Prefrontal cortex lesions differentially disrupt cocaine-reinforced conditioned place preference but not conditioned taste aversion

The reinforcing efficacy of cocaine is thought to involve, at least in part, mesocortical dopaminergic (DA) neurons. Rats will self-administer cocaine applied directly into the medial prefrontal cortex but not into nucleus accumbens or the ventral tegmental area (Goeders & Smith, 1983). The present experiments were conducted to assess whether lesions of prefrontal cortex (mesocortical DA target regions) attenuate the reinforcing properties of systemically administered cocaine. Male Sprague-Dawley rats were anesthetized, and one of three subfields (medial, orbital, or precentral) of the prefrontal cortex was removed by aspiration or no brain injury was done (sham operates). In four experiments the rats were tested on conditioned place preference (CPP), conditioned taste aversion (saccharin conditioned stimulus, cocaine unconditioned stimulus), general activity in the running wheel and open field, and food-reinforced spatial alternation in the T-maze. Sham operates demonstrated a cocaine-induced place preference, rats with medial frontal lesions showed a cocaine-induced place aversion, and other operates showed neither a conditioned place preference nor an aversion. The results of this experiment suggest that lesions of the DA projection fields of the prefrontal cortex in the rat reduce the positive reinforcing properties of systemically injected cocaine. In the second experiment, all subjects showed a conditioned taste aversion of equal magnitude. This suggests that whereas the positive reinforcing properties were affected differentially by prefrontal cortex lesions, the aversive properties were not affected. In Experiment 3 there were no lesion-induced differences in activity in either the running wheel or the open field. Therefore, changes in motor activity cannot account for the CPP data. In the final experiment, the medial frontal operates were impaired relative to the precentral and sham operates on learning to alternate choices in the T-maze, but the orbital frontal operates' performance was not different from that of any other group. This suggests that a general disruption of all reinforcement mechanisms did not occur following these lesions. Instead, these results indicate that mesocortical DA projection regions are involved with mediating the reinforcing properties of cocaine and that there is a separate system mediating the aversive properties of cocaine.     

Obesity-resistant S5B rats showed greater cocaine conditioned place preference than the obesity-prone OM rats

Background

Dopamine (DA) and the DA D2 receptor (D2R) are involved in the rewarding and conditioned responses to food and drug rewards. Osborne-Mendel (OM) rats are genetically prone and S5B/P rats are genetically resistant to obesity when fed a high-fat diet. We hypothesized that the differential sensitivity of these two rat strains to natural rewards may also be reflected in sensitivity to drugs of abuse. Therefore, we tested whether OM and S5B/P rats showed a differential preference to cocaine using conditioned place preference (CPP). To also evaluate whether there is specific involvement of the D2R in this differential conditioning sensitivity, we then tested whether the D2R agonist bromocriptine (BC) would differentially affect the effects of cocaine in the two strains.

Methods

OM and S5B/P rats were conditioned with cocaine (5 or 10 mg/kg) in one chamber and saline in another for 8 days. Rats were then tested for cocaine preference. The effects of BC (0.5, 1, 5, 10, 20 mg/kg) on cocaine preference were then assessed in subsequent test sessions.

Results

OM rats did not show a significant preference for the cocaine-paired chamber on test day. Only the S5B/P rats showed cocaine CPP. Later treatment with only the highest dose of BC resulted in reduced cocaine CPP in S5B/P rats when treated with 5 mg/kg cocaine and in OM rats treated with 10 mg/kg cocaine.

Conclusion

Our results indicated that obesity-resistant S5B rats showed greater cocaine CPP than the obesity-prone OM rats. These findings do not support a theory of common vulnerability for reinforcer preferences (food and cocaine). However, they show that BC reduced cocaine conditioning effects supporting at least a partial regulatory role of D2R in conditioned responses to drugs.     

Dopamine antagonists do not block conditioned place preference induced by paced mating behavior in female rats

The authors assessed the behavioral effects of dopamine (DA) receptor antagonists, Cis (Z) flupentixol and S(+)-raclopride L-tartrate, on conditioned place preference (CPP) induced by paced mating behavior. Ovariectomized female rats of the Wistar strain were used. The administration of amphetamine (1 mg/kg) induced a clear CPP that was completely blocked by the DA antagonists flupentixol (0.25 mg/kg) or raclopride (0.125 mg/kg). These doses had no effect on motor coordination. Female rats that mated in a pacing chamber developed a clear CPP. Neither flupentixol nor raclopride blocked the reward state induced by paced mating behavior. These results indicate that DA is not involved in the reward state induced by paced mating behavior in female rats.     

