent
significantly (p ⬍ 0.05; Tukey’s
test) higher responding on active
lever versus the inactive lever
and a significantly higher level
of responding than during sessions 4 to 7.
Self-Infusion of Cocaine into Accumbens
that the AcbSh is a neuroanatomical substrate for the rewarding properties of cocaine, involving the activation of
D2-like receptors.
Acknowledgments
We thank Robert S. Crile and Bradley Glazier for assistance.
Separate, corollary, preliminary findings concerning cocaine ICSA
into the AcbSh were reported at the New York Academy of Science
meeting in 1999.
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