Nitric oxide involvement in estrous cycle-dependent changes of the behavioral responses of female rats in the elevated plus-maze test

Nitric oxide (NO)/cGMP pathway is known as a mediator in anxiety modulation. In this study, we assessed the involvement of NO pathway in the estrous cycle-related changes of anxiety level in rat. By using elevated plus-maze test, we studied the changes of serum nitrate and nitrite (NOx) levels in comparison to the estrous cycle-dependent changes of anxiety state. Then, we tested the effects of nitric oxide synthase (NOS) inhibitor, L-NAME (10, 60 mg/kg, i.p.), and the NO precursor, l-arginine (100 mg/kg, i.p.) on anxiety modulatory properties of exogenous ovarian hormones in ovariectomized (OVX) rats. Compared with other cycle phases and with OVX rats, cycling rats spent more time in open arms and had lower levels of serum NOx levels during metestrous while they spent less time in open arms and had lower levels of serum NOx levels during proestrous. In OVX rats, L-NAME (60 mg/kg, i.p.) exerted anxiolytic effect while l-arginine showed no effect. In comparison with corn oil-treated controls, estradiol benzoate (10 μg/kg, subcutaneously (s.c.)) significantly increased the serum NOx level and exerted anxiogenic effect, which was dose-dependently inhibited by L-NAME but was not changed by l-arginine. In contrast, progesterone (25 mg/kg, s.c.) significantly decreased the serum NOx level and exerted anxiolytic effect, which was abolished by l-arginine but was not affected by L-NAME. These findings suggest that NO system might be involved in the estrous cycle-related changes of anxiety level, probably by mediating the effect of ovarian sex hormones.