Sex-Specific Differences and the Role of Environmental Enrichment in the Expression of Hippocampal CB 1 Receptors following Chronic Unpredictable Stress.

Stress-related mental disorders have become increasingly prevalent, thus endangering mental health worldwide. Exploring stress-associated brain alterations is vital for understanding the possible neurobiological mechanisms underlying these changes. Based on existing evidence, the brain endogenous cannabinoid system (ECS) plays a significant role in the stress response, and disruptions in its function are associated with the neurobiology of various stress-related disorders. This study primarily focuses on investigating the impact of chronic unpredictable stress (CUS) on the expression of hippocampal cannabinoid type 1 (CB 1 ) receptors, part of the ECS, in adult male and female Wistar rats. Additionally, it explores whether environmental enrichment (EE) initiated during adolescence could mitigate the CUS-associated alterations in CB 1 expression. Wistar rats, shortly after weaning, were placed in either standard housing (SH) or EE conditions for a duration of 10 weeks. On postnatal day 66, specific subgroups of SH or EE animals underwent a 4-week CUS protocol. Western blot (WB) analysis was conducted in the whole hippocampus of the left brain hemisphere to assess total CB 1 protein expression, while immunohistochemistry (IHC) was performed on the right hemisphere to estimate the expression of CB 1 receptors in certain hippocampal areas (i.e., CA1, CA3 and dentate gyrus-DG). The WB analysis revealed no statistically significant differences in total CB 1 protein levels among the groups; however, reduced CB 1 expression was found in specific hippocampal sub-regions using IHC. Specifically, CUS significantly decreased CB 1 receptor expression in the CA1 and DG of both sexes, whereas in CA3 the CUS-associated decrease was limited to SH males. Interestingly, EE housing proved protective against these reductions. These findings suggest a region and sex-specific endocannabinoid response to chronic stress, emphasizing the role of positive early experiences in the protection of the adolescent brain against adverse conditions later in life.