A Sexually Dimorphic Role for Intestinal Cannabinoid Receptor Subtype-1 in the Behavioral Expression of Anxiety

Background: Increasing evidence suggests that the endocannabinoid system (ECS) in the brain controls anxiety and may be a therapeutic target for the treatment of anxiety disorders. For example, both pharmacological and genetic disruption of cannabinoid receptor subtype-1 (CB1R) signaling in the central nervous system is associated with increased anxiety-like behaviors in rodents, while activating the system is anxiolytic. Sex is also a critical factor that controls the behavioral expression of anxiety; however, roles for the ECS in the gut in these processes and possible differences between sexes are largely unknown.Objective: In this study, we aimed to determine if CB1Rs in the intestinal epithelium exert control over anxiety-like behaviors in a sex-dependent manner.Methods: We subjected male and female mice with conditional deletion of CB1Rs in the intestinal epithelium (intCB1-/-) and controls (intCB1+/+) to the elevated plus maze (EPM), light/dark box, and open field test. Corticosterone (CORT) levels in plasma were measured at baseline and immediately after EPM exposure.Results: When compared with intCB1+/+ male mice, intCB1-/- male mice exhibited reduced levels of anxiety-like behaviors in the EPM and light/dark box. In contrast to male mice, no differences were found between female intCB1+/+ and intCB1-/- mice. Circulating CORT was higher in female versus male mice for both genotype groups at baseline and after EPM exposure; however, there was no effect of genotype on CORT levels.Conclusions: Collectively, these results indicate that genetic deletion of CB1Rs in the intestinal epithelium is associated with an anxiolytic phenotype in a sex-dependent manner.