（2R,6R）-羟基去甲氯胺酮在大鼠习得性无助模型中缺乏抗抑郁作用：与（R）-氯胺酮的比较。
Lack of Antidepressant Effects of (2R,6R)-Hydroxynorketamine in a Rat Learned Helplessness Model: Comparison with (R)-Ketamine.
机构信息
Department of Psychiatry, Teikyo University Chiba Medical Center, Chiba, Japan.
Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.
出版信息
Int J Neuropsychopharmacol. 2018 Jan 1;21(1):84-88. doi: 10.1093/ijnp/pyx108.
BACKGROUND
(R)-Ketamine exhibits rapid and sustained antidepressant effects in animal models of depression. It is stereoselectively metabolized to (R)-norketamine and subsequently to (2R,6R)-hydroxynorketamine in the liver. The metabolism of ketamine to hydroxynorketamine was recently demonstrated to be essential for ketamine's antidepressant actions. However, no study has compared the antidepressant effects of these 3 compounds in animal models of depression.
METHODS
The effects of a single i.p. injection of (R)-ketamine, (R)-norketamine, and (2R,6R)-hydroxynorketamine in a rat learned helplessness model were examined.
RESULTS
A single dose of (R)-ketamine (20 mg/kg) showed an antidepressant effect in the rat learned helplessness model. In contrast, neither (R)-norketamine (20 mg/kg) nor (2R,6R)-hydroxynorketamine (20 and 40 mg/kg) did so.
CONCLUSIONS
Unlike (R)-ketamine, its metabolite (2R,6R)-hydroxynorketamine did not show antidepressant actions in the rat learned helplessness model. Therefore, it is unlikely that the metabolism of ketamine to hydroxynorketamine is essential for ketamine's antidepressant actions.
背景
（R）-氯胺酮在抑郁动物模型中表现出快速和持续的抗抑郁作用。它在肝脏中立体选择性地代谢为（R）-去甲氯胺酮，然后再代谢为（2R，6R）-羟基去甲氯胺酮。最近的研究表明，氯胺酮代谢为羟基去甲氯胺酮对于氯胺酮的抗抑郁作用是必不可少的。然而，没有研究比较这 3 种化合物在抑郁动物模型中的抗抑郁作用。
方法
在大鼠习得性无助模型中，研究了单次腹腔注射（R）-氯胺酮、（R）-去甲氯胺酮和（2R，6R）-羟基去甲氯胺酮的效果。
结果
单次剂量的（R）-氯胺酮（20mg/kg）在大鼠习得性无助模型中表现出抗抑郁作用。相比之下，（R）-去甲氯胺酮（20mg/kg）和（2R，6R）-羟基去甲氯胺酮（20 和 40mg/kg）均没有这种作用。
结论
与（R）-氯胺酮不同，其代谢产物（2R，6R）-羟基去甲氯胺酮在大鼠习得性无助模型中没有表现出抗抑郁作用。因此，氯胺酮代谢为羟基去甲氯胺酮对于氯胺酮的抗抑郁作用可能并非必不可少。
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