NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses.
NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses.
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DOI：
10.1038/nature10130
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发表时间：
2011-06-15
期刊：
影响因子：
64.8
通讯作者：
Monteggia, Lisa M.
中科院分区：
文献类型：
--
作者：
Autry, Anita E.;Adachi, Megunai;Nosyreva, Elena;Na, Elisa S.;Los, Maarten F.;Cheng, Peng-fei;Kavalali, Ege T.;Monteggia, Lisa M.
临床研究一致表明，单次亚拟精神剂量的氯胺酮（一种离子型谷氨酸能N-甲基-d-天冬氨酸受体（NMDAR）拮抗剂）在重度抑郁症（MDD）患者中产生速效抗抑郁反应，尽管其潜在机制尚不清楚。抑郁症患者报告在单次低剂量氯胺酮静脉输注后两小时内缓解MDD症状，效果持续长达两周，而传统的抗抑郁药（即5-羟色胺再摄取抑制剂）需要数周才能达到疗效。这种延迟是目前MDD治疗的主要缺点，因此需要更快起效的抗抑郁药，特别是对有自杀风险的患者。氯胺酮在抑郁症患者中产生快速作用、持久的抗抑郁反应的能力为研究潜在的细胞机制提供了独特的机会。我们发现氯胺酮和其他NMDAR拮抗剂在依赖于脑源性神经营养因子（BDNF）快速合成的小鼠模型中产生快速作用的行为抗抑郁样作用。我们发现，氯胺酮介导的NMDAR阻断在休息失活真核细胞延伸因子2（eEF 2）激酶（也称为CaMK III），导致减少eEF 2磷酸化和BDNF翻译的去抑制。此外，我们发现eEF 2激酶抑制剂诱导快速作用的行为抗抑郁样作用。我们的研究结果表明，蛋白质合成调节自发神经传递可能作为一个可行的治疗目标，快速作用的抗抑郁药的发展。
Clinical studies consistently demonstrate that a single sub-psychomimetic dose of ketamine, an ionotropic glutamatergic n-methyl-d-aspartate receptor (NMDAR) antagonist, produces fast-acting antidepressant responses in patients suffering from major depressive disorder (MDD), although the underlying mechanism is unclear. Depressed patients report alleviation of MDD symptoms within two hours of a single low-dose intravenous infusion of ketamine with effects lasting up to two weeks, unlike traditional antidepressants (i.e. serotonin reuptake inhibitors), which take weeks to reach efficacy. This delay is a major drawback to current MDD therapies, leaving a need for faster acting antidepressants particularly for suicide-risk patients. Ketamine's ability to produce rapidly acting, long-lasting antidepressant responses in depressed patients provides a unique opportunity to investigate underlying cellular mechanisms. We show that ketamine and other NMDAR antagonists produce fast-acting behavioural antidepressant-like effects in mouse models that depend on rapid synthesis of brain-derived neurotrophic factor (BDNF). We find that ketamine-mediated NMDAR blockade at rest deactivates eukaryotic elongation factor 2 (eEF2) kinase (also called CaMKIII) resulting in reduced eEF2 phosphorylation and desuppression of BDNF translation. Furthermore, we find inhibitors of eEF2 kinase induce fast-acting behavioural antidepressant-like effects. Our findings suggest that protein synthesis regulation by spontaneous neurotransmission may serve as a viable therapeutic target for fast-acting antidepressant development.
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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：
3.6
作者：
Poleszak, Ewa;Wlaz, Piotr;Nowak, Gabriel
通讯作者：
Nowak, Gabriel
影响因子：
10.6
作者：
Berman, RM;Cappiello, A;Krystal, JH
通讯作者：
Krystal, JH
影响因子：
16.2
作者：
Jakawich, Sonya K.;Nasser, Hassan B.;Strong, Michael J.;McCartney, Amber J.;Perez, Amanda S.;Rakesh, Neal;Carruthers, Cynthia J. L.;Sutton, Michael A.
通讯作者：
Sutton, Michael A.
影响因子：
2.3
作者：
Detke, MJ;Johnson, J;Lucki, I
通讯作者：
Lucki, I