Laboratory of Molecular Psychiatry, Center for Genes and Behavior, Department of Psychiatry, Yale University School of Medicine, 34 Park Street, New Haven, CT 06508, USA.
Science. 2010 Aug 20;329(5994):959-64. doi: 10.1126/science.1190287.
The rapid antidepressant response after ketamine administration in treatment-resistant depressed patients suggests a possible new approach for treating mood disorders compared to the weeks or months required for standard medications. However, the mechanisms underlying this action of ketamine [a glutamate N-methyl-D-aspartic acid (NMDA) receptor antagonist] have not been identified. We observed that ketamine rapidly activated the mammalian target of rapamycin (mTOR) pathway, leading to increased synaptic signaling proteins and increased number and function of new spine synapses in the prefrontal cortex of rats. Moreover, blockade of mTOR signaling completely blocked ketamine induction of synaptogenesis and behavioral responses in models of depression. Our results demonstrate that these effects of ketamine are opposite to the synaptic deficits that result from exposure to stress and could contribute to the fast antidepressant actions of ketamine.
氯胺酮在治疗抵抗性抑郁患者中的快速抗抑郁反应表明，与标准药物所需的数周或数月相比，它可能为治疗情绪障碍提供了一种新的方法。然而，氯胺酮（一种谷氨酸 N-甲基-D-天冬氨酸（NMDA）受体拮抗剂）作用的机制尚未确定。我们观察到氯胺酮可快速激活雷帕霉素靶蛋白（mTOR）途径，导致前额叶皮层中突触信号蛋白增加，以及新的棘突触数量和功能增加。此外，mTOR 信号通路的阻断完全阻断了氯胺酮在抑郁模型中诱导的突触发生和行为反应。我们的结果表明，氯胺酮的这些作用与应激引起的突触缺失相反，可能有助于氯胺酮的快速抗抑郁作用。
