Although (S)-ketamine was approved for use in treatment-resistant depression in 2019, new preclinical findings suggest that (R)-ketamine might produce better efficacy and tolerability relative to (S)-ketamine. Here we evaluated the effects of (R)-, (S)-, and (R,S)-ketamine on executive functions as measured in the attentional set shifting task (ASST) and on their discriminative stimulus effects in rats. Earlier data demonstrated that cognitive flexibility is compromised by (R,S)-ketamine, but the effects of enantiomers in rats are unknown. Separate cohorts of rats were tested in ASST and trained to discriminate either (R,S)-ketamine, (S)-ketamine, or (R)-ketamine (all at 10 mg/kg) from saline; in order to maintain the discrimination, a higher (R)-ketamine dose (17.5 mg/kg) was subsequently instituted. In ASST, all three forms increased the trials to criterion measure at reversal learning and extra-dimensional set-shifting phases. However, in contrast to (R)- and (S)-ketamine, (R,S)-ketamine prolonged the mean time to complete a single trial during early stages, suggesting increased reaction time, and/or unspecific side-effects related to motor or motivational impairments. In the drug discriminations, all rats acquired their respective discriminations between drug and saline. In (R,S)-ketamine-trained rats, (R)-ketamine and (S)-ketamine only partially substituted for the training dose of (R,S)-ketamine. Further, (R)-ketamine did not fully substitute in rats trained to (S)-ketamine. The data suggest more serious cognitive deficits produced by (R,S)-ketamine than its enantiomers. Furthermore, (R,S)-ketamine and its isomers share overlapping but not isomorphic discriminative stimulus effects predicting distinct subjective responses to (R)- vs. (S)-ketamine in humans.

尽管（S）-氯胺酮已于2019年获准用于抗药性抑郁症，但新的临床前研究结果表明，（R）-氯胺酮相对于（S）-氯胺酮可能产生更好的疗效和耐受性。在这里，我们评估了（R）-，（S）-和（R，S）-氯胺酮对执行功能的影响，该功能在注意力集中转移任务（ASST）中进行了测量，并对它们的歧视性刺激作用产生了影响。较早的数据表明，（R，S）-氯胺酮会损害认知柔韧性，但对映体在大鼠中的作用尚不清楚。在ASST中对单独的大鼠进行了测试，并对其进行了区分（R，S盐水中的）-氯胺酮，（S）-氯胺酮或（R）-氯胺酮（均为10 mg / kg）; 为了保持区别，随后制定了更高的（R）-氯胺酮剂量（17.5 mg / kg）。在ASST中，这三种形式都增加了在逆向学习和超维设定转换阶段进行标准测量的试验。但是，与（R）-和（S）-氯胺酮相反，（R，S）-氯胺酮延长了完成早期单个试验的平均时间，这表明反应时间增加和/或与下列药物相关的非特异性副作用运动或动机障碍。在药物鉴别中，所有大鼠都获得了它们各自在药物和生理盐水之间的鉴别。在（R，S）-氯胺酮训练的大鼠，（R）-氯胺酮和（S）-氯胺酮仅部分替代了（R，S）-氯胺酮的训练剂量。此外，（R）-氯胺酮在训练为（S）-氯胺酮的大鼠中不能完全替代。数据表明（R，S）-氯胺酮比其对映异构体产生更严重的认知缺陷。此外，（R，S）-氯胺酮及其异构体具有重叠但不同构的区别性刺激作用，从而预测人类对（R）-（S）-氯胺酮有不同的主观反应。