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.