Rapid antidepressant actions of scopolamine: Role of medial prefrontal cortex and M1-subtype muscarinic acetylcholine receptors.
Rapid antidepressant actions of scopolamine: Role of medial prefrontal cortex and M1-subtype muscarinic acetylcholine receptors.
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DOI：
10.1016/j.nbd.2015.06.012
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发表时间：
2015-10
影响因子：
6.1
通讯作者：
Duman RS
中科院分区：
文献类型：
--
作者：
Navarria A;Wohleb ES;Voleti B;Ota KT;Dutheil S;Lepack AE;Dwyer JM;Fuchikami M;Becker A;Drago F;Duman RS
临床研究表明，东莨菪碱，一种非选择性毒蕈碱乙酰胆碱受体（mAchR）拮抗剂，对抑郁症患者产生快速的治疗效果，临床前研究报告东莨菪碱的作用需要谷氨酸受体激活和内侧前额叶皮层（mPFC）中雷帕霉素复合物1（mTORC1）的机制靶点。本研究扩展了这些发现，以确定的mPFC和特定的毒蕈碱乙酰胆碱受体（M-AchR）亚型的作用，东莨菪碱的行动。东莨菪碱的管理增加的活动标志物Fos的mPFC，包括边缘下（IL）和边缘前（PrL）亚区。在强迫游泳试验中，将东莨菪碱微量输注到IL或PrL中产生显著的抗抑郁反应，IL或PrL的神经元沉默阻断了全身性东莨菪碱的抗抑郁作用。结果还表明，全身给予选择性M1-AChR拮抗剂VU0255035产生抗抑郁反应，并刺激PFC中的mTORC 1信号传导，类似于东莨菪碱的作用。最后，我们使用慢性不可预测的压力模型作为快速抗抑郁作用的更严格的测试，发现东莨菪碱或VU0255035给药阻断了由CUS引起的快感缺失反应，这种作用需要长期服用典型的抗抑郁药。总之，这些研究结果表明，mPFC是东莨菪碱的行为作用的关键介质，并确定M1-AChR作为开发新型和选择性速效抗抑郁药的治疗靶点。
Clinical studies demonstrate that scopolamine, a nonselective muscarinic acetycholine receptor (mAchR) antagonist, produces rapid therapeutic effects in depressed patients, and preclinical studies report that the actions of scopolamine require glutamate receptor activation and the mechanistic target of rapamycin complex 1 (mTORC1) in the medial prefrontal cortex (mPFC). The present study extends these findings to determine the role of the mPFC and specific muscarinic acetylcholine receptor (M-AchR) subtypes in the actions of scopolamine. Administration of scopolamine increases the activity marker Fos in the mPFC, including the infralimbic (IL) and prelimbic (PrL) subregions. Microinfusions of scopolamine into either the IL or PrL produced significant antidepressant responses in the forced swim test, and neuronal silencing of IL or PrL blocked the antidepressant effects of systemic scopolamine. The results also demonstrate that systemic administration of a selective M1-AChR antagonist, VU0255035 produced an antidepressant response and stimulated mTORC1 signaling in the PFC, similar to the actions of scopolamine. Finally, we used a chronic unpredictable stress model as a more rigorous test of rapid antidepressant actions, and found that scopolamine or VU0255035 administration blocked the anhedonic response caused by CUS, an effect that requires chronic administration of typical antidepressants. Taken together, these findings indicate that mPFC is a critical mediator of the behavioral actions of scopolamine, and identify the M1-AChR as a therapeutic target for the development of novel and selective rapid-acting antidepressants.