Sex Differences in Endocannabinoid Regulation of Behavioral Flexibility

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Project Summary Around 30% of individuals who try drugs of abuse transition to addiction, suggesting that individual differences prior to drug experience contribute to addiction vulnerability. Sign-tracking and goal-tracking phenotypes which predict distinct drug relapse vulnerabilities, have been modelled in humans and rodents. Sign-tracking rats show enhanced cue sensitivity prior to drug experience which predicts heightened cue-driven drug seeking and increased cue-induced relapse as compared to goal-trackers. Men and women also differ in their addiction vulnerability, where women show enhanced escalation of drug use and higher probability to relapse. Female rats are more likely to be sign-trackers, suggesting a need to study sex differences in sign-tracking rats to understand the unique neurobiological vulnerabilities in females. Sign-trackers and females are similarly inflexible when rewarding outcomes are devalued. I have found that decreasing cannabinoid 1 receptors (CB1R) signaling in the dorsomedial striatum (DMS) makes female sign-tracking rats flexible, but has the opposite effect in male sign-tracking rats. CB1R are expressed on orbitofrontal cortex (OFC) inputs to the DMS and on GABAergic interneurons and medium spiny neurons in the DMS. This project will focus on the intersection of sex and sign-tracking, investigating DMS endocannabinoid regulation of behavioral flexibility. I hypothesize that a CB1R-mediated decrease in OFC-DMS transmission prevents flexibility in female sign- tracking rats, while a CB1R-mediated decrease in GABAergic transmission promotes flexibility of male sign- tracking rats. First, I will use slice electrophysiology and RNAscope to understand the functional and expression-based differences in CB1R within the DMS between male and female ST rats. Second, I will use chemogenetics and slice electrophysiology to investigate the contribution of OFC-DMS projection to behavioral flexibility and the influence of CB1R activation on this projection. Through these experiments, I aim to uncover critical molecular and circuit-based mechanisms that contribute to impairments in flexibility that are associated with addiction vulnerability.