Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China.
Neuroimmunomodulation. 2014;21(4):183-8. doi: 10.1159/000356517. Epub 2014 Feb 6.
Ketamine may produce rapid and sustained antidepressant effects. Despite the fact that the detailed underlying mechanism remains unknown, recent studies have suggested the involvement of the mammalian target of rapamycin (mTOR) pathway and glycogen synthase kinase-3 (GSK-3) signal, respectively, in the process of ketamine exerting antidepressant actions. This study aimed to investigate the mechanism by which ketamine phosphorylates GSK-3β in the rat prefrontal cortex (PFC) via applying vehicle or the antagonists of mTOR signalling pathway proteins including PI3K/Akt, mTOR and p70S6 kinase to the rats in the forced swimming test (FST) prior to ketamine administration, and subsequently observing the levels of phosphorylated GSK-3β, mTOR and p70S6K in rat PFC as well as the immobility time of rats in the FST. Our results revealed that compared to treatment with vehicle, ketamine increased the levels of phosphorylated GSK-3β in rat PFC (p < 0.05), which was attenuated by PI3K/Akt antagonist pretreatment (p < 0.05), but could not be affected by mTOR antagonist or p70S6K antagonist pretreatment. In addition, all the antagonists reversed the ketamine-induced increases in the phosphorylation of mTOR and p70S6K (p < 0.05). They also all abolished the rapid-acting antidepressant actions of ketamine demonstrated by the increased immobility time of rats in the FST. In conclusion, Akt mediates the phosphorylation of GSK-3β in rat PFC during the process of ketamine exerting rapid antidepressant actions.
氯胺酮可能产生快速而持续的抗抑郁作用。尽管其详细的潜在机制尚不清楚，但最近的研究分别表明，哺乳动物雷帕霉素靶蛋白（mTOR）途径和糖原合成酶激酶-3（GSK-3）信号参与了氯胺酮发挥抗抑郁作用的过程。本研究旨在通过在强迫游泳试验（FST）中预先给予大鼠 mTOR 信号通路蛋白（包括 PI3K/Akt、mTOR 和 p70S6 激酶）的拮抗剂，来研究氯胺酮通过何种机制在大鼠前额皮质（PFC）中使 GSK-3β磷酸化，随后观察大鼠 PFC 中磷酸化 GSK-3β、mTOR 和 p70S6K 的水平以及 FST 中大鼠的不动时间。我们的结果表明，与用载体处理相比，氯胺酮增加了大鼠 PFC 中磷酸化 GSK-3β的水平（p < 0.05），而这一作用可被 PI3K/Akt 拮抗剂预处理所减弱（p < 0.05），但不能被 mTOR 拮抗剂或 p70S6K 拮抗剂预处理所影响。此外，所有的拮抗剂均逆转了氯胺酮诱导的 mTOR 和 p70S6K 磷酸化增加（p < 0.05）。它们还消除了氯胺酮对大鼠 FST 中不动时间增加所产生的快速抗抑郁作用。总之，Akt 在氯胺酮发挥快速抗抑郁作用过程中介导了大鼠 PFC 中 GSK-3β的磷酸化。
