Effects of chronic Δ9‐tetrahydrocannabinol and ovariectomy on cannabinoid type‐1 and type‐2 receptors and receptor trafficking in the hippocampus of female rats (838.3)

Abstract

Previous research from this laboratory has shown that 40 days of chronic Δ9‐tetrahydrocannabinol (THC) administration in female rats during adolescence increased their adult sensitivity to the acute error‐increasing effects of THC on a learning and performance task. These error‐increasing effects of THC were correlated with increased cannabinoid type‐1 receptor (CB1R) levels in the hippocampus, a region of the brain associated with learning. To determine the direct effects of long‐term chronic administration of THC on cannabinoid receptors, we administered THC daily to rats for five months, beginning in adolescence. Female rats underwent either ovariectomy or sham surgery on post‐natal day 30, which was then followed by either saline or 5.6 mg/kg of THC daily. This yielded four treatment groups with respect to hormone status and THC administration (intact/saline, intact/THC, OVX/saline, OVX/THC). Hippocampal tissue was collected and analyzed by western blotting. Dependent measures included chaperone proteins responsible for maturation and trafficking of CB1R, such as heat shock protein 90 (HSP90) and its co‐chaperone activator of heat‐shock 90kDa protein ATPase homolog 1 (AHA1). The results indicated that OVX rats, irrespective of chronic treatment, had decreased total CB1R, CB2R, and AHA1 levels. In addition, brain‐derived neurotrophic factor (BDNF) and HSP90β levels were increased in OVX rats. Together, these results show that ovarian hormones directly modulate cannabinoid receptors and specific chaperone proteins in the hippocampus. These findings may help explain the many sexually dimorphic effects of the cannabinoids.