BACKGROUND The role of the mechanistic target of rapamycin (mTOR) signaling in the antidepressant effects of ketamine is controversial. In addition to mTOR, extracellular signal-regulated kinase (ERK) is a key signaling molecule in prominent pathways that regulate protein synthesis. (R)-Ketamine has a greater potency and longer-lasting antidepressant effects than (S)-ketamine. Here we investigated whether mTOR signaling and ERK signaling play a role in the antidepressant effects of two enantiomers. METHODS The effects of mTOR inhibitors (rapamycin and AZD8055) and an ERK inhibitor (SL327) on the antidepressant effects of ketamine enantiomers in the chronic social defeat stress (CSDS) model (n = 7 or 8) and on those of ketamine enantiomers in these signaling pathways in mouse brain regions were examined. RESULTS The intracerebroventricular infusion of rapamycin or AZD8055 blocked the antidepressant effects of (S)-ketamine, but not (R)-ketamine, in the CSDS model. Furthermore, (S)-ketamine, but not (R)-ketamine, significantly attenuated the decreased phosphorylation of mTOR and its downstream effector, ribosomal protein S6 kinase, in the prefrontal cortex of susceptible mice after CSDS. Pretreatment with SL327 blocked the antidepressant effects of (R)-ketamine but not (S)-ketamine. Moreover, (R)-ketamine, but not (S)-ketamine, significantly attenuated the decreased phosphorylation of ERK and its upstream effector, mitogen-activated protein kinase/ERK kinase, in the prefrontal cortex and hippocampal dentate gyrus of susceptible mice after CSDS. CONCLUSIONS This study suggests that mTOR plays a role in the antidepressant effects of (S)-ketamine, but not (R)-ketamine, and that ERK plays a role in (R)-ketamine's antidepressant effects. Thus, it is unlikely that the activation of mTOR signaling is necessary for antidepressant actions of (R)-ketamine.

中文翻译：

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( R )-氯胺酮在社会失败压力模型中的雷帕霉素独立抗抑郁作用的机制靶点

背景 雷帕霉素 (mTOR) 信号传导机制靶点在氯胺酮抗抑郁作用中的作用存在争议。除了 mTOR，细胞外信号调节激酶 (ERK) 是调节蛋白质合成的重要途径中的关键信号分子。(R)-氯胺酮比(S)-氯胺酮具有更强的效力和更持久的抗抑郁作用。在这里，我们研究了 mTOR 信号和 ERK 信号是否在两种对映异构体的抗抑郁作用中起作用。方法 mTOR 抑制剂（雷帕霉素和 AZD8055）和 ERK 抑制剂（SL327）对慢性社会失败压力 (CSDS) 模型（n = 7 或 8）中氯胺酮对映体的抗抑郁作用以及这些模型中氯胺酮对映体的抗抑郁作用的影响检查了小鼠大脑区域的信号通路。结果 在 CSDS 模型中，雷帕霉素或 AZD8055 的脑室内输注可阻断 (S)-氯胺酮的抗抑郁作用，但不能阻断 (R)-氯胺酮的抗抑郁作用。此外，(S)-氯胺酮，而不是 (R)-氯胺酮，显着减弱了 CSDS 后易感小鼠前额叶皮层中 mTOR 及其下游效应子核糖体蛋白 S6 激酶的磷酸化降低。用 SL327 预处理可阻断 (R)-氯胺酮而非 (S)-氯胺酮的抗抑郁作用。此外，（R）-氯胺酮，而不是（S）-氯胺酮，显着减弱了 CSDS 后易感小鼠的前额叶皮层和海马齿状回中 ERK 及其上游效应物丝裂原活化蛋白激酶/ERK 激酶的磷酸化降低. 结论 本研究表明，mTOR 在 (S)-氯胺酮的抗抑郁作用中发挥作用，但不是 (R)-氯胺酮，并且 ERK 在 (R)-氯胺酮的抗抑郁作用中起作用。因此，mTOR 信号的激活不太可能是 (R)-氯胺酮的抗抑郁作用所必需的。