Modulation of Depression-Like Behavior by a Combination with Vitamin D3 and 17β-Estradiol in Middle-Aged Ovariectomized Rats Subjected to Chronic Mild Stress

The aim of this study was to examine the antidepressant-like responses to vitamin D3 (VD3) subcutaneous (s.c.) supplementation (1.0, 2.5, and 5.0 mg/kg) in middle-aged long-term ovariectomized (OVX) rats treated with a low dose of 17β-estradiol (17β-E2) (0.5 μg/rat, s.c.) exposed to the chronic unpredictable mild stress (CUMS). Sucrose preference (SPT), forced swimming (FST), and open-field (OFT) tests were performed to measure anhedonia, depressionlike state, and locomotor/grooming activities, respectively. Glial cell line-derived factor (GDNF) levels in the hippocampus of middle-aged long-term OVX rats following CUMS treated with VD3 were measured using ELISA and Western blotting. The serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations in the hippocampus were detected by high performance liquid chromatography (HPLC). The findings demonstrated that VD3 (1.0 mg/kg, s.c.) in a combination with a low dose of 17β-E2 increased sucrose consumption in the SPT and decreased depression-like behavior in the FST of middle-aged long-term OVX rats exposed to CUMS. This dose of VD3 elevated hippocampal GDNF protein expression and increased 5-HT/5-HIAA levels in middle-aged long-term OVX rats plus 17β-E2 compared to the middle-aged OVX rats plus 17β-E2 with CUMS. The other two doses of VD3 (2.5 and 5.0 mg/kg, s.c.) failed to modify both GDNF protein levels and 5-HT turnover in the hippocampus of middle-aged long-term OVX rats treated with 17β-E2 exposed to CUMS. Thus, treatment with a low dose of VD3 (1.0 mg/kg, s.c.) in a combination with a low dose of 17β-E2 enhanced antianhedonic-/antidepressant-like effects of both substances in middle-aged long-term OVX rats exposed to CUMS.