Shen Yiwei, Ran Wei, Liu Dawei, Lv Feng, Ren Li, Min Su
Department of Anesthesiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
Department of Anesthesiology, The Affiliated Yongchuan Hospital of Chongqing Medical University, Chongqing 400016, China.
Pharmacol Biochem Behav. 2025 Mar;248:173955. doi: 10.1016/j.pbb.2025.173955. Epub 2025 Jan 3.
Electroconvulsive therapy (ECT) is recognized as one of the most efficacious interventions for depression. However, it is associated with impairments in learning and memory functions. Ketamine has demonstrated potential in mitigating cognitive deficits. Notably, the metabotropic glutamate system is hypothesized to play a pivotal role in cognitive process regulation. Nevertheless, the involvement of the metabotropic glutamate system in esketamine-mediated alleviation of electroconvulsive shock (ECS, an animal analogue of ECT)-induced memory impairment remains to be elucidated. In this study, a depressive rat model was established using chronic unpredictable mild stress. The depressive-like behavior and cognitive performance of the rats were evaluated using the sucrose preference test, the open field test, and the Morris water maze test, respectively. The expression levels of type-5 metabotropic glutamate receptor (mGluR5) and N-methyl-d-aspartate receptor 1 (NMDAR1) were quantified through immunofluorescence and real-time PCR techniques. Long-term potentiation (LTP) of hippocampal Schaffer collateral (SC)-CA1 synapses was observed in electrophysiological experiments. The results of this investigation revealed that a low dose of esketamine administration upregulated the expression of mGluR5 and NMDAR1 in the hippocampus of stressed rats, alleviated ECS-induced cognitive impairment, and ameliorated depressive-like behavior. Conversely, the mGluR5 antagonist MTEP effectively reversed esketamine-mediated changes in the rat hippocampus and counteracted its protective effect on learning and memory functions following ECS. In conclusion, the findings of this study support the hypothesis that esketamine upregulates mGluR5 and NMDAR1 expression, thereby enhancing NMDAR activation in the hippocampus. This mechanism may be responsible for the protective effects on spatial learning and memory function observed in depressed rats subjected to ECS.
电休克疗法（ECT）被认为是治疗抑郁症最有效的干预措施之一。然而，它与学习和记忆功能受损有关。氯胺酮已显示出减轻认知缺陷的潜力。值得注意的是，代谢型谷氨酸系统被认为在认知过程调节中起关键作用。然而，代谢型谷氨酸系统在艾司氯胺酮介导的减轻电休克（ECS，ECT的动物模拟模型）诱导的记忆损伤中的作用仍有待阐明。在本研究中，使用慢性不可预测轻度应激建立了抑郁大鼠模型。分别使用蔗糖偏好试验、旷场试验和莫里斯水迷宫试验评估大鼠的抑郁样行为和认知表现。通过免疫荧光和实时PCR技术定量5型代谢型谷氨酸受体（mGluR5）和N-甲基-D-天冬氨酸受体1（NMDAR1）的表达水平。在电生理实验中观察海马体Schaffer侧支（SC）-CA1突触的长时程增强（LTP）。本研究结果表明，低剂量艾司氯胺酮给药上调了应激大鼠海马体中mGluR5和NMDAR1的表达，减轻了ECS诱导的认知损伤，并改善了抑郁样行为。相反，mGluR5拮抗剂MTEP有效地逆转了艾司氯胺酮介导的大鼠海马体变化，并抵消了其对ECS后学习和记忆功能的保护作用。总之，本研究结果支持以下假设：艾司氯胺酮上调mGluR5和NMDAR1表达，从而增强海马体中NMDAR的激活。这种机制可能是对遭受ECS的抑郁大鼠观察到的空间学习和记忆功能保护作用的原因。
