The modulatory effects of rimonabant and retrieval-extinction procedures on cocaine-associated memory in mice

Abstract

There are no effective pharmacological medications to treat cocaine relapse thus far. Since the endocannabinoid system plays an important role in modulating the reward system, which is responsible for cocaine addiction, the cannabinoid CB1 receptors are considered a promising target to treat cocaine addiction. On the other hand, some researchers believe that drug memory can be re-written via interfering memory reconsolidation. Therefore, the objectives of this study are to examine the role of the CB1 receptors in cocaine-associated memory in both sexes of C57BL/6N mice and to explore the efficacy of different retrieval-extinction behavioral procedures to eliminate cocaine-associated memory in male mice. We used conditioned place preference (CPP) as an animal model of drug-associated memory to verify the effects of pharmacological and behavioral manipulations in different memory processes. We found that the facilitating effect of a CB1 receptor antagonist/inverse agonist rimonabant on memory consolidation of cocaine-induced CPP was mediated by the CB1 receptors and by the elevated plasma level of corticosterone in male wild-type mice. However, there was no facilitating effect of rimonabant on cocaine CPP memory in female wild-type mice. Blockade of mGluR5 per se also facilitated cocaine memory in male mice. However, this enhancing effect was not synergistic with that of rimonabant. In order to examine the possible interaction between sex hormone and CB1 receptors, we used female ovariectomized (OVX) mice and found that rimonabant facilitated cocaine CPP memory in these mice. We also found that estrogen per se enhanced cocaine CPP memory in the OVX mice. However, combination of rimonabant with estrogen impaired the same memory. Furthermore, blockade of mGluR5 had no effect on cocaine memory in the OVX mice. We then used three different behavioral procedures (the extinction, the retrieval-extinction, and the extinction-retrieval procedures) to impair cocaine-associated memory. The results indicated that there was no significant difference of the memory-impairing effect on cocaine CPP among three behavioral procedures. However, we found that the effects of the behavioral procedures depended on the dosage of cocaine used in the CPP paradigm. The behavioral procedures had a long-lasting suppression on a high-dose cocaine-induced CPP, while their suppressing effect only transiently lasted on a low-dose cocaine-induced CPP. In conclusion, the CB1 receptors modulate cocaine-associated memory via corticosterone increase and mGluR5 signaling in male mice. In addition, estrogen interferes with the effect of CB1 receptors on cocaine-associated memory in female mice. Hence, there is a sex difference in the modulatory effect of CB1 receptors in cocaine-associated memory. Finally, the efficacy of different retrieval-extinction manipulations and memory reconsolidation theory awaits further investigation.

Date of Award	2016 Aug
Original language	English
Supervisor	Shu-Jung Hu (Supervisor)