Regiao Prelimbica Cocaina Preferencia Lugar

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Research report

Role of the prelimbic subregion of the medial prefrontal

cortex in acquisition, extinction, and reinstatement of

cocaine-conditioned place preference

Arturo R. Zavala, Suzanne M. Weber, Heather J. Rice,Andrea T. Alleweireldt, Janet L. Neisewander*

Department of Psychology, Arizona State University, PO Box 871104, Tempe, AZ 85287-1104, USA

Accepted 30 July 2003

Abstract

Previous research suggests that the prelimbic subregion of the medial prefrontal cortex (mPFC) is necessary for acquisition of cocaine-

conditioned place preference (CPP). Recently, it has been shown that extinguished cocaine-CPP can be reinstated by cocaine priming

injections, and that this effect reflects the incentive motivational effects of the cocaine prime. To determine whether the prelimbic cortex is

necessary for cocaine-reinstated CPP, rats received bilateral infusions of quinolinic acid (lesion group) or vehicle (sham group) into the

prelimbic cortex and were later tested for acquisition, extinction, and reinstatement of cocaine-CPP. Both sham and lesion rats exhibited

robust CPP established by systemic injections of cocaine (15 mg/kg, ip) following either one or three drug-environment pairings. Following

repeated exposure to the cocaine- and saline-paired environments, sham and lesion rats showed similar rates of extinction of cocaine-CPP. In

contrast, reinstatement of cocaine-CPP by cocaine priming injections (5 and 10 mg/kg, ip) was attenuated in rats with prelimbic cortex

lesions relative to sham controls. This finding suggests that the prelimbic cortex is involved in the incentive motivational effects of cocaine

priming.

D

2003 Elsevier B.V. All rights reserved.

Theme: Neural basis of behavior

Topic: Drugs of abuse: cocaine

Keywords: Cocaine; Conditioned place preference; Prelimbic cortex; Prefrontal cortex; Reinstatement; Incentive motivation

1. Introduction

Conditioned place preference (CPP) is a model common-

ly used to study the rewarding and incentive motivational

effects of drugs and drug-paired stimuli [23,36]. During

conditioning, animals receive a drug paired with a distinct

environment and saline paired with another environment.

On the test day, animals are given free access to both

environments in a drug-free state and their preferences for

drug- versus saline-paired environments are assessed. CPP

is evident as an increase in preference for the drug-paired

environment.

Recently, it has been demonstrated that preference for the

drug-paired environment can be extinguished and subse-

quently reinstated by drug priming injections [25,29,39].

Drug-primed reinstatement of CPP is thought to reflect

renewed incentive value of the environmental stimuli via

the incentive motivational effects of the prime [25]. A

growing number of studies have demonstrated reinstatement

of CPP using a variety of drugs. For instance, drug priming

injections have been shown to reinstate CPP in animals

conditioned with cocaine [13,22,25,31,32] , morphine

[19,21,26,39,40], methamphetamine [14,18], and ethanol

[16]. CPP reinstatement is not limited to drug primes,

however, since presentation of intermittent footshock

[20,22,39], conditioned fear stimuli [31], or immobilization

stress [32] are also effective in reinstating CPP.

Although the neuronal circuitry mediating drug-primed

and stress-induced reinstatement of CPP has yet to be

determined, there is evidence suggesting that they are

mediated by different neuronal circuitries. For example,

electrolytic lesions of either the nucleus accumbens or

0006-8993/$ - see front matterD 2003 Elsevier B.V. All rights reserved.

doi:10.1016/S0006-8993(03)03452-8

* Corresponding author. Tel.: +1-480-965-0209; fax: +1-480-965-

8544.

