mTOR activation is required for the antidepressant effects of mGluR₂/₃ blockade.
mTOR activation is required for the antidepressant effects of mGluR₂/₃ blockade.
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DOI：
10.1017/s1461145711001702
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发表时间：
2012-05
期刊：
影响因子：
--
通讯作者：
Duman RS
中科院分区：
文献类型：
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作者：
Dwyer JM;Lepack AE;Duman RS
最近的研究表明，氯胺酮，一种快速起效的抗抑郁药，迅速激活哺乳动物雷帕霉素靶蛋白（mTOR），并增加前额叶皮层（PFC）的突触发生。由于氯胺酮的副作用和滥用潜力，我们正在研究产生类似效果的替代药物。在这里，我们证明了单剂量的LY341495，mGluR2/3拮抗剂，产生氯胺酮样的生化和行为效应。LY341495给药快速（1小时）激活mTOR通路（mTOR、p70S6K、4E-BP1），随后（24小时）增加24小时后突触蛋白（PSD-95、GluR1和突触蛋白I）的水平，与氯胺酮的作用相似。最后，LY341495在大鼠强迫游泳试验中的抗抑郁作用被mTOR抑制剂雷帕霉素完全阻断。结果表明，LY341495的抗抑郁作用是通过激活mTOR介导的，并表明这种和其他mGluR2/3拮抗剂可以在抑郁症患者中产生快速的抗抑郁作用。
Recent studies demonstrate that ketamine, a fast-acting antidepressant, rapidly activates the mammalian target of rapamycin (mTOR) and increases synaptogenesis in the prefrontal cortex (PFC). Because of the side effect and abuse potential of ketamine we are investigating alternative agents that produce similar effects. Here we demonstrate that a single dose of LY341495, an mGluR2/3 antagonist, produces ketamine-like biochemical and behavioral effects. LY341495 administration rapidly (1 hr) activates the mTOR pathway (mTOR, p70S6K, 4E-BP1) and subsequently (24 hrs) increases levels of synaptic proteins (PSD-95, GluR1 and Synapsin I) 24 hrs later, similar to the effects of ketamine. Finally, the antidepressant effects of LY341495 in the rat forced swim test are completely blocked by the mTOR inhibitor, rapamycin. The results indicate that the antidepressant actions of LY341495 are mediated by activation of mTOR and suggest that this and other mGluR2/3 antagonists could produce rapid antidepressant effects in depressed patients.