Key Laboratory of Neuroscience, Department of Biomedical Science, City University of Hong Kong, Hong Kong; Faculty of Forensic Medicine, Zhongshan School of Medicine, Sun Yat-sen University, China; Guangdong Province Translational Forensic Medicine Engineering Technology Research Center, Zhongshan School of Medicine, Sun Yat-sen University, China.
Faculty of Forensic Medicine, Zhongshan School of Medicine, Sun Yat-sen University, China; Guangdong Province Translational Forensic Medicine Engineering Technology Research Center, Zhongshan School of Medicine, Sun Yat-sen University, China.
Mol Cell Neurosci. 2022 May;120:103723. doi: 10.1016/j.mcn.2022.103723. Epub 2022 Mar 26.
Post-traumatic stress disorder (PTSD) is a devastating mental illness with high morbidity and major social and economic burden. Currently, there is no promising therapy available for the treatment of PTSD. Some clinical studies showed that ketamine could effectively alleviate PTSD symptoms. However, it is still unclear which brain region ketamine targets and how it attenuates the PTSD-like effects. In this study, we examined the effect of ketamine on fear generalization (a core symptom of PTSD) by using a mice model of fear generalization induced by fear conditioning procedure. Before retrieval, ketamine was locally infused into the nucleus accumbens (a brain region closely associated with PTSD). Fear generalization mice were subjected to behavioral testing and biochemical assessments, following ketamine infusion. The results showed that the foot shock strength-dependently induced fear generalization in mice with increased c-fos activity, and a lower level of GluR1(S845), GluR1(S831) protein, and a higher level of P-GluN2B protein in the nucleus accumbens (NAc). Local infusion of ketamine into NAc decreased the fear generalization together with an increased level of GluR1(S845), GluR1(S831) protein, and decreased level of P-GluN2B protein. Altogether, these results conclude that ketamine might affect the glutamatergic signaling in the NAc to attenuate the fear generalization in mice.
创伤后应激障碍（PTSD）是一种严重的精神疾病，发病率高，社会和经济负担重。目前，尚无有效的治疗方法。一些临床研究表明氯胺酮可以有效缓解 PTSD 症状。然而，氯胺酮作用于哪个脑区以及如何减轻 PTSD 样效应仍不清楚。在这项研究中，我们通过使用恐惧条件反射程序诱导的恐惧泛化小鼠模型，研究了氯胺酮对恐惧泛化（PTSD 的核心症状）的影响。在检索之前，将氯胺酮局部输注到伏隔核（与 PTSD 密切相关的脑区）。在氯胺酮输注后，对恐惧泛化的小鼠进行行为测试和生化评估。结果表明，在增加 c-fos 活性和伏隔核（NAc）中 GluR1(S845)、GluR1(S831)蛋白水平降低以及 P-GluN2B 蛋白水平升高的情况下，脚电击强度可引起小鼠恐惧泛化。将氯胺酮局部输注到 NAc 中可减轻恐惧泛化，同时增加 GluR1(S845)、GluR1(S831)蛋白水平，并降低 P-GluN2B 蛋白水平。总之，这些结果表明，氯胺酮可能通过影响 NAc 中的谷氨酸能信号来减弱小鼠的恐惧泛化。