The medial preoptic area is necessary for motivated choice of pup- over cocaine-associated environments by early postpartum rats

Converging evidence suggests that the motivation to seek cocaine during the postpartum period is significantly impacted by the competing incentives of offspring, a stimulus unique to this life stage. In the present study, the functional role of the medial preoptic area (mPOA), a critical site involved in maternal responsiveness, on processing incentive value of pup-associated cues and influencing response allocation for pup- over cocaine-associated environments was investigated using a concurrent pup/cocaine choice conditioned place preference (CPP) paradigm. Early postpartum females with bilateral guide cannulae aimed into the mPOA or into anatomical control sites were conditioned, from postpartum days (PPD) 4 to 7, to associate different uniquely featured environments with pups or cocaine. CPP was tested on PPD8 following intra-mPOA infusions of either 2% bupivacaine or saline vehicle. In two additional experiments, the effects of intra-mPOA infusions of bupivacaine on expression of conditioned responding induced by environments associated with either pups or cocaine were examined separately. Transient inactivation of the mPOA selectively blocked the conditioned preferences for pup-associated environments, significantly contrasting the robust pup-CPP found in non-surgical and intra-mPOA vehicle-treated females. In contrast, mPOA inactivation failed to alter cocaine-CPP in postpartum females. When given a choice between environments associated with pups or cocaine, transient functional inactivation of the mPOA altered choice behavior, biasing the preference of females toward cocaine-associated environments, such that almost all preferred cocaine- and none the pup-associated option. The anatomical specificity was revealed when inactivation of adjacent regions to the mPOA did not affect CPP responses for pups. The findings support a critical role for the mPOA in mediating pup-seeking behavior, and further suggest that the competing properties of pups over alternative incentives, including drugs of abuse, rely on mPOA integrity to provide relevant pup-related information to the circuitry underlying the choice behavior between pups and alternative stimuli.     

A morphine-paired environment alters c-Fos expression in the forebrain of rats displaying conditioned place preference or aversion

The question of whether a common mechanism mediates both aversive and rewarding drug-paired cues is still unclear. In this study, we used a place preference conditioning paradigm to train rats to associate 1 chamber with morphine and the other chamber with saline. On the test day, rats were divided into those displaying conditioned place preferences (CPP) versus conditioned place aversion (CPA). After the test, all rats were killed and c-Fos immunocytochemistry was performed. For the control group, rats were treated with the same procedure except that the injections of morphine or saline had no association with the chambers. Compared with the control group, the CPP and CPA groups showed a significant increase of c-Fos expression in the dorsomedial striatum, central medial nucleus of the thalamus, and the basolateral amygdala. However, we saw no difference between CPP and CPA rats in any brain region examined. These results suggest that a morphine-paired environment can elicit neural activity in brain regions that are involved in emotional learning. Morphine-conditioned place preference and aversion may share a common neural circuitry elicited by a morphine-paired environment.     

An antisense oligodeoxynucleotide to the mu opioid receptor attenuates cocaine-induced behavioral sensitization and reward in mice

