Comparison of the Effects of Estradiol and Progesterone on Serotonergic Function

Abstract

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.

Influence of acute or chronic administration of ovarian hormones on the effects of desipramine in the forced swim test in female rats

“…In our present study, estrogen (as EB or E2) and P were administered in combination. Consistent with our previous report (Benmansour et al 2012), acute administration of these hormones did not produce an antidepressant-like effect. Our group has previously reported using chronoamperometry to measure the rate of clearance of exogenous serotonin from the CA3 region of the hippocampus, that progesterone blocked the antidepressant-like effect of EB (Benmansour et al 2009).…”

“…Therefore, results of the acute study indicate a reduced efficacy of DMI in the FST in the presence of ovarian hormones. This phenomenon seems consistent with the diminished SSRI efficacy reported in a previous study from our group (Benmansour et al 2012) with an identical hormone administration paradigm. In that study, the effect of estrogen on SSRI function was found to be dependent on the ER subtype, with ERα mediating its inhibitory effect on the ability of an SSRI to inhibit the SERT.…”

“…This test was performed essentially as described by Detke et al (Detke et al 1995) except the 15-min training session (for acute studies) was carried out 75 h before the 5-min test session, instead of the usual 24 h. The training session for the FST was carried out 75 h prior to testing, as previously described (Benmansour et al 2012), in order to train all animals in the absence of hormones or drug. There was no training session for chronic studies as the effects of chronic AD treatment in the FST are observed even in the absence of the training session, as shown by others (Cryan et al 2005) and by us (Furmaga et al 2011).…”

“…Whereas the AD-like effects of estrogen and P have been demonstrated in the forced swim test (FST) in rats (Estrada-Camarena et al 2003; Molina-Hernandez and Tellez-Alcantara 2001), the impact of these ovarian hormones on the effects of ADs in the FST has not been investigated in depth. Our group recently found that EB and/or P blocked the decrease in immobility and increase in swimming caused by the SSRI, fluvoxamine (Benmansour et al 2012). …”

Depression and Serotonergic Changes during the Climacteric and Postmenopausal Stages: Hormonal Influences

“…The slowing of the 5-HT clearance was due to activation of β-estrogen and/or GPR30. Meanwhile, the blockade of luvoxamine's inhibitory efect on 5-HT clearance was mediated by α-estrogen [42]. Both of them used diferent signaling mechanisms.…”