E-mail address: [email protected] (J.L. Neisewander).

www.elsevier.com/locate/brainres

Brain Research 990 (2003) 157 164


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ventral tegmental area, but not the central amygdala, block

reinstatement of morphine-CPP by a drug prime, whereas

only electrolytic lesions of the central amygdala block

stress-induced reinstatement of morphine-CPP [40]. To date,

the neuroanatomical basis of cocaine-reinstated CPP has not

been investigated and, therefore, is the focus of the present

study.It is likely that the medial prefrontal cortex (mPFC)

plays a role in reinstatement of cocaine-CPP because

several lines of evidence suggest that this region is in-

volved in the reinforcing and incentive motivational effects

of cocaine. First, preconditioning lesions of the mPFC

disrupt acquisition of cocaine-CPP [12,38]. Second, rats

will readily self-administer cocaine directly into the mPFC

[7,9,10]. Moreover, lesions of the mPFC enhance acquisi-

tion and maintenance of self-administration with low doses

of cocaine [41], implicating this region in the reinforcing

effects of cocaine. Third, intracranial injections of cocaine

directly into the mPFC reinstate cocaine-seeking behavior

using the extinction/reinstatement model [28], whereas

inactivation of the dorsal region of the prefrontal cortex

by intracranial injections of GABA agonists attenuate

reinstatement of cocaine-seeking behavior elicited by a

systemic cocaine injection [24]. These latter findings sug-

gest that the mPFC is necessary for the response-reinstating

effects of cocaine.

Anatomical and functional studies have revealed that the

mPFC is not a homogeneous structure [15]. For instance,

recent evidence suggests that a specific subregion of the

mPFC mediates acquisition of cocaine-CPP. Specifically,

Tzschentke and Schmidt [37,38] have demonstrated that

discrete excitotoxic lesions of the prelimbic subregion of themPFC, but not the infralimbic or anterior cingulate sub-

regions, can disrupt acquisition of cocaine-CPP. The role of

the prelimbic cortex in the reinstatement of cocaine-CPP has

yet to be determined. In the present study, we hypothesized

that the prelimbic cortex plays a role in the rewarding and

incentive motivational effects of cocaine and predicted that

excitotoxic lesions of this region would disrupt acquisition

and reinstatement of cocaine-CPP.

2. Methods

2.1. Animals

Male SpragueDawley rats weighing 225275 g at the

start of the experiment were housed individually in a

temperature-controlled colony with a 12-h reversed light/

dark cycle (lights on at 6:00 PM). Behavioral testing was

conducted during the rats dark cycle. Food and water

were available ad libitum. Housing facilities and animal

care were in accordance with the conditions set forth in

the National Institute of Health Guide for the Care and

Use of Laboratory Animals (NIH Publications No. 80-23,

1996).

2.2. Apparatus

CPP was assessed in rectangular Plexiglas chambers that

had two equal-sized compartments (362430 cm each)

separated by a removable solid partition. One compartment

had three walls painted black, cedar bedding beneath a bar

grid floor, and a fluorescent light located 32 cm above thetop of compartment. The other compartment had three walls

painted white and pine bedding beneath a wire mesh floor.

The front wall of the chamber was constructed from clear

Plexiglas to allow observation of the rats. The tops of the

chambers were enclosed by a clear Plexiglas cover. A

second removable partition, which had a small opening

(812 cm), allowed rats to move freely between compart-

ments during preference tests.

2.3. Surgery

After 5 days of handling, rats were pretreated with

atropine (10 mg/kg, ip) and anesthetized using sodium

pentobarbital (50 mg/kg, ip). A standard Kopf stereotaxic

instrument was then used to localize infusions of quinolinic

acid (45 nmol, Sigma, St. Louis, MO) or phosphate-buffered

saline (PBS) into the prelimbic cortex using 30-gauge

injector cannulae attached to 10-Al Hamilton syringes

mounted on an infusion pump via PE 10 tubing. Quino-

linic acid was dissolved in 0.1 M PBS and adjusted to a

pH of 7.4. Bilateral infusions were made at two sites per

side with coordinates used previously by Tzschentke and

Schmidt [37]: +3.2 anteroposterior (AP), F0.8 medio-

lateral (ML), 4.4 and 3.8 dorsoventral (DV) from

bregma. For each infusion, the injector was lowered tothe appropriate coordinate and left in place for 1 min

prior to infusing 0.25 Al of quinolinic acid or PBS over 1

min. The injector was then left in place for an additional

5 min following the infusion. After surgery, rats were

allowed to recover for 1 week, during which they were

handled daily.

