Brain Research 990 (2003) 157 164 www.elsevier.

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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 cocaineconditioned 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 commonly 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* Corresponding author. Tel.: +1-480-965-0209; fax: +1-480-9658544. E-mail address: janet.neisewander@asu.edu (J.L. Neisewander). 0006-8993/$ - see front matter D 2003 Elsevier B.V. All rights reserved. doi:10.1016/S0006-8993(03)03452-8

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

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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 involved 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 acquisition 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 suggest 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 the mPFC, but not the infralimbic or anterior cingulate subregions, 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.

2.2. 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 the top 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 compartments 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. Quinolinic 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 mediolateral (ML), 4.4 and 3.8 dorsoventral (DV) from bregma. For each infusion, the injector was lowered to the 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.,<50% of the total test time) was designated as the nonpreferred side. Baseline preferences revealed that the white compartment was the nonpreferred side for 15 rats [average time ( FS.E.M.) in black 498.02 F9.02 and white 401.98F9.02] and the black compartment was the nonpreferred side for 21 rats [average time (FS.E.M.) in black 397.93F11.43 and white 502.06F9.02], consistent with previous research from our laboratory demonstrating that rats do not exhibit a strong initial preference for a

2. Methods 2.1. Animals Male Sprague Dawley rats weighing 225 275 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).

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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 exposed 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 underwent 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 average time 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 training 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 compartment). Order of exposure to the compartments was counterbalanced. 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 at 70 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-subjects factor. 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 thereafter. Reinstatement data was analyzed using a 23 mixed factor ANOVA with Group (sham/lesion) as a betweensubjects 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<0.05). Lesion rats without sufficient damage to the prelimbic cortex were removed from the analyses. Final ns/group are reported below.

3. Results 3.1. Histology Histological results indicated that rats given infusions of quinolinic acid into the prelimbic cortex exhibited moderate to extensive damage throughout the extent of this region (see Fig. 1). A small amount of extrastructural damage was also observed in some rats in the ventral region of the Cg1 cortex and the dorsal portions of the infralimbic cortex (see Fig. 2).

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enhance sensitivity for detecting a lesion effect, Experiment 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. 1. Photomicrographs of coronal sections (Nissl stain) showing representative 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.

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 cocaine-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; P<0.05]. Importantly, animals expressing CPP spent >50% 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

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.

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Fig. 3. Effects of preconditioning prelimbic cortex lesions on acquisition of cocaine-CPP established with (A) three cocaine-environment pairings and (B) one cocaine-environment pairing. (*) represents a significant difference from baseline (ANOVA main effect of Day, P<0.05).

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 cocaineCPP. 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<0.001; see Fig. 3B]. Rates of extinction for both sham and lesion rats revealed a general decrease in time spent in the cocaine-paired side across the first two extinction tests regardless of group [Day main effect, F(2,32)=7.75; P<0.05], with a significant decline in CPP during extinction test 2 (Tukey HSD test, P<0.05; see Fig. 4A). Although lesion rats exhibited a sharp decline in time spent on the cocaine-paired side on the first extinction test relative to sham rats, there was no significant GroupDay interaction. Moreover, the mean number of weeks for

Fig. 4. (A) Effects of preconditioning prelimbic lesions on extinction of cocaine-conditioned place preference across the first two extinction (Ext) tests. (B) Effects of preconditioning prelimbic cortex lesions on reinstatement of cocaine-CPP after priming injections of cocaine (5 and 10 mg/kg, ip). (*) represents a significant difference from respective saline prime test (Tukey HSD test, P<0.05). ( ) represents a significant difference from sham animals primed with 10 mg/kg cocaine (Tukey HSD test, P<0.05).

individual rats to reach the extinction criterion did not differ between sham and lesion rats (see Table 1). Rats that met the extinction criterion within 8 weeks (6 sham and 10 lesion) were tested for reinstatement of CPP (see Fig. 4B). Importantly, reinstatement of CPP differed according to whether the prelimbic cortex was intact[(Prime main effect, F(2,28)=11.35; P<0.05; GroupPrime interacTable 1 Rates of extinction for sham and prelimbic lesion rats Group Average number of weeks on extinction trainingFS.E.M. (n) 3.83F0.60 (6) 4.00F0.67 (10) Range

Sham Lesion

28 27

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tion, F(2,28)=3.51; P<0.05]. Specifically, only sham rats exhibited a significant increase in time spent in the cocainepaired side after either the 5 or 10 mg/kg cocaine primes compared to the saline prime (Tukey HSD test, P<0.05). In contrast, lesion rats failed to exhibit an increase in time spent in the cocaine-paired side across reinstatement tests and spent significantly less time in the cocaine-paired side than sham rats when primed with 10 mg/kg cocaine (Tukey HSD test, P<0.05).

