The role of nucleus accumbens Fos expression in sex-dependent cocaine-induced locomotion, cocaine self-administration, and primed cocaine seeking in rats

Individuals using cocaine, particularly those with Cocaine Use Disorder, experience long-lasting neurobiological alterations that contribute to high rates of relapse and increased morbidity and mortality. Rodent models suggest that neuronal activation, as represented by Fos expression, in the nucleus accumbens (NAc) is crucial for cocaine-related behaviors. However, the role of biological sex in NAc activation in these behaviors remains unclear. Therefore, the present study examined the impact of sex on cocaine-induced locomotor activity (LMA), cocaine self-administration, cocaine seeking, and associated NAc Fos expression. We hypothesized that, relative to males, female rats would display heightened behavioral responses in the tested models and greater numbers of Fos+ cells in the NAc, and that Fos expression would correlate with the outcome measures of the assessed behaviors (i.e., locomotor activity and cocaine seeking). In this study, females displayed greater cocaine-induced locomotor activity, cocaine self-administration, and cocaine seeking than males. However, neither sex nor cocaine treatment impacted NAc Fos expression in the LMA study, and NAc Fos levels did not correlate with LMA in either sex. Following cocaine seeking, NAc Fos expression was not sex-dependent, though it correlated with cocaine seeking in males, but not in females. Taken together, these results suggest that the number of Fos+ cells in the NAc do not underlie sex differences in cocaine use or relapse-like behaviors. Future work should characterize the proteomic or electrophysiologic profiles in specific cell types of Fos+ cells in the NAc following cocaine use to determine how these behaviors differ by sex.