Sex-dependence of anxiety-like behavior in cannabinoid receptor 1 (Cnr1) knockout mice

•We compare anxiety-like behavior of male and female Cnr1 transgenic mice.•Male Cnr1 KOs make less percent open arm entries on an elevated plus maze compared to male WTs.•Female WTs and female Cnr1 KOs do not significantly differ on percent open arm entries.•Ovariectomy does not affect percent open arm entries.•Cnr1 antagonist administration decreases percent open arm entries in both sexes.

Epidemiological data suggest women are at increased risk for developing anxiety and depression, although the mechanisms for this sex/gender difference remain incompletely understood. Pre-clinical studies have begun to investigate sex-dependent emotional learning and behavior in rodents, particularly as it relates to psychopathology; however, information about how gonadal hormones interact with the central nervous system is limited. We observe greater anxiety-like behavior in male mice with global knockout of the cannabinoid 1 receptor (Cnr1) compared to male, wild-type controls as measured by percent open arm entries on an elevated plus maze test. A similar increase in anxiety-like behavior, however, is not observed when comparing female Cnr1 knockouts to female wild-type subjects. Although, ovariectomy in female mice did not reverse this effect, both male and female adult mice with normative development were sensitive to Cnr1 antagonist-mediated increases in anxiety-like behavior. Together, these data support an interaction between sex, potentially mediated by gonadal hormones, and the endocannabinoid system at an early stage of development that is critical for establishing adult anxiety-like behavior.