Differential Learned Helplessness Phenotypes in Male and Female Rats: Exploring the Therapeutic Impact of Cannabidiol Treatment

Abstract Evidence suggests a bidirectional relationship between depressive symptoms and neuroinflammation. We studied the effects of chronic treatment with cannabidiol (CBD) in male and female rats exposed to an unpredictable chronic mild stress (UCMS) model of depression. We analyzed gene expression related to neuroinflammation, cannabinoids, and estrogen receptors, as well as specific microRNAs (miRs) in the ventromedial prefrontal cortex (vmPFC), CA1, and ventral subiculum (VS). We found sex- and brain region-dependent effects of UCMS and CBD. UCMS exerted sex-specific effects on immobility, increasing it in males while decreasing it in females; CBD reversed this effect in both sexes. Regarding neuroinflammation, CBD restored Tumor Necrosis Factor α (TNF-α) gene upregulation in the CA1 and VS in males. In both sexes, UCMS led to nuclear factor kappa B subunit 1 (NF-κB1) gene upregulation in the VS, unaffected by CBD. In males, UCMS-induced CB1 gene downregulation in the VS was restored by CBD. UCMS resulted in CB1 gene downregulation in the vmPFC in both sexes, with no CBD effect. In males, CBD restored UCMS-induced downregulation of VS ERα and ERβ genes. Finally, UCMS downregulated miR-146a-5p in the VS in females and upregulated it in the CA1 in males without CBD restoring effects. Our findings highlight sex-specific differences in learned helplessness and CBD’s modulation of neuroinflammatory, cannabinoid, and estrogen gene expression following exposure to chronic stress. Specifically, in males, hippocampal neuroinflammatory and estrogenic mechanisms play pivotal roles in mediating CBD's antidepressant effects.