背景:每年,3-4%的全球人口经历创伤后应激障碍(PTSD),一种具有重大社会和经济影响的慢性精神障碍。尽管已经证明氯胺酮可以有效缓解个体的PTSD症状,其抗PTSD作用的具体作用机制尚不清楚.在这项研究中,我们调查了一个人,低剂量氯胺酮影响单一长期应激(SPS)诱导的PTSD大鼠模型中糖原合成酶激酶3β(GSK-3β)/糖皮质激素受体(GR)信号通路。
方法:建立模型后,腹膜内注射氯胺酮(10mg/kg)和GSK-3β拮抗剂SB216763(5mg/kg)后,评估大鼠与应激相关的行为改变。在海马中,与PTSD发展有关的特定蛋白质表达的改变,例如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),被评估。我们还测量了GRmRNA表达水平的变化,BDNF,GSK-3β,FK501结合蛋白51(FKBP5),促肾上腺皮质激素释放激素(CRH),以及突触超微结构,在海马中,并测量血液中皮质酮水平的变化。
结果:SPS引起大鼠焦虑样和抑郁样行为,并引起突触的形态学改变,伴随着较高的GSK-3β蛋白表达,相反,GR的表达减少,BDNF,p-GSK-3β,FKBP5和CRH。SPS后腹膜内施用氯胺酮(10mg/kg)可预防SPS诱导的焦虑样行为。最重要的是,氯胺酮减轻SPS诱导的GSK-3β/GR信号传导和突触缺陷的功能障碍。此外,GSK-3β抑制剂对SPS模型大鼠的行为改变具有与氯胺酮相同的作用。
结论:单剂量氯胺酮可有效改善SPS引起的焦虑样症状,可能通过调节GSK-3β/GR信号来改善海马的突触可塑性。
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.