NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses

抗抑郁药 神经营养因子 NMDA受体 脑源性神经营养因子 药理学 氯胺酮 医学 谷氨酸的 重性抑郁障碍 致电离效应 兴奋剂 神经科学 谷氨酸受体 心理学 海马体 内科学 受体 认知
作者
Anita E. Autry,Megumi Adachi,E. D. Nosyreva,Elisa S. Na,Maarten F. Los,Peng-fei Cheng,Ege T. Kavalali,Lisa M. Monteggia
出处
期刊:Nature [Nature Portfolio]
卷期号:475 (7354): 91-95 被引量:1892
标识
DOI:10.1038/nature10130
摘要

Antidepressants such as selective serotonin re-uptake inhibitors can take months to take effect, but small doses of ketamine, a glutamatergic N-methyl-D-aspartate receptor (NMDAR) agonist, can have antidepressant effects within hours. The antidepressant mechanism of ketamine is not well understood. Work in mice shows that antidepressant-like effects of ketamine depend on rapid synthesis of brain-derived neurotrophic factor (BDNF). Ketamine-mediated NMDAR blockade deactivates eukaryotic elongation factor 2 (eEF2) kinase, resulting in reduced eEF2 phosphorylation and de-suppression of BDNF translation. These findings raise the possibility of this pathway as a therapeutic target for fast-acting antidepressants. Clinical studies consistently demonstrate that a single sub-psychomimetic dose of ketamine, an ionotropic glutamatergic NMDAR (N-methyl-D-aspartate receptor) antagonist, produces fast-acting antidepressant responses in patients suffering from major depressive disorder, although the underlying mechanism is unclear1,2,3. Depressed patients report the alleviation of major depressive disorder symptoms within two hours of a single, low-dose intravenous infusion of ketamine, with effects lasting up to two weeks1,2,3, unlike traditional antidepressants (serotonin re-uptake inhibitors), which take weeks to reach efficacy. This delay is a major drawback to current therapies for major depressive disorder and faster-acting antidepressants are needed, particularly for suicide-risk patients3. The ability of ketamine to produce rapidly acting, long-lasting antidepressant responses in depressed patients provides a unique opportunity to investigate underlying cellular mechanisms. Here we show that ketamine and other NMDAR antagonists produce fast-acting behavioural antidepressant-like effects in mouse models, and that these effects depend on the rapid synthesis of brain-derived neurotrophic factor. We find that the ketamine-mediated blockade of NMDAR at rest deactivates eukaryotic elongation factor 2 (eEF2) kinase (also called CaMKIII), resulting in reduced eEF2 phosphorylation and de-suppression of translation of brain-derived neurotrophic factor. Furthermore, we find that inhibitors of eEF2 kinase induce fast-acting behavioural antidepressant-like effects. Our findings indicate that the regulation of protein synthesis by spontaneous neurotransmission may serve as a viable therapeutic target for the development of fast-acting antidepressants.
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