氯胺酮抗创伤后应激障碍的效应及其相关机制研究

发布时间：2018-02-03 17:39

本文关键词： 氯胺酮一氧化氮创伤后应激障碍神经元再生神经可塑性　出处：《河北北方学院》2014年硕士论文　论文类型：学位论文

【摘要】：氯胺酮是一种非竞争性N-甲基-D-天冬氨酸（NMDA）受体拮抗剂，研究已证实氯胺酮具有显著的抗焦虑、抗抑郁作用，而目前关于其是否具有抗创伤后应激障碍（Post-Traumatic Stress Disorder, PTSD）作用尚无研究涉及。本研究采用多个公认的PTSD动物模型，以行为药理学方法研究其抗PTSD作用，在此基础上从一氧化氮(NO)通路、神经可塑性、神经元再生等，多角度多层次探讨氯胺酮抗PTSD的作用机理，为氯胺酮能否作为防治PTSD有效药物提供可靠的实验依据。建立包括小鼠单程短暂电击模型和大鼠时间依赖性敏化应激（Time-dependent sensitization, TDS)模型在内的两种PTSD模型，采用僵住行为测试、高架十字迷宫实验和爬梯实验评价氯胺酮在这两个模型上抗PTSD的行为学效应、以开场实验评价氯胺酮是否对动物自发活动性产生影响，在此基础上，基于PTSD发生的神经可塑性假说，采用蛋白印记（Werstern Blot）法检测氯胺酮对PTSD动物海马组织蛋白脑源性神经营养因子（Brain derived neurotrophic factor BDNF）、环磷酸腺苷反应元件（cAMP response element bingding protein CREB）、诱导型一氧化氮合酶（inducible nitric oxide synthase iNOS）、神经元型一氧化氮合酶（neurons nitric oxide synthase nNOS）表达的影响。（1）小鼠单程短暂电击模型：开场实验行为测试结果显示，氯胺酮对小鼠自主活动性无影响；小鼠僵住行为测试结果显示，与模型组相比，氯胺酮(0.625、1.25、2.5mg/kg)僵住时间显著缩短；高架十字迷宫结果显示，与空白组相比模型组小鼠停留开臂的时间显著缩短，进入开臂的次数显著下降，与模型组相比，氯胺酮(0.625、1.25、2.5mg/kg)均显著延长小鼠停留开臂的时间，增加进入开臂的次数；爬梯实验结果显示，各组小鼠爬梯次数没有显著差异，模型组与空白组相比站立次数明显增加，与模型组相比，氯胺酮0.625mg/kg和1.25mg/kg组小鼠站立次数显著减少。（2）大鼠TDS模型结果：开场实验测试结果显示，氯胺酮对大鼠自主活动性无影响；僵住行为测试结果表明，氯胺酮0.625mg/kg和2.5mg/kg可显著逆转TDS模型大鼠僵住时间的延长；高架十字迷宫结果显示，与正常对照组相比，TDS模型大鼠停留开臂的时间显著缩短，进入开臂的次数减少，氯胺酮2.5mg/kg可显著延长TDS模型大鼠停留开臂的时间延长，增加进入开臂的次数。（3）Werstern Blot结果显示：氯胺酮可增加PTSD动物海马BDNF、p-CREB的表达；氯胺酮降低PTSD动物海马iNOS、nNOS的表达。氯胺酮在小鼠单程短暂电击模型和大鼠TDS模型中表现出显著的改善PTSD的行为学效应；氯胺酮改善模型动物PTSD的作用机制可能与促进神经营养和神经元再生及调控NO信号转导通路相关。
[Abstract]:Ketamine is a non-competitive NMDA-NMDA-receptor antagonist. It has been proved that ketamine has significant antianxiety and antidepressant effects. But whether it has Post-Traumatic Stress Disorder or not. In this study, we used a number of recognized animal models of PTSD to study its role in anti-#en1# by behavioral pharmacology, and based on it, we studied the nitric oxide (no) pathway. Neural plasticity, neuronal regeneration and so on. The mechanism of ketamine on PTSD was discussed in different angles and levels. To provide a reliable experimental basis for ketamine as an effective drug for the prevention and treatment of PTSD. The model of one-pass transient electric shock in mice and the time-dependent sensitized stress in rats were established. Time-dependent sensitization. Two kinds of PTSD models, including TDs, were used to evaluate the behavioral effect of ketamine against PTSD in the two models by means of frozen behavior test, elevated cross maze test and climbing ladder test. The effect of ketamine on the spontaneous activity of animals was evaluated by an open field experiment, and based on the hypothesis of neuroplasticity of PTSD. The effect of ketamine on brain derived neurotrophic factor (BDNF) in hippocampal tissue of PTSD animals was detected by Werstern Blot method. Brain derived neurotrophic factor BDNF. Cyclic adenosine monophosphate (camp response element bingding protein CREBB). Inducible nitric oxide synthase iNOS. Effects of neurons nitric oxide synthase nNOSs expression on neuronal nitric oxide synthase. One-way transient electric shock model in mice: the results of the behavior test showed that. Ketamine had no effect on autonomous activity in mice. Compared with the model group, the freezing time of ketamine was significantly shorter than that of the model group. The results of elevated cross labyrinth showed that compared with the blank group, the open arm time of the model group was significantly shorter, and the number of entering the open arm was significantly decreased. Compared with the model group, ketamine was 0.625 / 1.25. 2.5 mg / kg significantly prolonged the opening time and increased the number of times of entering the open arm. The results of ladder climbing experiment showed that there was no significant difference in climbing times between each group, and the standing times of model group and blank group were significantly increased, compared with model group. Ketamine 0.625 mg / kg and 1.25 mg / kg decreased the standing times of rats significantly.) the results of TDS model in rats: the results of open field test showed. Ketamine had no effect on autonomous activity in rats. The results of freezing behavior test showed that ketamine 0.625 mg / kg and 2.5 mg / kg could significantly reverse the prolonged freezing time of TDS model rats. The results of elevated cross labyrinth showed that compared with the normal control group, the open arm time of TDs rats was significantly shortened and the number of open arm entry was decreased. Ketamine 2.5 mg / kg significantly prolonged the open arm retention time of TDS model rats. The results of Werstern Blot showed that ketamine could increase the expression of BDNF p-CREB in hippocampus of PTSD animals. Ketamine reduced the expression of iNOSnNOS in hippocampus of PTSD animals. Ketamine showed a significant behavioral effect on improving PTSD in mice and TDS models. The mechanism of ketamine in improving PTSD may be related to the promotion of neurotrophic and neuronal regeneration and regulation of no signal transduction pathway.
【学位授予单位】：河北北方学院
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R965

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