Park Sung Woo, Lee Jung Goo, Seo Mi Kyoung, Lee Chan Hong, Cho Hye Yeon, Lee Bong Ju, Seol Wongi, Kim Young Hoon
Paik Institute for Clinical Research, Inje University,Busan,Republic of Korea.
Department of Psychiatry, School of Medicine,Haeundae Paik Hospital, Inje University,Busan,Republic of Korea.
Int J Neuropsychopharmacol. 2014 Nov;17(11):1831-46. doi: 10.1017/S1461145714000534. Epub 2014 Jun 5.
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.
近期研究表明，氯胺酮通过刺激雷帕霉素哺乳动物靶蛋白（mTOR）产生抗抑郁作用，导致前额叶皮质中突触蛋白水平升高。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。本研究的目的是使用氯胺酮作为阳性对照，确定抗抑郁药物治疗后是否观察到mTOR信号传导的改变。我们使用蛋白质免疫印迹法测量了大鼠海马培养物中mTOR介导的蛋白质和突触蛋白的变化。通过神经突测定法确定树突生长。我们的研究结果表明，艾司西酞普兰、帕罗西汀和反苯环丙胺显著提高了磷酸化mTOR及其下游调节因子（磷酸化4E-BP-1和磷酸化p70S6K）的水平；氟西汀、舍曲林和丙咪嗪没有效果。所有测试药物均提高了上游调节因子（磷酸化Akt和磷酸化ERK）的水平。在分别存在特异性PI3K、MEK或mTOR抑制剂的情况下，艾司西酞普兰、帕罗西汀或反苯环丙胺诱导的磷酸化mTOR增加被显著阻断。所有测试药物还增加了海马树突生长和突触蛋白水平。mTOR抑制剂雷帕霉素显著阻断了对艾司西酞普兰、帕罗西汀和反苯环丙胺的这些作用，而氟西汀、舍曲林和丙咪嗪的作用未受影响。艾司西酞普兰、帕罗西汀和反苯环丙胺的作用与氯胺酮相似。本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途径起作用。mTOR信号传导可能是开发新型抗抑郁药物的一个有前景的靶点。
