Evaluation of the anti-depressant effect of metformin in ovariectomized mice: possible involvement of nitrergic and serotoninergic systems

Depressive disorders are the most prevalent form of the mental disorders in postmenopausal and there is information for beneficial effects of the metformin (MET) in depression. However, there is no report on anti-depressant effect of the MET during postmenopausal period. Thus, the aim of this study was to determine anti-depressant effect of the MET in ovariectomized (OVX) mice and possible involvement of nitrergic and serotoninergic systems. Two hundred and fifty female NMRI mice were randomly allocated into 5 experimental groups (each with 5 groups [A-E], n=50). In experiment 1, mice allocated as (A) control, (B) OVX injected with saline, (C) OVX injected with MET (100 mg/kg), (D) OVX mice injected with MET (200 mg/kg), (E) OVX injected with MET (400 mg/kg) at 24, 6 and 1 h prior the test. In experiment 2, experimental grouping was (A) control, (B) OVX injected with saline, (C) OVX mice injected with MET (400 mg/kg), (D) OVX mice injected with L-NAME (10 mg/kg), (E) OVX mice injected with MET (400 mg/kg) + L-NAME (10 mg/kg). Experiments 3-5 were similar to experiment 2, except OVX mice injected with L-arginine (50 mg/kg), cyproheptadine (4 mg/kg) and fluoxetine (5 mg/kg) instead of L-arginine. Following injections forced swimming test (FST), tail suspension test (TST) and open field test (OFT) were done. At the end of the study, serum malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx) and total antioxidant status (TAS) were determined. According to the results, MET (200 and 400 mg/kg) decreased immobility time in TST and FST (P<0.05). Co-injection of the MET+L-NAME decreased immobility time in TST and FST (P<0.05). Co-injection of MET+L-arginine significantly diminished antidepressant activity of the MET (P<0.05). MET + cyproheptadine decreased antidepressant activity of the MET (P<0.05). MET + fluoxetine significantly amplified antidepressant activity of the MET (P<0.05).  MET (200 and 400mg/kg) improved serum MDA, SOD and GPx levels (P<0.05). It seems that antidepressant activity of the MET is mediated by nitrergic and serotoninergic system in OVX mice.