Laboratory of Molecular Psychiatry, Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
Neuropsychopharmacology. 2013 Oct;38(11):2268-77. doi: 10.1038/npp.2013.128. Epub 2013 May 17.
A single dose of the short-acting NMDA antagonist ketamine produces rapid and prolonged antidepressant effects in treatment-resistant patients with major depressive disorder (MDD), which are thought to occur via restoration of synaptic connectivity. However, acute dissociative side effects and eventual fading of antidepressant effects limit widespread clinical use of ketamine. Recent studies in medial prefrontal cortex (mPFC) show that the synaptogenic and antidepressant-like effects of a single standard dose of ketamine in rodents are dependent upon activation of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) signaling pathway together with inhibitory phosphorylation of glycogen synthase kinase-3 (GSK-3), which relieves its inhibitory in influence on mTOR. Here, we found that the synaptogenic and antidepressant-like effects of a single otherwise subthreshold dose of ketamine were potentiated when given together with a single dose of lithium chloride (a nonselective GSK-3 inhibitor) or a preferential GSK-3β inhibitor; these effects included rapid activation of the mTORC1 signaling pathway, increased inhibitory phosphorylation of GSK-3β, increased synaptic spine density/diameter, increased excitatory postsynaptic currents in mPFC layer V pyramidal neurons, and antidepressant responses that persist for up to 1 week in the forced-swim test model of depression. The results demonstrate that low, subthreshold doses of ketamine combined with lithium or a selective GSK-3 inhibitor are equivalent to higher doses of ketamine, indicating the pivotal role of the GSK-3 pathway in modulating the synaptogenic and antidepressant responses to ketamine. The possible mitigation by GSK-3 inhibitors of the eventual fading of ketamine's antidepressant effects remains to be explored.
单次剂量的短效 NMDA 拮抗剂氯胺酮可迅速且持久地改善治疗抵抗性重度抑郁症（MDD）患者的抑郁症状，这被认为是通过恢复突触连接实现的。然而，氯胺酮的急性分离副作用和抗抑郁作用的最终消退限制了其在临床上的广泛应用。最近在中前额皮质（mPFC）的研究表明，在啮齿动物中，单次标准剂量氯胺酮的促突触生成和抗抑郁样作用依赖于哺乳动物雷帕霉素靶蛋白（mTOR）复合物 1（mTORC1）信号通路的激活，以及糖原合成激酶-3（GSK-3）的抑制性磷酸化，这可减轻其对 mTOR 的抑制作用。在这里，我们发现当给予单次锂盐（非选择性 GSK-3 抑制剂）或选择性 GSK-3β抑制剂时，单次亚阈值剂量的氯胺酮的促突触生成和抗抑郁样作用增强；这些作用包括 mTORC1 信号通路的快速激活、GSK-3β的抑制性磷酸化增加、mPFC 层 V 锥体神经元的兴奋性突触后电流增加、以及在强迫游泳测试模型中抗抑郁反应可持续长达 1 周。研究结果表明，低剂量、亚阈值剂量的氯胺酮与锂或选择性 GSK-3 抑制剂联合使用相当于更高剂量的氯胺酮，表明 GSK-3 途径在调节氯胺酮的促突触生成和抗抑郁反应中起关键作用。GSK-3 抑制剂是否可以减轻氯胺酮抗抑郁作用的最终消退仍有待探索。
