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摘要 : NMDAR拮抗剂氯胺酮有快速、持久的抗抑郁效应,这促使人们去寻找具有相同抗抑郁性质、但却没有氯胺酮的副作用的其他NMDAR拮抗剂。

 NMDAR拮抗剂氯胺酮有快速、持久的抗抑郁效应,这促使人们去寻找具有相同抗抑郁性质、但却没有氯胺酮的副作用的其他NMDAR拮抗剂。Todd Gould及同事现在发现,(R,S)-ketamine向(2S,6S;2R,6R)-hydroxynorketamine (HNK)的代谢是其抗抑郁活性所必需的,(2R,6R)-HNK对映异构体能对小鼠产生快速、持久的抗抑郁作用。这些效应是独立于NMDAR的,但需要AMPAR活化。重要的是,(2R,6R)-HNK没有与氯胺酮相关的副作用。这些发现为能够快速发挥作用的新型抗抑郁剂的研发提供了新选择。


NMDAR inhibition-independent antidepressant actions of ketamine metabolites


Major depressive disorder affects around 16 per cent of the world population at some point in their lives. Despite the availability of numerous monoaminergic-based antidepressants, most patients require several weeks, if not months, to respond to these treatments, and many patients never attain sustained remission of their symptoms. The non-competitive, glutamatergic NMDAR (N-methyl-D-aspartate receptor) antagonist (R,S)-ketamine exerts rapid and sustained antidepressant effects after a single dose in patients with depression, but its use is associated with undesirable side effects. Here we show that the metabolism of (R,S)-ketamine to (2S,6S;2R,6R)-hydroxynorketamine (HNK) is essential for its antidepressant effects, and that the (2R,6R)-HNK enantiomer exerts behavioural, electroencephalographic, electrophysiological and cellular antidepressant-related actions in mice. These antidepressant actions are independent of NMDAR inhibition but involve early and sustained activation of AMPARs (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors). We also establish that (2R,6R)-HNK lacks ketamine-related side effects. Our data implicate a novel mechanism underlying the antidepressant properties of (R,S)-ketamine and have relevance for the development of next-generation, rapid-acting antidepressants.

来源: Nature 浏览次数:0


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