Department of Clinical Medicine, Weifang Medical University, 7166# Baotong West Street, Weifang, 261053, Shandong, China.
Department of Psychology, Weifang Medical University, 7166# Baotong West Street, Weifang, 261053, Shandong, China.
Prog Neuropsychopharmacol Biol Psychiatry. 2018 Aug 30;86:313-321. doi: 10.1016/j.pnpbp.2018.03.019. Epub 2018 Mar 27.
Post-traumatic stress disorder (PTSD) is commonly associated with concurrent anxiety and depression symptoms, and reduce the expression of the Brain-Derived Neurotrophic Factor (BDNF) which promotes the proliferation and survival of neurons. The hyperpolarization-activated cyclic nucleotide-gated channel 1(HCN1) could be inhibited by the ketamine, a drug to alleviate depression and anxiety, and regulated the BDNF expression, however, the effects of ketamine in alleviating PTSD symptoms by regulating the HCN1-related BDNF have been poorly perceived.
In the present study, the effects of ketamine were examined on the PTSD-like effects in a rat model of PTSD induced by SPS&S procedure. After the SPS&S procedure and model testing, PTSD rats were subjected to behavioral testing and biochemical assessments, followed by single treatment with certain doses of ketamine (5, 10, 15 and 20 mg/kg IP).
The results showed that the SPS&S procedure induced severe PTSD-like behaviors, with lower levels of BDNF protein levels and higher level of the HCN1 protein in the prefrontal cortex (PFC). These were reversed by a single administration of ketamine. The ketamine with dose of 15 mg/kg significantly increased locomotor behavior in the open field test, aggrandized exploratory behavior in the elevated plus maze test, and decreased immobility time spent in the forced swim test. Meanwhile, ketamine with dose of 15 mg/kg could increase the BDNF protein level, while down-regulate the expression of the HCN1. Eventually, there was a negative correlation between the level of BDNF and HCN1 in the PFC.
Ketamine affects the HCN1-related BDNF signaling pathways to alleviate PTSD-like effects in rat.
创伤后应激障碍（PTSD）常伴有焦虑和抑郁症状，并降低脑源性神经营养因子（BDNF）的表达，后者促进神经元的增殖和存活。超极化激活环核苷酸门控通道 1（HCN1）可被氯胺酮抑制，氯胺酮是一种缓解抑郁和焦虑的药物，可调节 BDNF 的表达，但氯胺酮通过调节与 HCN1 相关的 BDNF 来缓解 PTSD 症状的作用尚未得到充分认识。
本研究采用 SPS&S 程序诱导 PTSD 大鼠模型，考察氯胺酮对 PTSD 样效应的影响。SPS&S 程序和模型测试后，PTSD 大鼠进行行为测试和生化评估，然后单次给予不同剂量的氯胺酮（5、10、15 和 20mg/kg IP）。
结果表明，SPS&S 程序诱导了严重的 PTSD 样行为，前额叶皮层（PFC）中的 BDNF 蛋白水平降低，HCN1 蛋白水平升高。单次给予氯胺酮可逆转这些变化。氯胺酮 15mg/kg 剂量显著增加旷场试验中的运动行为，增加高架十字迷宫试验中的探索行为，减少强迫游泳试验中的不动时间。同时，氯胺酮 15mg/kg 剂量可增加 BDNF 蛋白水平，下调 HCN1 表达。最终，PFC 中 BDNF 和 HCN1 的水平呈负相关。
氯胺酮通过影响 HCN1 相关的 BDNF 信号通路缓解大鼠 PTSD 样效应。
