(R,S)-Ketamine has rapid and sustained antidepressant effects in depressed patients. Although the metabolism of (R,S)-ketamine to (2 R,6 R)-hydroxynorketamine (HNK), a metabolite of (R)-ketamine, has been reported to be essential for its antidepressant effects, recent evidence suggests otherwise. The present study investigated the role of the metabolism of (R)-ketamine to (2 R,6 R)-HNK in the antidepressant actions of (R)-ketamine. Antidepressant effects were evaluated using the forced swimming test in the lipopolysaccharide (LPS)-induced inflammation model of mice and the tail suspension test in naive mice. To prevent the metabolism of (R)-ketamine to (2 R,6 R)-HNK, mice were pretreated with cytochrome P450 (CYP) inhibitors. The concentrations of (R)-ketamine, (R)-norketamine, and (2 R,6 R)-HNK in plasma, brain, and cerebrospinal fluid (CSF) samples were determined using enantioselective liquid chromatography-tandem mass spectrometry. The concentrations of (R)-norketamine and (2 R,6 R)-HNK in plasma, brain, and CSF samples after administration of (R)-norketamine (10 mg/kg) and (2 R,6 R)-HNK (10 mg/kg), respectively, were higher than those generated after administration of (R)-ketamine (10 mg/kg). Nonetheless, while (R)-ketamine attenuated, neither (R)-norketamine nor (2 R,6 R)-HNK significantly altered immobility times of LPS-treated mice. Treatment with CYP inhibitors prior to administration of (R)-ketamine increased the plasma levels of (R)-ketamine, while generation of (2 R,6 R)-HNK was almost completely blocked. (R)-Ketamine exerted the antidepressant effects at a lower dose in the presence of CYP inhibitors than in their absence, which is consistent with exposure levels of (R)-ketamine but not (2 R,6 R)-HNK. These results indicate that metabolism to (2 R,6 R)-HNK is not necessary for the antidepressant effects of (R)-ketamine and that unmetabolized (R)-ketamine itself may be responsible for its antidepressant actions.

中文翻译：

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（2R，6R）-羟基降甲胺酮对于（R）-氯胺酮在小鼠中的抗抑郁作用不是必需的。

（R，S）-氯胺酮在抑郁症患者中具有快速和持续的抗抑郁作用。尽管据报道（R，S）-氯胺酮代谢为（R）-氯胺酮的代谢产物（2 R，6 R）-羟基降甲胺（HNK）对于其抗抑郁作用至关重要，但最近的证据表明并非如此。本研究调查了（R）-氯胺酮代谢为（2 R，6 R）-HNK在（R）-氯胺酮的抗抑郁作用中的作用。使用在脂多糖（LPS）诱导的小鼠炎症模型中的强迫游泳试验和在幼稚小鼠中的尾部悬吊试验，评估了抗抑郁作用。为防止（R）-氯胺酮代谢为（2 R，6 R）-HNK，对小鼠进行了细胞色素P450（CYP）抑制剂预处理。（R）-氯胺酮，（R）-去甲酮胺和（2 R，6 R）-HNK在血浆，脑中的浓度，使用对映选择性液相色谱-串联质谱法测定脑脊液（CSF）和脑脊液（CSF）样品。施用（R）-去甲酮胺（10 mg / kg）和（2 R，6 R）-HNK后血浆，脑和CSF样品中（R）-去甲酮胺和（2 R，6 R）-HNK的浓度（10 mg / kg）分别高于（R）-氯胺酮（10 mg / kg）给药后产生的那些。然而，尽管（R）-氯胺酮减弱，但（R）-去甲酮胺和（2R，6R）-HNK都没有显着改变LPS处理的小鼠的固定时间。给予（R）-氯胺酮之前用CYP抑制剂治疗可增加（R）-氯胺酮的血浆水平，而（2 R，6 R）-HNK的生成几乎被完全阻断。（R）-氯胺酮在存在CYP抑制剂的情况下比在不存在CYP抑制剂的情况下以更低的剂量发挥抗抑郁作用，这与（R）-氯胺酮的暴露水平一致，但与（2 R，6 R）-HNK的暴露水平一致。这些结果表明，对于（R）-氯胺酮的抗抑郁作用，不需要代谢为（2 R，6 R）-HNK，并且未代谢的（R）-氯胺酮本身可能是其抗抑郁作用的原因。