Dorsomedial Striatum CB1R signaling promotes Pavlovian devaluation sensitivity in male Long Evans rats and reduces DMS inhibitory synaptic transmission in both sexes.

Cannabinoid receptor-1 (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 (DMS) CB1R signaling in driving rigid responding in Pavlovian autoshaping and outcome devaluation. We trained male and female Long Evans rats in Pavlovian Lever Autoshaping (PLA). We gave intra-DMS infusions of the CB1R inverse agonist, rimonabant, before satiety-induced outcome devaluation test sessions, where we sated rats on training pellets or home cage chow and tested them in brief nonreinforced PLA sessions. Overall, inhibition of DMS CB1R signaling prevented Pavlovian outcome devaluation but did not affect behavior in reinforced PLA sessions. Males were sensitive to devaluation while females were not and DMS CB1R blockade impaired devaluation sensitivity in males. Because these results suggest DMS CB1R signaling supports flexible responding, we investigated how DMS CB1R signaling impacts local inhibitory synaptic transmission in male and female Long Evans rats. We recorded spontaneous inhibitory postsynaptic currents (sIPSC) from DMS neurons at baseline and after application of a CB1R agonist, WIN 55,212-2. We found that male rats showed decreased sIPSC frequency compared to females, and that CB1R activation reduced DMS inhibitory transmission independent of sex. Altogether our results demonstrate that DMS CB1Rs regulate Pavlovian devaluation sensitivity and DMS inhibitory synaptic transmission and suggest that basal sex differences in inhibitory synaptic transmission may underly sex differences in DMS function and behavioral flexibility. Adaptive behavior requires both flexible and habitual actions depending on environmental conditions. The dorsal striatum regulates shifts from flexible to habitual behaviors and the dorsomedial striatum (DMS) endocannabinoid system regulates this shift in instrumental reward devaluation. Individual and sex differences in Pavlovian reward devaluation suggest differences in endocannabinoid regulation of behavioral flexibility in the DMS. The current study 1) falsifies the hypothesis that DMS cannabinoid receptor-1 (CB1R) signaling promotes habitual behaviors, finding instead that DMS CB1R signaling promotes flexibility in Pavlovian devaluation, and 2) establishes sex differences in Pavlovian devaluation and DMS inhibitory synaptic transmission.