2.4. Habituation and baseline preference

Following recovery from surgery, rats were tested for

baseline preference on three consecutive days. During

preference tests, rats were given 15 min free access to

both compartments and the amount of time spent in each

compartment across the 3 days was computed. The side in

which animals spent the least amount of time (i.e.,


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particular side of our apparatus [27]. During conditioning,

cocaine injections (RTI International, Research Triangle

Park, NC) were always paired with confinement to the

rats nonpreferred side in order to enhance sensitivity for

detecting a shift in preference and for detecting extinction

of the preference.

2.5. Conditioned place preference procedure

The day after baseline preference tests were completed,

rats underwent conditioning during which they were ex-

posed to each of the following conditions in 3-day cycles,

with one condition per day in a counterbalanced order: (1)

a cocaine injection (15 mg/kg, ip) immediately followed

by confinement to the nonpreferred compartment; (2) a

saline injection immediately followed by confinement to

the preferred compartment; and (3) a saline injection

immediately followed by confinement to an alternative

environment. Rats remained in the respective environments

for 30 min. Exposure to the alternative environment was

used because follow-up neurochemical experiments are

planned that will require controls to be placed in an

alternative environment. The alternative environment was

an opaque plastic box (363430 cm) that had a solid

floor and corn cob bedding. Rats in Experiment 1 under-

went three conditioning cycles, whereas rats in Experiment

2 underwent only one conditioning cycle. CPP was

assessed the day after conditioning was completed by

allowing rats free access to both compartments for 15

min. Cocaine-CPP was evident when rats exhibited an

increase in time spent in the cocaine-paired side (i.e., the

initially nonpreferred compartment) relative to the averagetime spent in that side during the three baseline preference

tests.

2.6. Extinction and reinstatement of conditioned place

preference

Beginning the day after the test for CPP, rats in

Experiment 2 underwent 6-day cycles of extinction train-

ing consisting of daily 30-min exposures to the saline- and

cocaine-paired compartments without any injections on

alternating days (i.e., three exposures to each compart-

ment). Order of exposure to the compartments was coun-

terbalanced. Tests for extinction of CPP were conducted

following each extinction cycle (i.e., every 7 days) by

allowing rats free access to both compartments for 15

min. Extinction of CPP was operationally defined as a

decrease in time spent in the cocaine-paired side to within

40 s of each rats preconditioning baseline. Rats who

failed to meet this criterion continued extinction training

for a maximum of 8 weeks. Rats meeting the criterion

were given a saline priming injection and immediately

tested for reinstatement of extinguished cocaine-CPP the

following day. Rats that failed to maintain extinction of

cocaine-CPP after receiving the saline prime (5 out of 18)

underwent additional extinction training. Rats that

remained extinguished after the saline prime were then

tested the next day for reinstatement of CPP immediately

after an injection of 5 mg/kg cocaine, ip, and then again

after 10 mg/kg cocaine, ip, with five rest days in between

each test.

2.7. Histology

After the last test day for each given rat (i.e., after 2

8 weeks of extinction depending on the rat), the rats were

deeply anesthetized using sodium pentobarbital (100 mg/kg,

ip). Their brains were then removed and rapidly frozen in

20 jC 2-methylbutane. Brains were then stored at70 jC

until they were later sectioned in a 15 jC cryostat.

Coronal sections were made at a thickness of 40 Am and

collected across the range of the prelimbic cortex. Sections

were thaw mounted on gelatin-coated slides and stained

with cresyl violet. The extent and placement of the lesion

was determined by an observer unaware of the rats CPP

data.

2.8. Statistical analyses

Time (s) spent in the cocaine-paired side was analyzed

using a 22 mixed factor ANOVA with Group (sham/

lesion) as a between-subjects factor, and Day (baseline/test)

as a within-subjects factor. For Experiment 2, time spent in

the cocaine-paired side during the extinction tests was

analyzed using a 23 mixed factor ANOVA with Group

(sham/lesion) as a between subjects factor, and Day (CPP

test/extinction test 1/ extinction test 2) as a within-subjectsfactor. Only data from the first two extinction tests were

analyzed because all rats were tested at least twice, with

individual rats extinguishing at different time points there-

after. Reinstatement data was analyzed using a 23 mixed

factor ANOVA with Group (sham/lesion) as a between-

subjects factor, and Prime (saline/5 mg/kg cocaine/10 mg/kg

cocaine) as a within-subjects factor. When appropriate, post

hoc analyses were made using Tukey HSD tests (P


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3.2. Experiment 1: effects of preconditioning prelimbic

