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 (10mg/kg) or 7-NI (25mg/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.