Numerous studies support a role for the endogenous opioid system in cocaine-influenced behavior. Few of these studies, however, selectively delineate a role for the mu opioid receptor (MOR) in this regard. This investigation examined if the MOR modulates cocaine-induced behavior in mice using a 17-base antisense oligodeoxynucleotide (AS ODN) directed against the MOR coding sequence 16-32. Specifically, cocaine-induced behavioral sensitization and conditioned reward were investigated. For the sensitization study, C57BL/6J mice received eight intermittent i.c.v. infusions of saline, mismatch oligodeoxynucleotide (ODN) (20 microg/4 microl) or AS ODN (20 microg/4 microl) over 20 days. Mice also received concomitant once daily i.p. injections of saline (4 ml/kg) or cocaine (15 mg/kg) for 10 days. There was a 7-day withdrawal period, after which all mice were challenged with cocaine (15 mg/kg) to test for behavioral sensitization. For the conditioned place preference (CPP) study, mice received five i.c.v. infusions of mismatch ODN or MOR AS ODN (days 1-5). An unbiased counterbalanced conditioning procedure was used where mice were conditioned with saline (4 ml/kg, i.p.) and cocaine (15 mg/kg, i.p.) on alternate days for four sessions (days 3-6). Mice were tested on day 7 for CPP. Immediately following testing, [3H]DAMGO (D-Ala2, N-Me-Phe4, Gly-ol5-enkephalin) receptor binding to brain homogenates was conducted. MOR AS attenuated cocaine-induced behavioral sensitization and conditioned reward. MOR AS ODN also reduced [3H]DAMGO binding. Collectively, these findings implicate the MOR as playing an important neuromodulatory role in the behavioral effects of cocaine in mice.     

Experience-dependent effects of cocaine self-administration/conditioning on prefrontal and accumbens dopamine responses

Experiments were performed to examine the effects of cocaine self-administration and conditioning experience on operant behavior, locomotor activity, and nucleus accumbens (NAcc) and prefrontal cortex (PFC) dopamine (DA) responses. Sensory cues were paired with alternating cocaine and nonreinforcement during 12 (limited training) or 40 (long-term training) daily operant sessions. After limited training, NAcc DA responses to cocaine were significantly enhanced in the presence of cocaine-associated cues compared with nonreward cues and significantly depressed after cocaine-paired cues accompanied a nonreinforced lever response. PFC DA levels were generally nonresponsive to cues after the same training duration. However, after long-term training, cocaine-associated cues increased the magnitude of cocaine-stimulated PFC DA levels significantly over levels observed with nonreinforcement cues. Conversely, conditioned cues no longer influenced NAcc DA levels after long-term training. In addition, cocaine-stimulated locomotor activity was enhanced by cocaine-paired cues after long-term, but not after limited, training. Findings demonstrate that cue-induced cocaine expectation exerts a significant impact on dopaminergic and behavioral systems, progressing from mesolimbic to mesocortical regions and from latent to patent behaviors as cocaine and associative experiences escalate.     

Involvement of brain catalase activity in the acquisition of ethanol-induced conditioned place preference

It has been suggested that some of the behavioral effects produced by ethanol are mediated by its first metabolite, acetaldehyde. The present research addressed the hypothesis that catalase-dependent metabolism of ethanol to acetaldehyde in the brain is an important step in the production of ethanol-related affective properties. Firstly, we investigated the contribution of brain catalase in the acquisition of ethanol-induced conditioned place preference (CPP). Secondly, the specificity of the catalase inhibitor 3-amino-1,2,4-triazole (AT) was evaluated with morphine- and cocaine-induced CPP. Finally, to investigate the role of catalase in the process of relapse to ethanol seeking caused by re-exposure to ethanol, after an initial conditioning and extinction, mice were primed with saline and ethanol or AT and ethanol and tested for reinstatement of CPP. Conditioned place preference was blocked in animals treated with AT and ethanol. Morphine and cocaine CPP were unaffected by AT treatment. However, the reinstatement of place preference was not modified by catalase inhibition. Taken together, the results of the present study indicate that the brain catalase-H(2)O(2) system contributes to the acquisition of affective-dependent learning induced by ethanol, and support the involvement of centrally-formed acetaldehyde in the formation of positive affective memories produced by ethanol.     

Gonadal hormones differentially modulate cocaine-induced conditioned place preference in male and female rats

