Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure.
Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure.
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DOI：
10.1016/j.biopsych.2010.12.015
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发表时间：
2011-04-15
影响因子：
10.6
通讯作者：
Duman, Ronald S.
中科院分区：
文献类型：
--
作者：
Li, Nanxin;Liu, Rong-Jian;Dwyer, Jason M.;Banasr, Mounira;Lee, Boyoung;Son, Hyeon;Li, Xiao-Yuan;Aghajanian, George;Duman, Ronald S.
尽管广泛报道了谷氨酸N-甲基-D-天冬氨酸（NMDA）受体拮抗剂的快速抗抑郁作用的临床和临床前研究，但很少有研究这些药物在需要长期服用抗抑郁药的抑郁症应激模型中的作用，或者可以解释快速反应的分子机制。我们使用大鼠21天的慢性不可预测的压力（CUS）模型来测试NMDA受体拮抗剂对抑郁样行为，神经化学，前额叶皮层（PFC）神经元的棘密度和突触功能的快速作用。结果表明，用非竞争性NMDA通道阻断剂氯胺酮或选择性NR 2B拮抗剂Ro 25-6981进行急性治疗可迅速改善多巴胺诱导的快感缺失和焦虑行为。我们还发现，CUS暴露降低了PFC中V层锥体神经元中突触蛋白的表达水平和棘数目以及突触电流（EPSC）的频率/振幅，并且这些缺陷被氯胺酮迅速逆转。阻断哺乳动物雷帕霉素靶蛋白（mTOR）合成级联反应可消除氯胺酮的行为和生化效应。结果表明，结构和功能的缺陷，从长期的压力暴露，这可能有助于抑郁症的病理生理学，迅速逆转的NMDA受体拮抗剂的mTOR依赖性的方式。
Despite widely reported clinical and preclinical studies of rapid antidepressant actions of glutamate N-methyl-D-aspartic acid (NMDA) receptor antagonists, there has been very little work examining the effects of these drugs in stress models of depression that require chronic administration of antidepressants, or the molecular mechanisms that could account for the rapid responses. We used a rat 21-day chronic unpredictable stress (CUS) model to test the rapid actions of NMDA receptor antagonists on depressant-like behavior, neurochemistry, and spine density and synaptic function of prefrontal cortex (PFC) neurons. The results demonstrate that acute treatment with the non-competitive NMDA channel blocker ketamine or the selective NR2B antagonist Ro 25-6981 rapidly ameliorates CUS-induced anhedonia and anxiogenic behaviors. We also find that CUS exposure decreases the expression levels of synaptic proteins and spine number and the frequency/amplitude of synaptic currents (EPSCs) in layer V pyramidal neurons in the PFC, and that these deficits are rapidly reversed by ketamine. Blockade of the mammalian target of rapamycin (mTOR) protein synthesis cascade abolishes both the behavioral and biochemical effects of ketamine. The results indicate that the structural and functional deficits resulting from long-term stress exposure, which could contribute to the pathophysiology of depression, are rapidly reversed by NMDA receptor antagonists in an mTOR-dependent manner.
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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：
5.2
作者：
Gourley SL;Wu FJ;Taylor JR
通讯作者：
Taylor JR
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