cortex lesions on acquisition of cocaine-conditioned place

preference with three pairings

Contrary to our expectations, bilateral lesions of the

prelimbic cortex failed to alter cocaine-CPP. Both sham

(n=7) and lesion (n=11) groups demonstrated robust co-

caine-CPP (see Fig. 3A), evident as an increase in time

spent in the cocaine-paired side during the test day

compared to the baseline preference test [Day main effect,

F(1,16)=24.38; P50% of the test time in the drug-paired

environment, indicating that conditioning shifted the rats

preference rather than simply decreasing aversion to their

initially nonpreferred side. The lack of a lesion effect was

surprising since lesions of the prelimbic cortex have been

shown to disrupt cocaine-CPP [37,38]. Thus, in order to

enhance sensitivity for detecting a lesion effect, Experi-

ment 2 was conducted using a single drug environment

pairing based on the rationale that a weaker conditioned

preference may be more susceptible to lesion-induced

disruption.

Fig. 2. Schematic representation of prelimbic cortex lesions. The extent of

damage is shown on coronal sections from the most posterior to anterior

portions of the observed lesion. The shaded areas indicate the smallest

(black) and largest (gray) areas of damage observed. The numbers indicate

distance from Bregma in millimeters. Schematic figures were adapted from

Paxinos and Watson [30] with permission from Elsevier.

Fig. 1. Photomicrographs of coronal sections (Nissl stain) showing repre-

sentative sections from sham (A) and lesion (B) animals. Arrows point to the

prelimbic region of the medial prefrontal cortex. Numbers indicate

approximate distance relative to Bregma.

A.R. Zavala et al. / Brain Research 990 (2003) 157164160


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3.3. Experiment 2: effects of preconditioning prelimbic

cortex lesions on acquisition with a single pairing, extinction,

and reinstatement of cocaine-conditioned place preference

Prelimbic cortex lesions again failed to alter cocaine-

CPP. Both sham (n=8) and lesion (n=10) groups exhibited a

similar increase in time spent on the cocaine-paired side on

the CPP test day relative to baseline [Day main effect,

F(1,16)=72.67; P


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tion, F(2,28)=3.51; P


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conducted the experiments during the light phase and

counterbalanced the side paired with cocaine. Future studies

will need to determine the significance of these procedural

differences when assessing the effects of prelimbic cortex

lesions on the acquisition of cocaine-CPP.

Prelimbic cortex lesions did not affect the rates of

extinction of cocaine-CPP (see Fig. 4A). Previous researchfrom our laboratory has found that postconditioning lesions

of the basolateral amygdala increase resistance to extinction

of cocaine-CPP, suggesting that lesion animals may be

unable to process changes in previously learned stimulus

reward associations [6]. The finding that no change in the

rate of extinction was observed in the present study is

surprising given that there are reciprocal connections be-

tween the basolateral amygdala and prelimbic cortex [11]. In

fact, a nonsignificant trend toward the opposite effect was

evident in rats with prelimbic cortex lesions. If anything,

prelimbic cortex lesions may decrease resistance to (i.e.,

facilitate) extinction of cocaine-CPP, perhaps reflecting a

more weakly established CPP relative to controls. Collec-

tively, these findings suggest that extinction of cocaine-CPP

is influenced differently by the prelimbic cortex and baso-

lateral amygdala despite the fact that these regions are

interconnected.

In summary, the present findings implicate the prelimbic

subregion of the mPFC in the reinstatement of extinguished

cocaine-CPP by priming injections of cocaine. Prelimbic

cortex lesions likely diminish the incentive motivational

effects of cocaine priming. Previous research suggests that

the prelimbic cortex is involved in acquisition of cocaine-

CPP [37,38]; however, the present findings suggest its role

may be nonessential.

Acknowledgements

We thank Ryan Meyers, Jeffrey Burmeister, Natalie

Krok, and Kenneth Kirshner for their expert technical

assistance and Dr. Brock Schroeder for his comments on an

earlier version of this manuscript. This study was supported

by the Minority Access to Research Careers program, the

Howard Hughes Medical Institute Undergraduate Biology

Enrichment Program, and NIDA Grants DA11064 and

DA13649.

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