The antidepressant-like effects of escitalopram in mice require salt-inducible kinase 1 and CREB-regulated transcription co-activator 1 in the paraventricular nucleus of the hypothalamus

Abstract

BackgroundThe salt-inducible kinase 1 (SIK1)-CREB-regulated transcription co-activator 1 (CRTC1) system in the paraventricular nucleus (PVN) of the hypothalamus has been demonstrated to participate in not only depression neurobiology but also the antidepressant mechanisms of fluoxetine, paroxetine, venlafaxine, and duloxetine. Like fluoxetine and paroxetine, escitalopram is also a well-known selective serotonin (5-HT) reuptake inhibitor (SSRI). However, recently it has been found that escitalopram can modulate a lot of targets other than the 5-HT system. Here, we speculate that escitalopram produces effects on the SIK1-CRTC1 system in the PVN. MethodsTwo mice models of depression (chronic social defeat stress (CSDS) and chronic unpredictable mild stress (CUMS)), various behavioral tests, enzyme linked immunosorbent assay (ELISA), western blotting, co-immunoprecipitation (Co-IP), quantitative real-time reverse transcription PCR (qRT-PCR), immunofluorescence, and adeno-associated virus (AAV)-mediated gene transfer were used together in the present study. ResultsIt was found that escitalopram administration not only significantly prevented the hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis induced by CSDS and CUMS, but also notably reversed the effects of CSDS and CUMS on SIK1, CRTC1, and CRTC1-CREB binding in the PVN of mice. AAV-based genetic knock-down of SIK1 in PVN neurons evidently abolished the antidepressant-like effects of escitalopram in mice. LimitationA shortage of this study is that only rodent models of depression were used, while human samples were not included. ConclusionsIn summary, regulating the SIK1-CRTC1 system in the PVN participates in the antidepressant mechanism of escitalopram, which extends the knowledge of the pharmacological actions of escitalopram.