(S)-norketamine and (2S, 6S)-hydroxynorketamine exert potent antidepressant-like effects in a chronic corticosterone-induced mouse model of depression
(S)-norketamine and (2S, 6S)-hydroxynorketamine exert potent antidepressant-like effects in a chronic corticosterone-induced mouse model of depression
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DOI：
10.1016/j.pbb.2020.172876
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发表时间：
2020-04-01
影响因子：
3.6
通讯作者：
Ago, Yukio
中科院分区：
文献类型：
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作者：
Yokoyama, Rei;Higuchi, Momoko;Ago, Yukio
临床和临床前研究表明，N-甲基-U-天冬氨酸受体拮抗剂氯胺酮可发挥快速且持久的抗抑郁作用。尽管氯胺酮代谢物也可能具有潜在的抗抑郁特性，但特别是 (2R,6R)-羟基去甲氯胺酮 ((2R,6R)-HNK) 已报道了有争议的结果，并且关于其他氯胺酮代谢物的作用的信息很少。在这里，我们的目的是比较 (R)-去甲氯胺酮 ((R)-NK)、(S)-NK、(2R,6R)-HNK 和 (2S,6S)-HNK 在慢性皮质酮 (COAT) 注射诱导的抑郁症小鼠模型中的作用。在剂量高达 20 mg/kg 的氯胺酮代谢物中，没有一种在幼稚雄性 C57BL6/J 小鼠中显示出抗抑郁样活性。慢性 COAT 治疗增加了强迫游泳测试中的不动性，并在女性遭遇测试中引起快感缺失样行为。在慢性 CORT 治疗的小鼠中，单次施用 (S)-NK 和 (2S,6S)-HNK 会剂量依赖性地减少注射后 30 分钟增强的不动性，而 (R)-NK 或 (2R,6R)-HNK 则不会。此外，(S)-NK和(2S,6S)-HNK，但不是(R)-NK或(2R,6R)-HNK，在注射后24小时改善了慢性CORT诱导的快感缺失。这些结果表明，(S)-氯胺酮代谢物 (S)-NK 和 (2S,6S)-HNK 对啮齿类动物具有有效的急性和持续抗抑郁作用。
Clinical and preclinical studies have shown that the N-methyl-u-aspartate receptor antagonist ketamine exerts rapid and long-lasting anti-depressant 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 (COAT) injection. None of the ketamine metabolites at doses up to 20 mg/kg showed antidepressant-like activity in naive male C57BL6/J mice. Chronic COAT 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.