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

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 (CBR) 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. In this study, we aimed to determine if CBRs in the intestinal epithelium exert control over anxiety-like behaviors in a sex-dependent manner. We subjected male and female mice with conditional deletion of CBRs in the intestinal epithelium (intCB) and controls (intCB) 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. When compared with intCB male mice, intCB 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 intCB and intCB mice. Circulating CORT was higher in female male mice for both genotype groups at baseline and after EPM exposure; however, there was no effect of genotype on CORT levels. Collectively, these results indicate that genetic deletion of CBRs in the intestinal epithelium is associated with an anxiolytic phenotype in a sex-dependent manner.