4. Discussion Contrary to our hypothesis and previous research [37,38], prelimbic cortex lesions had no effect on the acquisition of cocaine-CPP. Prelimbic cortex lesions also failed to alter rates of extinction of cocaine-CPP. Consistent with our hypothesis, however, prelimbic cortex lesions attenuated reinstatement of cocaine-CPP by cocaine priming injections (see Fig. 4B). Specifically, sham rats, but not lesion rats, exhibited reinstatement of cocaine-CPP after a priming injection of either 5 or 10 mg/kg of cocaine. Furthermore, at the higher dose of cocaine prime (10 mg/ kg), lesion rats spent significantly less time in the cocainepaired side relative to sham controls given the same priming dose. The latter findings should be interpreted with caution, however, given that order of dose was not counterbalanced and that rats were not exposed to further extinction training between the two cocaine priming tests. Thus, it is possible that the greater magnitude of CPP after the 10 mg/kg prime in sham animals may be due, at least in part, to spontaneous recovery in sham animals because they had reinstated after 5 mg/kg prime or to group differences in sensitization of the incentive motivational effects of cocaine priming since the mPFC is involved in cocaine sensitization [34]. These caveats notwithstanding, the present findings are consistent with previous studies demonstrating an involvement of the mPFC in the reinstatement of cocaine-seeking behavior using the extinction/reinstatement model [24,28]. Importantly, CPP is established using a different procedure than the extinction/reinstatement model, and expression of cocaine-CPP involves a different behavioral response. Thus, consistent findings across these models offer strong converging lines of evidence that the prelimbic subregion of the mPFC is involved in processing the incentive motivational effects of the cocaine prime. However, the specific processes affected, such as perceiving cocaine and/or translating the effects into approach behavior, remain unclear. The present study failed to detect an effect of prelimbic cortex lesions on acquisition of cocaine-CPP after either three or one cocaine environment pairings during conditioning. These findings were surprising since excitotoxic lesions of the prelimbic cortex have been shown to reliably block cocaine-CPP [37,38]. Moreover, previous research has demonstrated that the prelimbic cortex is activated by exposure to a contextual discriminative stimulus for cocaine

availability that reinstates extinguished cocaine-seeking behavior, suggesting a role of this region in the incentive motivational effects of the cocaine-paired context [5]. When considered together, the present and previous findings suggest that the prelimbic cortex is involved in the incentive motivational effects of cocaine-associated stimuli; however, its role may be nonessential and, when damaged, compensated for by other parallel systems. The reason for the discrepant findings of a lesion effect on acquisition of cocaine-CPP in previous research [37,38] and no lesion effect in the present study is unclear. However, it is unlikely that the discrepancy is due to differences in extent of lesion since the same lesion parameters were used and the histological results were similar. Rather, a number of procedural differences between the present and previous studies may account for the lack of a lesion effect in the present study. First, in previous experiments demonstrating a lesion effect [37,38], the conditioning apparatus was only differentiated by visual stimuli, whereas visual, tactile, and olfactory stimuli differentiated the compartments in the present experiment. Thus, it is possible that rats with prelimbic cortex lesions may not have been able to discriminate between the two chambers when only visual stimuli were used, and as a result, failed to acquire cocaine-CPP. However, with additional information about the two chambers (i.e., olfactory and tactile stimuli) as in the present study, lesion rats may have been able to discriminate between the compartments and acquire cocaine-CPP. Contrary to this idea, however, discrimination studies have failed to demonstrate an impairment in visual or olfactory discrimination learning in rats with prelimbic cortex lesions [2,17]. Second, differences in food availability between the present and previous studies may account for the discrepancy in findings. In previous studies [37,38], rats were maintained on a food-restricted diet (12 or 14 g of food per animal) throughout the experiment, whereas rats in the present study were given free access to food. Similar food restriction regimens have been demonstrated to facilitate acquisition of cocaine-CPP [1,35]. It is possible that with the methods used in the previous experiments demonstrating a prelimbic cortex lesion effect [37,38], food restriction was necessary for establishing CPP in controls and that the prelimbic cortex lesions disrupted this facilitating effect of food restriction on acquisition of CPP. Indeed, food restriction, as well as other stressors, enhance dopamine activity in the mPFC [3,4,33], and dopamine in the mPFC is thought to be involved in the reinforcing effects of cocaine [8], as well as cocaine-seeking behavior [24,28]. Other noteworthy differences across studies that may have contributed to the discrepant findings were the time when the experiments were conducted and the method of assigning cocaine injections during conditioning. Specifically, in the present study, the experiments were conducted during the dark phase of the rats light cycle and cocaine was paired with the initially nonpreferred side of the apparatus, whereas previous studies demonstrating a lesion effect on acquisition

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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 research from 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 between 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. Collectively, these findings suggest that extinction of cocaine-CPP is influenced differently by the prelimbic cortex and basolateral 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 cocaineCPP [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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