Cocaine-induced interindividual variability in female rats: From behavior to gene expression

Cocaine use disorder is marked by strong interindividual variability, yet the molecular determinants underlying vulnerability in females remain poorly characterized. Here, we adapted a statistical model previously validated in males to classify female rats exposed to a cocaine-induced conditioned place preference paradigm into two subgroups: those expressing cocaine reward (CPP expression (CPPE), score >74 s) and those showing no preference ((nCPPE), score between -19 and 53 s), independently of estrous-cycle influences. Despite identical cocaine exposure, two clear behavioral phenotypes emerged, with no differences in baseline emotional-like, cognitive, or hedonic-like measures. Whole-transcriptome sequencing of the nucleus accumbens during CPP expression and following reinstatement revealed extensive transcriptional differences between subgroups. CPPE females showed strong upregulation of immediate early genes (Egr1, Egr2, Egr4) and enrichment of pathways implicated in addiction-related neuroplasticity, including MAPK, cAMP signalling, axon guidance, and glutamatergic transmission. Reinstatement further differentiated CPPE and nCPPE rats, notably through persistent IEG activation and modulation of circadian regulators such as Rorb and Per2, suggesting a potential involvement of circadian-related mechanisms signature in cocaine vulnerability. Additional novel candidates, including SLC transporters and genes involved in synaptic organization, were identified in resilient females. Together, these findings provide an integrated behavioral and transcriptomic characterization of cocaine-induced interindividual variability in female rats and highlight molecular mechanisms that may contribute to vulnerability and resilience to cocaine's rewarding effects.