There is accumulating evidence that suggests there are sex differences in behavioral and subjective responses to cocaine. However, it is not known whether differences in cocaine reward contribute to sex differences in these responses or whether gonadal hormones affect the rewarding properties of cocaine. In the present study, conditioned place preference (CPP), a measure of non-contingent reward, was used to determine the effects of endogenous gonadal hormones and of estrogen and progesterone replacement on cocaine reward. Neurochemical measurements were also taken to identify monoaminergic substrates which underlie the behavioral phenotype. Although both intact and gonadectomized male and female rats showed a significant CPP for cocaine, ovariectomy attenuated the magnitude of CPP. These alterations coincided with a decrease in serum levels of corticosterone. In ovariectomized rats, pretreatment with progesterone inhibited cocaine CPP while estrogen plus progesterone potentiated the magnitude of CPP. Additionally, gonadectomy and ovarian hormone replacement in female rats affected serotonin/dopamine levels and turnover ratios in the ventral tegmental area and nucleus accumbens shell. While no effects of castration were observed, ovariectomy decreased levels of dopamine and serotonin in the ventral tegmental area. In females, progesterone replacement increased levels of serotonin and dopamine in the ventral tegmental area, while estrogen plus progesterone replacement increased dopamine levels in the nucleus accumbens. Collectively, these results indicate that ovarian hormones may influence cocaine reward by altering monoaminergic systems, which, in turn, may contribute to the current sex disparities in overall cocaine use.     

Dorsal hippocampus inhibition disrupts acquisition and expression, but not consolidation, of cocaine conditioned place preference

Cocaine abusers may experience drug craving upon exposure to environmental contexts where cocaine was experienced. The dorsal hippocampus (DHC) is important for contextual conditioning, therefore the authors examined the specific role of the DHC in cocaine conditioned place preference (CPP). Muscimol was used to temporarily inhibit the DHC and was infused before conditioning sessions or tests for CPP to investigate acquisition and expression of cocaine CPP, respectively. To investigate consolidation, rats received intra-DHC muscimol either immediately or 6 hr after conditioning sessions. Inhibition of DHC, but not the overlying cortex, disrupted acquisition and expression of cocaine CPP. It is interesting to note that there was no effect of post-conditioning DHC inhibition. The findings suggest that the DHC is important for both acquisition and recall, but not consolidation, of context-cocaine associations.     

Intracerebroventricular ethanol-induced conditioned place preferences are prevented by fluphenazine infusions into the nucleus accumbens of rats

The rewarding properties of centrally administered ethanol (EtOH) were examined using a conditioned place preference (CPP) test. Male rats subjected to bilateral intracerebroventricular (icv) infusions of EtOH (0-240 nmol) produced a dose-dependent preference for the drug-paired environment that was potentiated by concurrent intravenous (iv) administration of heroin (0.025 mg/kg). The role of mesolimbic dopamine (DA) pathways in the development of EtOH reward was then examined by challenging EtOH-treated rats with bilateral intra-accumbens shell applications of a DA receptor antagonist. Fluphenazine (10 or 50 microg/side), infused immediately prior to daily place conditioning trials, was found to reliably attenuate the development of CPPs produced by icv EtOH administration. When fluphenazine was administered into the nucleus accumbens shell prior to the final test trial only (i.e., in already conditioned rats), intra-accumbens shell DA receptor blockade was found to prevent the expression of CPPs produced by icv EtOH. In summary, rats form reliable learned preferences for EtOH-paired locations (CPPs) that are potentiated by iv heroin and whose acquisition and expression rely on intact DA functionality within the nucleus accumbens.     

18-Methoxycoronaridine blocks acquisition but enhances reinstatement of a cocaine place preference

The iboga alkaloid congener, 18-methoxycoronaridine (18-MC), decreases self-administration of multiple drugs of abuse. Here, in a biased procedure, we investigated whether 18-MC would have a similar effect on the acquisition, expression and reinstatement of a cocaine conditioned place preference (CPP) in male Sprague-Dawley rats. While 18-MC attenuated acquisition of a cocaine CPP, it had no effect on CPP expression, and enhanced the reinstatement of cocaine CPP following extinction. Our results are consistent with those obtained using ibogaine, but reinforce the notion that acquisition, expression and reinstatement of a CPP likely involve separate mechanisms.     

Pre-treatment with high doses of cocaine decreases the reinforcing effects of cocaine in the conditioned place preference paradigm

The aim of the present study was to determine if pre-exposure to high doses of cocaine can subsequently alter the rewarding effects of this drug. Adult male mice received a pretreatment of physiological saline, or 12.5 or 25 mg/kg of cocaine (one injection a day for five days). After an interval of six days without injections, the rewarding effects of low doses of cocaine (0.5, 1 or 1.5 mg/kg) were evaluated in the conditioned place preference (CPP) paradigm. Doses of 1 and 1.5 mg/kg induced a clear CPP in animals pre-treated with saline but were ineffective in those pre-treated with 25 mg/kg of cocaine. Only the dose of 1.5 mg/kg induced CPP in mice pre-treated with 12.5 mg/kg of cocaine. Our results, which reveal a decrease in the conditioned rewarding effects of threshold doses of cocaine, demonstrate that exposure to high doses of this drug can alter the reward system.     

