Sex differences in cocaine-associated memory: The interplay between CB₁, mGluR5, and estradiol

We know surprisingly little about the sex differences in the neurobiology of cocaine addiction, except females are more susceptible to the rewarding effects of cocaine than their male counterparts. Only a handful of recent studies have examined the neurobiology of cocaine-induced conditioned place preference (CPP) memory among female rodents. We contribute to this emerging line of research by documenting sex differences in cocaine-associated memory and illustrating the underlying signaling pathways in five experiments. Rimonabant (Rim), a cannabinoid CB₁ antagonist and inverse agonist, exerted a facilitating effect for low-dose cocaine and an impairing effect for high-dose cocaine CPP memory in male mice, as in our previous study, but not in female mice. Nor did we observe the effect exist among CB₁ knockout male mice, which indicated that the CB₁ receptors played a mediating role. We also found that the metabotropic glutamate receptor 5 (mGluR5) was located in the same signaling pathway as CB₁ in male mice. To clarify the mechanisms behind the sex differences, we used ovariectomized (OVX) female mice with estradiol benzoate (EB) replacement. In the OVX female mice, we showed that Rim-alone and EB-alone, but not Rim-and-EB-combined, facilitated the low-dose cocaine CPP memory. Moreover, 4-hydroxytamoxifen (4-OHT), an estrogen receptor (ER) antagonist, blocked Rim's and EB's facilitating effect. Finally, 2-methyl-6-(phenylethynyl)pyridine (MPEP), an mGluR5 antagonist, partially blocked EB's facilitating effect. In sum, we identified sex-specific effects of Rim on cocaine-induced CPP memory and the respective signaling pathways: mGluR5-CB₁ for male mice and ER-mGluR5-CB₁ for female mice. These findings may have merits for the development of sex-specific treatment for cocaine addiction.