Differential effects of antidepressant drugs on mTOR signalling in rat hippocampal neurons
Differential effects of antidepressant drugs on mTOR signalling in rat hippocampal neurons
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DOI：
10.1017/s1461145714000534
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发表时间：
2014-11-01
影响因子：
4.8
通讯作者：
Kim, Young Hoon
中科院分区：
文献类型：
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作者：
Park, Sung Woo;Lee, Jung Goo;Kim, Young Hoon
最近的研究表明，氯胺酮通过刺激哺乳动物雷帕霉素靶点（mTOR）产生抗抑郁作用，导致前额皮质突触蛋白水平增加。因此，mTOR 激活可能与抗抑郁作用有关。然而，抗抑郁药物作用背后的 mTOR 信号传导尚未得到充分研究。本研究的目的是确定在使用抗抑郁药物治疗后是否观察到 mTOR 信号传导的改变，并使用氯胺酮作为阳性对照。使用蛋白质印迹法，我们测量了大鼠海马培养物中 mTOR 介导的蛋白质和突触蛋白质的变化。通过神经突测定测定树突生长。我们的研究结果表明，艾司西酞普兰、帕罗西汀和反苯环丙明显着增加了磷酸-mTOR 及其下游调节因子（磷酸-4E-BP-1 和磷酸-p70S6K）的水平；氟西汀、舍曲林和丙咪嗪没有效果。所有测试的药物都增加了上游调节因子（磷酸-Akt 和磷酸-ERK）水平。在特定的 PI3K、MEK 或 mTOR 抑制剂存在下，艾司西酞普兰、帕罗西汀或反苯环丙明诱导的磷酸化 mTOR 的增加分别被显着阻断。所有测试的药物也增加了海马树突的生长和突触蛋白的水平。 mTOR 抑制剂雷帕霉素显着阻断了艾司西酞普兰、帕罗西汀和反苯环丙明的这些作用，而氟西汀、舍曲林和丙咪嗪的作用不受影响。艾司西酞普兰、帕罗西汀和反苯环丙明的作用与氯胺酮相似。这项研究提供了新的体外证据，表明一些抗抑郁药物通过 mTOR 信号传导促进树突生长并增加突触蛋白水平。然而，其他抗抑郁药物似乎通过不同的途径发挥作用。 mTOR 信号传导可能是开发新型抗抑郁药物的一个有希望的靶点。
Recent studies suggest that ketamine produces antidepressant actions via stimulation of mammalian target of rapamycin (mTOR), leading to increased levels of synaptic proteins in the prefrontal cortex. Thus, mTOR activation may be related to antidepressant action. However, the mTOR signalling underlying antidepressant drug action has not been well investigated. The aim of the present study was to determine whether alterations in mTOR signalling were observed following treatment with antidepressant drugs, using ketamine as a positive control. Using Western blotting, we measured changes in the mTOR-mediated proteins and synaptic proteins in rat hippocampal cultures. Dendritic outgrowth was determined by neurite assay. Our findings demonstrated that escitalopram, paroxetine and tranylcypromine significantly increased levels of phospho-mTOR and its down-stream regulators (phospho-4E-BP-1 and phospho-p70S6K); fluoxetine, sertraline and imipramine had no effect. All drugs tested increased up-stream regulators (phospho-Akt and phospho-ERK) levels. Increased phospho-mTOR induced by escitalopram, paroxetine or tranylcypromine was significantly blocked in the presence of specific PI3K, MEK or mTOR inhibitors, respectively. All drugs tested also increased hippocampal dendritic outgrowth and synaptic proteins levels. The mTOR inhibitor, rapamycin, significantly blocked these effects on escitalopram, paroxetine and tranylcypromine whereas fluoxetine, sertraline and imipramine effects were not affected. The effects of escitalopram, paroxetine and tranylcypromine paralleled those of ketamine. This study presents novel in vitro evidence indicating that some antidepressant drugs promote dendritic outgrowth and increase synaptic protein levels through mTOR signalling; however, other antidepressant drugs seem to act via a different pathway. mTOR signalling may be a promising target for the development of new antidepressant drugs.