Clinical and preclinical studies have shown that the N-methyl-d-aspartate receptor antagonist ketamine exerts rapid and long-lasting antidepressant effects. Although ketamine metabolites might also have potential antidepressant properties, controversial results have been reported for (2R,6R)-hydroxynorketamine ((2R,6R)-HNK) in particular, and there is little information regarding the effects of other ketamine metabolites. Here we aimed to compare the effects of (R)-norketamine ((R)-NK), (S)-NK, (2R,6R)-HNK, and (2S,6S)-HNK in a mouse model of depression induced by chronic corticosterone (CORT) injection. None of the ketamine metabolites at doses up to 20 mg/kg showed antidepressant-like activity in naïve male C57BL6/J mice. Chronic CORT treatment increased immobility in the forced swim test and caused anhedonic-like behaviors in the female encounter test. A single administration of (S)-NK and (2S,6S)-HNK dose-dependently reduced the enhanced immobility at 30 min after injection in chronic CORT-treated mice, while (R)-NK or (2R,6R)-HNK did not. Additionally, (S)-NK and (2S,6S)-HNK, but not (R)-NK or (2R,6R)-HNK, improved chronic CORT-induced anhedonia at 24 h after the injection. These results suggest that (S)-ketamine metabolites (S)-NK and (2S,6S)-HNK have potent acute and sustained antidepressant effects in rodents.

临床和临床前研究已表明，Ñ甲基d天冬氨酸受体拮抗剂氯胺酮施加快速和持久的抗抑郁作用。尽管氯胺酮代谢物也可能具有潜在的抗抑郁特性，但已报道了有关（2R，6R）-羟基降氯胺酮（（2R，6R）-HNK）的有争议的结果，有关其他氯胺酮代谢物作用的信息很少。在这里我们旨在比较（R）-去甲胺（（R）-NK），（S）-NK，（2R，6R）-HNK和（2S，6S）-HNK在慢性皮质酮（CORT）注射诱导的抑郁症小鼠模型中。在初始的雄性C57BL6 / J小鼠中，剂量高达20 mg / kg的氯胺酮代谢物均未显示出抗抑郁样活性。慢性CORT治疗在强迫游泳测试中增加了不动感，并在女性遭遇测试中引起了类似于快感的行为。在慢性CORT治疗的小鼠中注射（S）-NK和（2S，6S）-HNK一次给药后30分钟剂量依赖性地降低了固定性的增强，而（R）-NK或（2R，6R）-HNK没有。此外，（S）-NK和（2S，6S）-HNK，但不是（R）-NK或（2R，6R）-HNK，注射后24 h改善了慢性CORT引起的快感缺失。这些结果表明（S）-氯胺酮代谢产物（S）-NK和（2S，6S）-HNK在啮齿动物中具有有效的急性和持续抗抑郁作用。