Synergic action of Vitamin D3 and 17β-estradiol on behavioral impairments induced by unpredictable mild stress in the adult ovariectomized female rats

The aim of the present study was study changes in antidepressant-like responses to Vitamin D3 (VD3) supplementation in three different doses (1.0, 2.5, and 5.0 mg/kg, s.c.) in long-term ovariectomized (OVX) rats treated with low dose of 17β-E2 (0.5 µg/rat, s.c.) during chronic unpredictable mild stress (CUMS). Sucrose preference (SPT), forced swimming (FST), and open-field (OFT) tests were administered to measure depression-like behavior. Brain-derived neurotrophic factor (BDNF), and serotonine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) levels in the hippocampus were measured by ELISA, western blotting analysis, and by using high performance liquid chromatography (HPLC) respectively. The findings demonstrated that VD3 at high dose (5.0 mg/kg, s.c.) in a combination with low dose of 17β-E2 increased sucrose consumption in the SPT and decreased depression-like in the FST of the long-term OVX rats submitted to CUMS. VD3 (5.0 mg/kg) resulted in significant elevated levels of hippocampal BDNF protein expression, as well as to the normalization of 5-HT and 5-HIAA levels in long-term OVX rats plus 17β-E2 compared to the OVX rats plus solvent or 17β-E2 submitted to CUMS. There were no significant effects of VD3 (1.0 and 2.5 mg/kg) treatment on both BDNF protein levels and 5-HT turnover in the hippocampus of the long-term OVX rats treated with 17β-E2 exposed to CUMS compared to the long-term OVX with CUMS rats plus solvent. In conclusion, VD3 at high dose (5.0 mg/kg, s.c.) in a combination with low dose of 17β-E2 had a synergic antianhedonic- and antidepressant-like effects in the adult female rats following long-term ovariectomy submitted to CUMS. This is the first study in long-term OVX female rats showing beneficial effects of VD3 on depression-like behavior that are depended on the presence/absence of stressful factors.