Comparison of the Antidepressant-Like Effects of Estradiol and That of Selective Serotonin Reuptake Inhibitors in Middle-Aged Ovariectomized Rats.

Saloua Benmansour,Luis D Arroyo,Alan Frazer

doi:10.3389/fnagi.2016.00311

Abstract

This study investigated the effect of age and that of the post-ovariectomy (OVX) time interval on the antidepressant (AD)-like effects of estradiol (E2) and selective serotonin reuptake inhibitors (SSRIs) in middle-aged (10 month) OVX rats (10m-OVX). Acute or chronic effects of these treatments in 10m-OVX were compared with those (1) in young adult (4-month) OVX rats (4m-OVX) or with older (14-month) OVX rats (14m-OVX), at a short time: 2 weeks post-OVX (+2w) and (2) in 10m-OVX rats after a longer times: 4 or 8 months post-OVX (+4m or +8m). Using in vivo chronoamperometry in the CA3 region of the hippocampus, E2 at 20 pmol, a dose shown previously to inhibit the serotonin transporter (SERT) in 4m-OVX, had no effect in 10m-OVX+2w. A higher dose of E2 (40 pmol) increased T80 value, a measure of serotonin or 5-hydroxytryptamine (5-HT) clearance, and also blocked the ability of fluvoxamine to increase T80. By contrast, estradiol had no effects on SERT function in 10m-OVX+4m, even at a higher dose than 40 pmol. Fluvoxamine slowed 5-HT clearance in 10m-OVX at +2w, +4m and +8m post-OVX as it did in the 4m-OVX. Using the forced swim test, 2 weeks treatment with E2 (5 μg/day), a dose shown previously to induce AD-like effects in 4m-OVX, had no effect in 10m-OVX+2w. However, a higher dose (10 μg/day) of E2 induced an AD-like effect as demonstrated by significantly increased swimming behavior and decreased immobility. This effect was not seen in 10m-OVX+4m. By contrast, significant AD-like effects were obtained in 14m-OVX+2w, thereby demonstrating that the lack of an AD effect of E2 is due to the 4-month hormone withdrawal and not to an age effect. After 2 weeks treatment with the SSRI sertraline, similar AD-like effects were obtained in 10m-OVX tested at +2w, +4m or +8m post-OVX as those found in 4m-OVX. Thus, the potency of estradiol to produce effects consistent with inhibition of the SERT was not only decreased in older rats but its effects were markedly diminished the longer hormonal depletion occurred. By contrast, the ability of SSRIs to inhibit the SERT was not affected either by age or the length of hormonal depletion.

Highlights

The efficacy of antidepressants (ADs) in the elderly suffering from major depressive disorder (MDD) is controversial (Kasper et al, 2005; Nelson et al, 2008)
The selective serotonin reuptake inhibitors (SSRIs) fluvoxamine was used in the in vivo chronoamperometry experiments as we found that it did not interfere with the electrochemical signal of 5-HT as other SSRIs such as fluoxetine or sertraline did
By contrast after 4 months of hormonal depletion, 40 pmol E2 had no effect on serotonin clearance nor did it alter the ability of fluvoxamine to slow 5HT clearance in 10–month-old OVX rats

Summary

Introduction

The efficacy of antidepressants (ADs) in the elderly suffering from major depressive disorder (MDD) is controversial (Kasper et al, 2005; Nelson et al, 2008). The onset or exacerbation of depressive symptoms has been associated with the time around perimenopause (Maki et al, 2010; Soares, 2013). This has provided a rationale to try either estrogen replacement therapy (ERT) or hormone replacement therapy (HRT) in such patients. Such treatment has been reported to have AD effects in peri- and postmenopausal women (Frey et al, 2008; Soares and Frey, 2010), this is not a universal finding (Morrison et al, 2004). There appears to be little evidence that taking SSRIs in conjunction with ERT produces greater improvement in depressive symptoms than that seen with an SSRI alone (Frey et al, 2008)

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