Cannabinoid receptor expression and phosphorylation are differentially regulated between male and female cerebellum and brain stem after repeated stress: Implication for PTSD and drug abuse

Recent study demonstrated a close relationship between cerebellum atrophy and symptom severity of pediatric maltreatment-related posttraumatic stress disorder (PTSD). It has also been known that females are more vulnerable than males in developing anxiety disorders after exposure to traumatic stress. The mechanisms are unknown. Because cannabinoid receptors (CB1 and CB2) are neuroprotective and highly expressed in the cerebellum, we investigated cerebellar CB expression in stressed rats. Young male and female Sprague-Dawley rats were given 40 unpredictable electric tail-shocks for 2 h daily on 3 consecutive days. CB1 and CB2 mRNA and protein levels in rat cerebellum and brain stem were determined using quantitative real-time PCR and Western blot, respectively. Two-way ANOVA revealed significant gender and stress effects on cerebellar CB1 mRNA expression, with females and non-stressed rats exhibiting higher CB1 mRNA levels than the males (3 fold, p < 0.01) and stressed rats (30%, p < 0.01), respectively. CB1 and CB2 mRNA levels in brain stem were also greater in female rats than males (p < 0.01, p < 0.05, respectively). Repeated stress increased the level of phosphorylated CB1 receptors, the inactivated CB1, in rat cerebellum (p < 0.01), particularly in female rats as revealed by the significant gender × stress interaction. Thus, repeated severe stress caused greater CB1 mRNA suppression and CB1 receptor phosphorylation in female cerebellum that could lead to increased susceptibility to stress-related anxiety disorders including PTSD.

► Cannabinoid receptors (CB1 and CB2) are determined in rat cerebellum and brain stem.
► Female rats show greater CB1 and CB2 mRNA expression levels than male rats.
► Repeated tail-shock stress induced greater suppression of CB1 mRNA level in female rats.
► Repeated stress selectively enhanced CB1 receptor phosphorylation in female cerebellum.
► CB1 hypoactivity could underlie sex-dimorphism in anxiety disorders including PTSD.