Background Ovarian hormones may contribute to the vulnerability to depression as well as to the response to antidepressants (ADs). Previously we reported that acute systemic treatment with estradiol or progesterone blocked the ability of the selective serotonin reuptake inhibitor (SSRI), fluvoxamine, to inhibit serotonin transporter (SERT) function in ovariectomized (OVX) rats. In this study, behavioral consequences as well as receptor mechanisms underlying these hormonal effects were investigated. Methods Using the forced swimming test (FST), the acute effect of estradiol and/or progesterone on fluvoxamine’s AD-like effects was investigated. Using in vivo chronoamperometry, the effect of local application of estradiol or progesterone into the CA3 region of the hippocampus of OVX rats on 5-HT clearance as well as on the ability of fluvoxamine to slow 5-HT clearance was investigated. Results The decreased immobility and increased swimming caused by fluvoxamine in the FST was blocked in rats treated with estradiol and/or progesterone. Local application of estradiol, but not progesterone, slowed 5-HT clearance and both hormones blocked the ability of fluvoxamine to slow 5-HT clearance. Use of hormone receptor agonists, antagonists and hormone-BSA complexes revealed that the effects of estradiol are mediated by activation of membrane as well as nuclear estrogen receptors (ER). The AD-like effect of estradiol involved ERβ and GPR30 whereas its blockade of fluvoxamine’s effects was ERα-mediated. The effects of progesterone occurred solely by activation of intracellular progesterone receptors. Conclusion Targeting of ERβ or GPR30 might reveal a strategy to permit beneficial effects of estrogen without its deleterious effect on SSRI-efficacy.
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