(R,S)-ketamine exerts robust antidepressant effects in patients with depression when given at sub-anesthetic doses. Each of the enantiomers in this racemic mixture, (R)-ketamine and (S)-ketamine, have been reported to exert antidepressant effects individually. However, the neuropharmacological effects of these enantiomers and the mechanisms underlying their antidepressive actions have not yet been fully elucidated. Therefore, we investigated the effect of (R,S)-, (R)-, and (S)-ketamine on brain activity by functional MRI (fMRI) in conscious rats and compared these with that of N-methyl-D-aspartate receptor (NMDAR) antagonist MK-801 (n = 5~7). We also assessed their pharmacokinetic profiles (n = 4) and their behavioral effects (n = 7~9). This pharmacological MRI study revealed a significant positive response to (S)-ketamine specifically in the cortex, nucleus accumbens and striatum. In contrast, negative fMRI responses were observed in various brain regions after (R)-ketamine administration. (R,S)-ketamine, evoked significant positive fMRI responses specifically in the cortex, nucleus accumbens and striatum, and this fMRI response pattern was comparable with that of (S)-ketamine. MK-801-induced similar fMRI response pattern to (S)-ketamine. The fMRI responses to (S)-ketamine and MK-801 showed differential temporal profiles, which corresponded with brain concentration profiles. (S)-ketamine and MK-801 significantly increased locomotor activity, while (R)-ketamine produced no noticeable change. (R,S)-ketamine tended to increase locomotor activity. Our novel fMRI findings show that (R)-ketamine and (S)-ketamine induce completely different fMRI response patterns on rat, and that the response produced by the latter is similar to that elicited by an NMDAR antagonist. Our findings provide insight into the antidepressant mechanism of (R,S)-ketamine.

中文翻译：

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（R）-和（S）-氯胺酮在清醒大鼠中诱导差异性fMRI反应。

当以亚麻醉剂量给药时，（R，S）-氯胺酮对抑郁症患者具有强大的抗抑郁作用。据报道，该外消旋混合物中的每种对映体（R）-氯胺酮和（S）-氯胺酮均单独发挥抗抑郁作用。但是，这些对映异构体的神经药理作用及其潜在的抗抑郁作用机理尚未完全阐明。因此，我们通过功能性MRI（fMRI）研究了清醒大鼠中（R，S）-，（R）-和（S）-氯胺酮对大脑活动的影响，并将其与N-甲基-D-天门冬氨酸进行了比较。受体（NMDAR）拮抗剂MK-801（n = 5〜7）。我们还评估了它们的药代动力学特征（n = 4）及其行为效应（n = 7〜9）。这项药理学MRI研究显示，在皮层，伏隔核和纹状体中，对（S）-氯胺酮有明显的阳性反应。相反，在（R）-氯胺酮给药后，在各个大脑区域均观察到了阴性fMRI反应。（R，S）-氯胺酮特别在皮质，伏隔核和纹状体中引起明显的功能磁共振成像阳性反应，这种功能磁共振成像反应模式与（S）-氯胺酮相当。MK-801诱导的功能磁共振成像反应模式与（S）-氯胺酮相似。对（S）-氯胺酮和MK-801的功能磁共振成像反应显示出不同的时间分布，与脑部浓度分布相对应。（S）-氯胺酮和MK-801显着提高了运动活性，而（R）-氯胺酮未产生明显变化。（R，S）-氯胺酮倾向于增加运动活性。我们的新功能磁共振成像发现表明，（R）-氯胺酮和（S）-氯胺酮在大鼠上诱导完全不同的fMRI应答模式，后者产生的应答与NMDAR拮抗剂引起的应答相似。我们的发现为（R，S）-氯胺酮的抗抑郁机制提供了见识。