Sex Differences in Antidepressant Effect of Sertraline in Transgenic Mouse Models.

Lei Ma,Xinzhu Zhang,Yong Xu,Gang Wang,Wei Jiang,Rena Li,Yuhong Li

doi:10.3389/fncel.2019.00024

Abstract

The main purpose of this study is to explore sex differences in the antidepressant effect of sertraline in genetic knockout or overexpression estrogen-synthesizing enzyme aromatase (Ar) gene mouse models in the forced swim test (FST). Our results demonstrated a significant reduction of depression-like behavior in the mice with overexpression of brain aromatase (Thy1-Ar) compared to sex- and age-matched Ar+/− mice or wild type control mice. Using HPLC analysis, we also found an association between the brain estrogen-related antidepressive behavior and the regulation of serotonin (5-HT) system. Interestingly, a single dose administration of sertraline (10 mg/kg, i.p.) induced reduction of immobility time was found in all genotypes, except male Ar+/− mice. While the underlying mechanisms of sex-specific response on antidepressive effect of sertraline remain to be investigated, our data showed that female mice appear to be more sensitive to sertraline-induced changes of 5-HT system than male mice in the prefrontal cortex (PFC) and the hippocampus (HPC). Further investigation of sex-specific effect of brain estrogen on antidepressant is needed.

Highlights

The prevalence of major depressive disorder (MDD) is more common in women than men (Pearson et al, 2013)
We found no effect of endogenous estrogen deficiency on immobile time in the forced swim test (FST) in both male and female Ar+/− mice compared to sex-matched wild type (WT) animals
These results imply that enriched brain estrogen promotes antidepressive-like behavior, whether reduction of endogenous estrogen failed to alter immobility time during the FST

Summary

Introduction

The prevalence of major depressive disorder (MDD) is more common in women than men (Pearson et al, 2013). While lower estrogen levels have been implicated in this increased risk in post-menopausal women (Albert et al, 2015), the hypothesis of sex hormone-related depression is supported by animal studies, such as more depression-like behaviors were seen in the ovariectomized (OVX) rodents vs intact rodents (Ye et al, 2016). Similar to the human clinical practice of treating depression with estrogen (Toffol et al, 2015), many animal studies suggest that estrogen supplementation can prolong the swimming time in the forced swim test (FST) as a support of estrogen antidepressive effect (Walf and Frye, 2010a; Saravi et al, 2016). Similar sex differences in SRIs response are seen in animal tests (Fernandez-Guasti et al, 2017). While very little is known about the mechanisms of this sex-dependent differential response, we hypothesized that estrogen level might be responsible for the sex-dependent SRIs action

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