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

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.

SUBMITTER: Ma L

PROVIDER: S-EPMC6369353 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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

Ma Lei L Xu Yong Y Jiang Wei W Li Yuhong Y Zhang Xinzhu X Wang Gang G Li Rena R

Frontiers in cellular neuroscience 20190201

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<sup>+/-</sup> mice or wild type control mice. Using HPLC analysis, we also found an associa ...[more]

PMID: 30778289

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Project description:Study questionDo selective serotonin reuptake inhibitor (SSRI) antidepressants affect the function of human sperm?Summary answerThe SSRI antidepressant Sertraline (e.g. Zoloft) inhibits the sperm-specific Ca2+ channel CatSper and affects human sperm function in vitro.What is known alreadyIn human sperm, CatSper translates changes of the chemical microenvironment into changes of the intracellular Ca2+ concentration ([Ca2+]i) and swimming behavior. CatSper is promiscuously activated by oviductal ligands, but also by synthetic chemicals that might disturb the fertilization process. It is well known that SSRIs have off-target actions on Ca2+, Na+ and K+ channels in somatic cells. Whether SSRIs affect the activity of CatSper is, however, unknown.Study design, size, durationWe studied the action of the seven drugs belonging to the most commonly prescribed class of antidepressants, SSRIs, on resting [Ca2+]i and Ca2+ influx via CatSper in human sperm. The SSRI Sertraline was selected for in-depth analysis of its action on steroid-, prostaglandin-, pH- and voltage-activation of human CatSper. Moreover, the action of Sertraline on sperm acrosomal exocytosis and penetration into viscous media was evaluated.Participants/materials, setting, methodsThe activity of CatSper was investigated in sperm of healthy volunteers, using kinetic Ca2+ fluorimetry and patch-clamp recordings. Acrosomal exocytosis was investigated using Pisum sativum agglutinin and image cytometry. Sperm penetration in viscous media was evaluated using the Kremer test.Main results and the role of chanceSeveral SSRIs affected [Ca2+]i and attenuated ligand-induced Ca2+ influx via CatSper. In particular, the SSRI Sertraline almost completely suppressed Ca2+ influx via CatSper. Remarkably, the drug was about four-fold more potent to suppress prostaglandin- versus steroid-induced Ca2+ influx. Sertraline also suppressed alkaline- and voltage-activation of CatSper, indicating that the drug directly inhibits the channel. Finally, Sertraline impaired ligand-induced acrosome reaction and sperm penetration into viscous media.Limitations, reasons for cautionThis is an in vitro study. Future studies have to assess the physiological relevance in vivo.Wider implications of the findingsThe off-target action of Sertraline on CatSper in human sperm might impair the fertilization process. In a research setting, Sertraline may be used to selectively inhibit prostaglandin-induced Ca2+ influx.Study funding/competing interest(s)This work was supported by the Swiss Centre for Applied Human Toxicology (SCAHT), the Département de l'Instruction Publique of the State of Geneva, the German Research Foundation (CRU326), the Interdisciplinary Center for Clinical Research, Münster (IZKF; Str/014/21), the Innovation Fund Denmark (grant numbers 14-2013-4) and the EDMaRC research grant from the Kirsten and Freddy Johansen's Foundation. The authors declare that no conflict of interest could be perceived as prejudicing the impartiality of the research reported.Trial registration numberNA.

Dataset Information

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

Publications

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

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