Competition between the conditioned rewarding effects of cocaine and novelty

Access to novelty might provide an alternative learning history that competes with conditioned drug reward. We tested this suggestion in rats using a place conditioning procedure with cocaine and novelty. In Experiment 1, rats were conditioned with cocaine to prefer one side of an apparatus. In a subsequent phase, cocaine exposure continued; however, on the unpaired side, separate group of rats had access to novel objects, cocaine injections, or saline with no objects. Pairings with novel objects or cocaine shifted a preference away from the cocaine-paired environment during drug-free and drug-challenge tests. Experiment 2 tested novelty's impact when cocaine exposure was discontinued. The identical procedures were used except drug exposure ceased on the cocaine-paired side during the second phase. Both groups expressed a preference for the cocaine compartment. This preference was maintained for rats that did not have novel objects; however, rats that experienced novelty spent similar amounts of time in both compartments during both tests. Overall, the conditioned rewarding effects of novelty competed with those of cocaine as evidenced by a change in choice behaviors motivated by drug reward.     

Nucleus accumbens and medial prefrontal cortex dopaminergic response to self-administered cocaine in naive rats

Cocaine reinforcement is strongly associated with increased nucleus accumbens dopamine (NAcc DA). The involvement of medial prefrontal cortex (mPFC) DA in cocaine reward is less defined, but substantial evidence indicates that increased mPFC DA may suppress NAcc DA levels. Using in vivo microdialysis, NAcc or mPFC DA was determined in cocaine-naive rats after a self-administered cocaine injection (3.0 mg/kg). Extracellular levels of NAcc DA were dramatically enhanced 10 min post-cocaine injection, but dropped significantly at each subsequent assessment. mPFC DA also increased significantly, but to a lesser extent than observed in the NAcc. Findings of prominent DA increases in both the NAcc and mPFC terminals during the test session indicate that NAcc DA responses do not appear to be inhibited by increased mPFC DA during cocaine self-administration.     

The effects of water-odor preference conditioning in the preadolescent nucleus accumbens septi

The mesolimbic dopamine (DA) pathway is critical in reward-mediated behavior. Water, sucrose, and drugs of abuse all increase DA in the nucleus accumbens septi (NAcc) in adult animals. Recently our laboratory has shown that cocaine and alcohol increase DA efflux in preadolescent animals. The present study used a natural reinforcer (i.e., water) at postnatal day 25 (PND 25) to determine the sensitivity and responsiveness of this pathway. Repeated pairing of a peppermint odor with water resulted in a behavioral odor preference and an odor-elicited increase in accumbal DA. Results show that this developing pathway is functional and responsive to conditioning using a natural reinforcer and that these behavioral and neurochemical responses can be conditioned to a previously novel environmental stimulus.     

Naloxone attenuates the conditioned place preference induced by wheel running in rats

Pairings, during which an episode of wheel running is followed by confinement in a distinctive place, produce conditioned place preference (CPP) in rats. This finding indicates that wheel running has a rewarding effect that outlasts the activity itself. In two similar experiments, we tested the hypothesis that this rewarding effect of wheel running is mediated by endogenous opioids. During a paired trial, the rats in the naloxone group were first allowed to wheel run for 2 h, then injected with naloxone (0.5 or 0.1 mg/kg in Experiments 1 and 2, respectively), and 10 min later placed in a distinctive chamber. During an unpaired trial, these rats were confined in an adjoining chamber without wheel running. Naloxone was injected before placement in both chambers, so that if naloxone-induced conditioned place aversion occurred, it would have counteracting effects on performance during the preference test. The rats in the saline group were similarly treated, except that saline was injected instead of naloxone. CPP occurred in the saline group, but not in the naloxone group. Thus, naloxone attenuated the CPP induced by wheel running. This finding supports the hypothesis that the rewarding effect of wheel running is mediated by endogenous opioids.     

