Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, 260-8670, Japan.
Wuxi Mental Health Center, Nanjing Medical University, Wuxi, China.
Psychopharmacology (Berl). 2018 Nov;235(11):3177-3185. doi: 10.1007/s00213-018-5017-2. Epub 2018 Sep 13.
(R,S)-ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, exhibits rapid and long-lasting antidepressant effects and anti-suicidal ideation in treatment-resistant patients with depression. However, the precise mechanisms underlying the antidepressant actions of (R,S)-ketamine are unknown. Although the previous report demonstrated the deuterium isotope effects in the antidepressant actions of (R,S)-ketamine, the deuterium isotope effects in the antidepressant actions of (R)-ketamine, which is more potent than (S)-ketamine, are unknown.
We examined whether deuterium substitution at the C6 position could affect antidepressant effects of (R)-ketamine in a chronic social defeat stress (CSDS) model.
Pharmacokinetic studies showed that levels of (2R,6R)-d-hydroxynorketamine [(2R,6R)-d-HNK], a final metabolite of (R)-d-ketamine, in the plasma and brain after administration of (R)-d-ketamine (10 mg/kg) were lower than those of (2R,6R)-HNK from (R)-ketamine (10 mg/kg), indicating deuterium isotope effects in the production of (2R,6R)-HNK. In contrast, levels of (R)-ketamine and its metabolite (R)-norketamine in the plasma and brain were the same for both compounds. In a CSDS model, both (R)-ketamine (10 mg/kg) and (R)-d-ketamine (10 mg/kg) showed rapid and long-lasting (7 days) antidepressant effects, indicating no deuterium isotope effect in the antidepressant effects of (R)-ketamine.
The present study suggests that deuterium substitution of hydrogen at the C6 position slows the metabolism from (R)-ketamine to (2R,6R)-HNK in mice. In contrast, we did not find the deuterium isotope effects in terms of the rapid and long-lasting antidepressant effects of (R)-ketamine in a CSDS model. Therefore, it is unlikely that (2R,6R)-HNK is essential for antidepressant effects of (R)-ketamine.
（R，S）-氯胺酮是一种 N-甲基-D-天冬氨酸受体（NMDAR）拮抗剂，在治疗抵抗性抑郁症患者中显示出快速和持久的抗抑郁作用和抗自杀意念。然而，（R，S）-氯胺酮抗抑郁作用的确切机制尚不清楚。尽管先前的报告表明（R，S）-氯胺酮抗抑郁作用存在氘同位素效应，但（R）-氯胺酮（比（S）-氯胺酮更有效）的氘同位素效应尚不清楚。
我们研究了 C6 位的氘取代是否会影响慢性社会挫败应激（CSDS）模型中（R）-氯胺酮的抗抑郁作用。
药代动力学研究表明，（R）-d-氯胺酮（10mg/kg）给药后（2R，6R）-d-羟基去甲氯胺酮[（2R，6R）-d-HNK]的血浆和脑中水平低于（R）-氯胺酮（10mg/kg）的（2R，6R）-HNK，表明（2R，6R）-HNK 的生成存在氘同位素效应。相比之下，两种化合物的血浆和脑中（R）-氯胺酮及其代谢物（R）-去甲氯胺酮的水平相同。在 CSDS 模型中，（R）-氯胺酮（10mg/kg）和（R）-d-氯胺酮（10mg/kg）均显示出快速和持久的（7 天）抗抑郁作用，表明（R）-氯胺酮的抗抑郁作用不存在氘同位素效应。
本研究表明，C6 位氢的氘取代会减缓（R）-氯胺酮向（2R，6R）-HNK 的代谢。相比之下，我们在 CSDS 模型中没有发现（R）-氯胺酮快速和持久抗抑郁作用的氘同位素效应。因此，（2R，6R）-HNK 不太可能是（R）-氯胺酮抗抑郁作用所必需的。
