School of Clinical Medicine, Shandong Second Medical University, 7166# Baotong West Street, Weifang, Shandong, 261053, PR China; Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun, 130021, PR China.
School of Psychology, Shandong Second Medical University, 7166# Baotong West Street, Weifang, Shandong, 261053, PR China; CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, 100101, PR China; Department of Psychology, University of Chinese Academy of Sciences, Beijing, 100049, PR China.
J Psychiatr Res. 2024 Oct;178:259-269. doi: 10.1016/j.jpsychires.2024.08.019. Epub 2024 Aug 14.
Each year, 3-4% of the global population experiences post-traumatic stress disorder (PTSD), a chronic mental disorder with significant social and economic repercussions. Although it has been shown that ketamine can effectively alleviate PTSD symptoms in individuals, the specific mechanism of action underlying its anti-PTSD effects remains unclear. In this study, we investigated how a single, low dose of ketamine affected the glycogen synthase kinase 3β (GSK-3β)/glucocorticoid receptor (GR) signaling pathway in a single prolonged stress (SPS)-induced PTSD rat model.
After establishing the model, stress-related behavioral alterations in the rats were assessed following intraperitoneal injections of ketamine (10 mg/kg) and GSK-3β antagonist SB216763 (5 mg/kg). In the hippocampus, alterations in the expression of specific proteins implicated in PTSD development, such as GR, brain-derived neurotrophic factor (BDNF), GSK-3β, and phosphorylated glycogen synthase kinase 3β (p-GSK-3β), were assessed. We also measured changes in the mRNA expression levels of GR, BDNF, GSK-3β, FK501 binding protein 51 (FKBP5), and corticotropin-releasing hormone (CRH), as well as synaptic ultrastructure, in the hippocampus, and measured changes in corticosterone levels in the blood.
SPS induced anxiety-like and depression-like behaviors in rats and induced morphological changes in synapse, which were accompanied by higher GSK-3β protein expression and conversely, decreased expression of GR, BDNF, p-GSK-3β, FKBP5 and CRH. Intraperitoneal administration of ketamine (10 mg/kg) after SPS prevented SPS-induced anxiety-like behaviors. Most importantly, ketamine attenuated SPS-induced dysfunctions in GSK-3β/GR signaling and synaptic deficits. Furthermore, treatment with a GSK-3β inhibitor played the same effect as ketamine on behavioral changes of SPS model rats.
Single doses of ketamine effectively ameliorate SPS-induced anxiety-like symptoms, potentially by improving synaptic plastic in the hippocampus by regulating GSK-3β/GR signaling.
每年有 3-4%的全球人口经历创伤后应激障碍（PTSD），这是一种具有重大社会和经济影响的慢性精神障碍。虽然已经表明氯胺酮可以有效缓解个体的 PTSD 症状，但它抗 PTSD 作用的具体机制尚不清楚。在这项研究中，我们研究了单次低剂量氯胺酮如何影响单次延长应激（SPS）诱导的 PTSD 大鼠模型中的糖原合成酶激酶 3β（GSK-3β）/糖皮质激素受体（GR）信号通路。
在建立模型后，通过腹腔注射氯胺酮（10mg/kg）和 GSK-3β 拮抗剂 SB216763（5mg/kg）评估大鼠的应激相关行为改变。在海马体中，评估了与 PTSD 发展相关的特定蛋白表达的变化，如 GR、脑源性神经营养因子（BDNF）、GSK-3β 和磷酸化糖原合成酶激酶 3β（p-GSK-3β）。我们还测量了海马体中 GR、BDNF、GSK-3β、FK501 结合蛋白 51（FKBP5）和促肾上腺皮质激素释放激素（CRH）的 mRNA 表达水平的变化，以及突触超微结构的变化，并测量了血液中皮质酮水平的变化。
SPS 诱导大鼠出现焦虑样和抑郁样行为，并诱导突触形态改变，同时伴有 GSK-3β 蛋白表达增加，而 GR、BDNF、p-GSK-3β、FKBP5 和 CRH 表达减少。SPS 后腹腔内给予氯胺酮（10mg/kg）可预防 SPS 诱导的焦虑样行为。最重要的是，氯胺酮减轻了 SPS 诱导的 GSK-3β/GR 信号和突触缺陷的功能障碍。此外，GSK-3β 抑制剂的治疗对 SPS 模型大鼠的行为变化产生了与氯胺酮相同的效果。
单次剂量的氯胺酮可有效改善 SPS 诱导的焦虑样症状，可能通过调节 GSK-3β/GR 信号改善海马体的突触可塑性。
