Fluoxetine regulates mTOR signalling in a region-dependent manner in depression-like mice

Abstract

Previous studies have demonstrated that the mammalian target of rapamycin (mTOR) signaling pathway has an important role in ketamine-induced, rapid antidepressant effects despite the acute administration of fluoxetine not affecting mTOR phosphorylation in the brain. However, the effects of long-term fluoxetine treatment on mTOR modulation have not been assessed to date. In the present study, we examined whether fluoxetine, a type of commonly used antidepressant agent, alters mTOR signaling following chronic administration in different brain regions, including the frontal cortex, hippocampus, amygdala and hypothalamus. We also investigated whether fluoxetine enhanced synaptic protein levels in these regions via the activation of the mTOR signaling pathway and its downstream regulators, p70S6K and 4E-BP-1. The results indicated that chronic fluoxetine treatment attenuated the chronic, unpredictable, mild stress (CUMS)-induced mTOR phosphorylation reduction in the hippocampus and amygdala of mice but not in the frontal cortex or the hypothalamus. Moreover, the CUMS-decreased PSD-95 and synapsin I levels were reversed by fluoxetine, and these effects were blocked by rapamycin only in the hippocampus. In conclusion, our findings suggest that chronic treatment with fluoxetine can induce synaptic protein expression by activating the mTOR signaling pathway in a region-dependent manner and mainly in the hippocampus.

Fast-acting antidepressants rapidly stimulate ERK signaling and BDNF release in primary neuronal cultures

“…In contrast to the rapid effects of these agents, incubation with the typical monoaminergic antidepressants fluoxetine and desipramine for 1 hr did not influence phospho-ERK and phospho-S6K, demonstrating specificity of this signaling to the rapid acting antidepressants within this short timeframe. This is consistent with previous studies demonstrating that acute or chronic administration of fluoxetine or imipramine has no effect mTORC1 signaling in PFC (Li et al, 2010; Liu et al, 2015), although chronic fluoxetine administration reverses the down-regulation of mTORC1 signaling in mice exposed to chronic stress (Liu et al, 2015). Primary neuronal culture studies also report no effect of fluoxetine or imipramine on mTORC1 signaling, although incubation with high doses of escitalopram and paroxetine for 4 days reversed the down regulation of mTORC1 signaling caused by incubation with B27 depleted media (Park et al, 2014).…”

Bafilomycin A1 alleviates depression‑like symptoms in chronic unpredictable mild stress rats

“…A previous study reported that restraint stress tended to decrease the expression of SYP in the rat hippocampus, although this was restored to pre-stress levels after 2 weeks of treatment with venlafaxine (2). The present results revealed that CUMS caused a significant reduction in PSD 95 and SYP expression in the hippocampus, which was consistent with a previous study (26). Administration of Baf A1 for 4 weeks significantly increased the expression levels of SYP and PSD 95 in the CUMS group.…”

Mechanistic Target of Rapamycin–Independent Antidepressant Effects of ( R )-Ketamine in a Social Defeat Stress Model

“…It was reported that both the immediate and long-term administration of fluoxetine has no effect on mTOR signaling in the PFC, although the chronic administration of fluoxetine reverses the downregulation of mTOR signaling in the hippocampus, but not in the PFC, of mice exposed to chronic stress (55). In the current study, we found that rapamycin and AZD8055 blocked the antidepressant effects of (S)-ketamine in a CSDS model, suggesting that mTOR signaling plays a role in the antidepressant effects of (S)-ketamine.…”