Dorsomedial Striatum CB1R signaling is required for Pavlovian outcome devaluation in male Long Evans rats and reduces inhibitory synaptic transmission in both sexes

Abstract

Cannabinoid-1 receptor (CB1R) signaling in the dorsal striatum regulates the shift from flexible to habitual behavior in instrumental outcome devaluation. Based on prior work establishing individual, sex, and experience-dependent differences in Pavlovian behaviors, we predicted a role for dorsomedial striatum CB1R signaling in driving sign-tracking and rigid responding in Pavlovian outcome devaluation. We trained male and female rats in Pavlovian Lever Autoshaping to determine sign-, or goal- or intermediate tracking groups. After extended Pavlovian training, we gave intra-DMS infusions of the CB1R inverse agonist, rimonabant, before satiety-induced outcome devaluation test sessions, in which we sated rats on training pellets (devalued) or home cage chow (valued) and examined responding to cues in brief nonreinforced Pavlovian Lever Autoshaping sessions. Overall, DMS CB1R signaling inhibition blocked Pavlovian outcome devaluation. After extended training, male rats were sensitive to devaluation while female rats were not. Inhibition of DMS CB1R signaling impaired Pavlovian outcome devaluation in male sign-tracking rats making their behavior more rigid but had no effects in female sign-tracking rats. Intra-DMS rimonabant infusions before reinforced sessions had no effects on Pavlovian sign- or goal-tracking in either sex. The sex-specific and CB1R-dependent effects were specific to outcome devaluation and were consistent between sign- and goal-tracking groups. Our results demonstrate that DMS endocannabinoid receptor signaling regulates behavioral flexibility in a sex-specific manner, suggesting differences in CB1R signaling in DMS between male and female rats.