Kindling modifies morphine, cocaine and ethanol place preference

Brailowsky and Garcia (1999) proposed the existence of a relationship between epilepsy and addiction. To prove this hypothesis, pentylenetetrazol kindled rats were tested in the conditioned place preference (CPP) paradigm for their reaction to various addictive drugs with different modes of action (morphine, cocaine and ethanol). In separate experiments, locomotor activity and body temperature after application of the same drugs were tested in kindled and non-kindled rats. In the CPP experiment there were significant differences between both groups of rats. Non-kindled animals showed place preference to morphine (5.0 mg/kg) or cocaine (20.0 mg/kg). This reaction was abolished in the kindled rats. Moreover, control rats demonstrated aversion to 2.0 g/kg ethanol. However, ethanol aversion was not detectable in kindled rats. Moreover, there was no difference between non-kindled and kindled rats in locomotor activity and body temperature after morphine (1.0 and 5.0 mg/kg), cocaine (10.0 and 20.0 mg/kg), or ethanol (0.5 and 2.0 g/kg) application. This suggests alterations in reward systems as a consequence of kindling. It is hypothesised that GABAergic neurones in the ventral tegmental area might play a major role in the alterations found.     

Effects of nitrous oxide on dopamine release in the rat nucleus accumbens and expectation of reward

Recently we have shown that nitrous oxide (N2O) was able to block the expression of morphine-induced conditioned place preference (CPP) in mice. Because dopamine (DA) has also been associated with the positive place conditioning we hypothesize that exposure to N2O would be significantly associated with a modification of extracellular level of DA. Unbiased place conditioning method was used for mice and rats. Levels of DA, in the nucleus accumbens (Nac), in awake and freely moving rats during positive place conditioning after morphine chronic treatment has been measured by microdialysis. Expression of morphine-induced CPP was totally abolished in mice and rats exposed to N2O. Results of animals placed in the morphine-paired compartment showed a 75% increase in the extracellular levels of DA, which was blocked by exposure of animals to N2O. In conclusion we showed the capacity of N2O to block the expression of morphine-induced CPP in mice and in rats. Then we demonstrated an increase of DA extracellular level in the Nac when animals were placed in the morphine-paired compartment and these increase of DA level was blocked by N2O.     

Contribution of the suprachiasmatic nucleus to day:night variation in cocaine-seeking behavior

Recent work has shown that time-of-day influences drug-seeking behavior. The present experiments tested the hypothesis that the master circadian pacemaker located in the suprachiasmatic nucleus of the hypothalamus (SCN) is required for generating day:night differences in drug-seeking behavior, specifically the acquisition, extinction, and reinstatement of cocaine-induced conditioned place preference (CPP). Sham and SCN-lesioned (SCNx) rats were trained for cocaine-induced CPP behavior at either ZT4 (Zeitgeber time 4, 4 h after lights-on) or ZT12 (lights-off). After being tested for side preference, rats were allowed to extinguish CPP. This was followed by cocaine-induced reinstatement with 5 mg/kg and 10 mg/kg of cocaine. SCNx animals exhibited no 24-h locomotor activity rhythm. Acquisition of CPP behavior did not vary with time-of-day, but was greater in SCNx animals. Sham rats tested at ZT12 took significantly longer to extinguish CPP behavior compared to ZT4, an effect completely abolished by SCN lesions. Cocaine-induced reinstatement of CPP did not vary with time of day in sham rats. However, SCNx animals tested at ZT4 trended towards greater reinstatement to the low dose of cocaine, and displayed significantly less reinstatement to the higher dose of cocaine than sham rats. Additionally, SCNx rats tested for reinstatement to the lower dose of cocaine displayed greater reinstatement at ZT4 than at ZT12. We conclude that: 1) acquisition of CPP behavior does not vary between the two times of day tested but is influenced tonically by the SCN, 2) extinction of cocaine CPP varies with time-of-day and this variation depends critically on the SCN, and 3) reinstatement of cocaine CPP does not vary between the two times of day tested. However, day:night differences in reinstatement are unmasked in animals lacking an SCN, suggesting the possibility that an extra-SCN oscillator is responsible for generating variation in this cocaine-seeking behavior.