Mammalian target of rapamycin (mTOR)/nitric oxide system possibly modulate antidepressant-like effect of 17α-ethinyl estradiol in ovariectomized mice

Due to a close association between depressive disorders and altered estrogen levels, this study was conducted to examine the hypothesis that antidepressant-like effect of ethinyl estradiol (EE2) in ovariectomized mice is modulated by mammalian target of rapamycin (mTOR)/nitric oxide pathways.Female mice were undergone bilateral ovariectomy and different doses of EE2 were intraperitoenally injected alone and combined with specific mTOR inhibitor, rapamycin, non-specific NOS inhibitor, L-NAME, nNOS inhibitor, 7-NI, NO precursor, l-arginine, and selective PDE5I, sildenafil. After locomotion assessment, immobility times were recorded in FST and TST. Moreover, hippocampal mTOR expression was assessed using western blot assay. The hippocampal concentrations of nitrite, a major metabolite of NO, were measured.Although EE2 demonstrated a significant antidepressant-like activity in OVX mice, acute rapamycin exerted an unmarked decrease of the anti-immobility effect of EE2 in FST and TST (P > 0.05). In contrast, combination of minimal effective dose of EE2 with sub- effective doses of either L-NAME (10 mg/kg) or 7-NI (25 mg/kg) resulted in a robust antidepressant-like effect in OVX mice. Administration of either L-NAME or 7-NI enhanced the decreased antidepressant activity of EE2 induced by combination with rapamycin. Moreover, decrement of hippocampal mTOR expression in OVX mice was significantly enhanced by acute EE2. The increased hippocampal nitrite concentrations caused by ovariectomy were also reversed by EE2 administration.The study demonstrated that acute treatment with lowest dose of EE2 exerts significant antidepressant-like behavior in OVX mice, possibly, through mTOR activation. This effect seems to be also mediated by the suppression of nitric oxide pathway.