Scopolamine rapidly increases mammalian target of rapamycin complex 1 signaling, synaptogenesis, and antidepressant behavioral responses.
Scopolamine rapidly increases mammalian target of rapamycin complex 1 signaling, synaptogenesis, and antidepressant behavioral responses.
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DOI：
10.1016/j.biopsych.2013.04.025
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发表时间：
2013-11-15
影响因子：
10.6
通讯作者：
Duman, Ronald S.
中科院分区：
文献类型：
--
作者：
Voleti, Bhavya;Navarria, Andrea;Liu, Rong-Jian;Banasr, Mounira;Li, Nanxin;Terwilliger, Rose;Sanacora, Gerard;Eid, Tore;Aghajanian, George;Duman, Ronald S.
东莨菪碱是一种乙酰胆碱毒蕈碱受体拮抗剂，临床研究表明，东莨菪碱对抑郁症患者产生快速的抗抑郁作用，但其治疗反应的机制尚未确定。本研究探讨了哺乳动物雷帕霉素复合物1（mTORC1）和突触发生的作用，这已经牵连在NMDA受体拮抗剂的快速行动。东莨菪碱对mTORC1信号传导的影响通过分析前额叶皮层（PFC）中mTORC1信号传导蛋白的磷酸化和活化形式来确定。采用全细胞膜片钳记录和双光子图像分析技术观察PFC神经元棘突触的数量和功能。在强迫游泳试验中，在不存在或存在选择性mTORC 1和AMPA受体抑制剂的情况下，检查东莨菪碱的作用。结果表明，一个单一的，低剂量的东莨菪碱迅速增加mTORC1信号传导和脊髓突触的数量和功能在第V层锥体神经元的PFC。东莨菪碱管理也产生了抗抑郁反应，在强迫游泳试验中，被阻断预处理与mTORC1抑制剂或谷氨酸AMPA受体拮抗剂。综上所述，结果表明东莨菪碱的抗抑郁作用需要mTORC 1信号传导，并与增加的谷氨酸传递和突触发生相关，类似于NMDA受体拮抗剂。这些发现为更安全、更有效的速效抗抑郁药提供了新的靶点。
Clinical studies report that scopolamine, an acetylcholine muscarinic receptor antagonist, produces rapid antidepressant effects in depressed patients, but the mechanisms underlying the therapeutic response have not been determined. The present study examines the role of the mammalian target of rapamycin complex 1 (mTORC1) and synaptogenesis, which have been implicated in the rapid actions of NMDA receptor antagonists. The influence of scopolamine on mTORC1 signaling was determined by analysis of the phosphorylated and activated forms of mTORC1 signaling proteins in the prefrontal cortex (PFC). The numbers and function of spine synapses were analyzed by whole cell patch clamp recording and 2-photon image analysis of PFC neurons. The actions of scopolamine were examined in the forced swim test in the absence or presence of selective mTORC1 and AMPA receptor inhibitors. The results demonstrate that a single, low dose of scopolamine rapidly increases mTORC1 signaling and the number and function of spine synapses in layer V pyramidal neurons in the PFC. Scopolamine administration also produces an antidepressant response in the forced swim test that is blocked by pretreatment with the mTORC1 inhibitor or by a glutamate AMPA receptor antagonist. Taken together, the results demonstrate that the antidepressant actions of scopolamine require mTORC1 signaling and are associated with increased glutamate transmission, and synaptogenesis, similar to NMDA receptor antagonists. These findings provide novel targets for safer and more efficacious rapid acting antidepressant agents.
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DOI：
10.1126/science.1190287
发表时间：
2010-08-20
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Li N;Lee B;Liu RJ;Banasr M;Dwyer JM;Iwata M;Li XY;Aghajanian G;Duman RS
通讯作者：
Duman RS
影响因子：
56.9
作者：
Cota, D;Proulx, K;Seeley, RJ
通讯作者：
Seeley, RJ
影响因子：
3.4
作者：
BORSINI, F;LECCI, A;MELI, A
通讯作者：
MELI, A
影响因子：
10.6
作者：
Berman, RM;Cappiello, A;Krystal, JH
通讯作者：
Krystal, JH
影响因子：
15.9
作者：
Hoeffer, Charles A.;Klann, Eric
通讯作者：
Klann, Eric