BACKGROUND Although recent studies provide insight into the molecular mechanisms of the effects of ketamine, the antidepressant mechanism of ketamine enantiomers and their metabolites is not fully understood. In view of the involvement of mechanisms other than the N-methyl-D-aspartate receptor in ketamine's action, we investigated the effects of (R)-ketamine, (S)-ketamine, (R)-norketamine [(R)-NK], (S)-NK, (2R,6R)-hydroxynorketamine [(2R,6R)-HNK], and (2S,6S)-HNK on monoaminergic neurotransmission in the prefrontal cortex of mice. METHODS The extracellular monoamine levels in the prefrontal cortex were measured by in vivo microdialysis. RESULTS (R)-Ketamine and (S)-ketamine acutely increased serotonin release in a dose-dependent manner, and the effect of (R)-ketamine was greater than that of (S)-ketamine. In contrast, (S)-ketamine caused a robust increase in dopamine release compared with (R)-ketamine. Both ketamine enantiomers increased noradrenaline release, but these effects did not differ. (2R,6R)-HNK caused a slight but significant increase in serotonin and noradrenaline but not dopamine release. (S)-NK increased dopamine and noradrenaline but not serotonin release. Differential effects between (R)-ketamine and (S)-ketamine were also observed in a lipopolysaccharide-induced model of depression. An α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor antagonist, 2,3-dioxo-6-nitro-1,2,3,4- tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX), attenuated (S)-ketamine-induced, but not (R)-ketamine-induced serotonin release, whereas NBQX blocked dopamine release induced by both enantiomers. Local application of (R)-ketamine into the prefrontal cortex caused a greater increase in prefrontal serotonin release than that of (S)-ketamine. CONCLUSIONS (R)-Ketamine strongly activates the prefrontal serotonergic system through an AMPA receptor-independent mechanism. (S)-Ketamine-induced serotonin and dopamine release was AMPA receptor-dependent. These findings provide a neurochemical basis for the underlying pharmacological differences between ketamine enantiomers and their metabolites.

中文翻译：

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（R）氯胺酮通过AMPA受体独立机制诱导的额叶5-HT释放量比（S）-氯胺酮和氯胺酮代谢物更大。

背景技术尽管最近的研究提供了关于氯胺酮作用的分子机理的见解，但是氯胺酮对映异构体及其代谢产物的抗抑郁机理尚未完全被理解。鉴于氯胺酮作用中除N-甲基-D-天冬氨酸受体以外的其他机制，我们研究了（R）-氯胺酮，（S）-氯胺酮，（R）-去甲酮胺[（R）-NK ]，（S）-NK，（2R，6R）-羟基去氧甲胺[[2R，6R）-HNK]和（2S，6S）-HNK对小鼠前额叶皮层中单胺能神经传递的影响。方法采用体内微透析法测定前额叶皮层中的细胞外单胺水平。结果（R）-氯胺酮和（S）-氯胺酮以剂量依赖性方式急剧增加5-羟色胺的释放，并且（R）-氯胺酮的作用大于（S）-氯胺酮的作用。相反，与（R）-氯胺酮相比，（S）-氯胺酮引起多巴胺释放的强劲增加。两种氯胺酮对映体均增加去甲肾上腺素的释放，但这些作用没有差异。（2R，6R）-HNK引起5-羟色胺和去甲肾上腺素的轻微但显着增加，但不释放多巴胺。（S）-NK增加多巴胺和去甲肾上腺素，但不释放5-羟色胺。在脂多糖诱导的抑郁模型中也观察到（R）-氯胺酮和（S）-氯胺酮之间的差异作用。α-氨基-3-羟基-5-甲基-4-异恶唑-丙酸（AMPA）受体拮抗剂，2,3-二氧-6-硝基-1,2,3,4-四氢苯并[f]喹喔啉-7 -磺酰胺（NBQX）减弱了（S）-氯胺酮诱导的，而不是（R）-氯胺酮诱导的5-羟色胺的释放，而NBQX阻止了两种对映体诱导的多巴胺释放。与（S）-氯胺酮相比，将（R）-氯胺酮局部应用到额叶前皮层会导致前额叶5-羟色胺释放的增加更大。结论（R）-氯胺酮通过AMPA受体独立机制强烈激活前额叶血清素系统。（S）-氯胺酮诱导的5-羟色胺和多巴胺的释放是AMPA受体依赖性的。这些发现为氯胺酮对映异构体及其代谢物之间的潜在药理差异提供了神经化学基础。