Sex specific effects of the fatty acid amide hydrolase inhibitor URB597 on memory and brain β2-adrenergic and D1-dopamine receptors.

Abstract An increasing body of evidence shows significant sex differences in the mammalian brain in multiple behaviours and psychiatric and neurological diseases and as well as that the endocannabinoid system may differ between males and females. In this study we investigated sex differences in working, short-term and long-term memory and the expression of β2-adrenergic and D1- and D2-receptors in the mPFC and hippocampus, brain regions that are involved in stress response and memory modulation in rats exposed to the chronic unpredictable stress (CUS) and the potential beneficial effects of the chronic fatty acid amide hydrolase inhibitor URB597 treatment. Chronically stressed male rats had an improvement of working memory, while stressed females showed very low object-recognition abilities. On the other hand, animals of both sexes exhibited long-term memory impairment. Our results showed that CUS decreased the expression of β2-adrenoceptors in the mPFC and D1 receptors in the mPFC and hippocampus of male rats and decreased β2-adrenoceptors and D1- receptors in the hippocampus of female. URB597 treatment had a positive effect on the short-term memory of stressed animals of both sexes whereas failed to restore long-term memory and did not affect the protein levels β2-adrenoceptors and D1 receptors in the hippocampus of CUS female rats. The present results support that endocannabinoids induced long-term memory and neurochemical alternations which are sex dependent, suggesting sex specific treatment strategies of mental disorders.