Administration of delta-9-tetrahydrocannabinol impacts hippocampal formation neurogenesis in female Wistar rats

Abstract

The world has been facing cannabis legalization modifications for recreational and medical usage. Women are not only becoming an increasing proportion of its users but also show a tendency to be more dependent than men. This fact regards the involvement of the endocannabinoid system (ECS) in several physiological and pathological processes. Exogenous cannabinoids like delta-9-tetrahydrocannabinol (THC) act on the same receptors as the endocannabinoids, anandamide and 2-arachidonylglycerol (2-AG): cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2). These receptors are abundant in the brain, especially in the hippocampal formation (HF), and are capable of influencing adult hippocampal neurogenesis (AHN). Thus, it becomes essential to better understand the ECS interaction with female gonadal hormones and its impact on neurogenesis. Sixteen young adult female Wistar rats underwent ovariectomy, following which they were divided into groups for treatment with THC and estradiol benzoate (EB), administered subcutaneously. Immunohistochemistry was performed to assess cell proliferation using Ki-67 protein, neurogenesis using doublecortin (DCX) and polysialylated neuronal cell adhesion molecule (PSA-NCAM), CB1 receptor expression, and inflammation using cyclooxygenase 2 (COX-2) and tumor necrosis factor alpha (TNF-α), within the HF. Fluorescence quantification was conducted and statistical analyses were performed to determine significant differences between experimental groups. The administration of THC promotes cell proliferation by affecting Ki-67 immunoreactivity on HF and it tendentially increases DCX expression, although no significant effects were observed for DCX and PSA-NCAM. The expression of CB1 receptor is modulated by THC, with a significant increase in dentate gyrus (DG) granular layer and hilus in EB-primed rats. Furthermore, THC exposure also influenced COX-2 and TNF-α expression levels differently across HF areas. The findings of this study suggest that administration of THC in female rats enhances AHN and reduces inflammation in HF, especially in the presence of EB. Our results shed light on the complexity of cannabinoid effects on neurogenesis, given the interaction of gonadal hormones, which provide insights into potential pharmacological interventions for neuropsychiatric disorders. Further research is warranted to clarify the interactions between molecular mechanisms and clinical implications.