伏隔核区硫氧还蛋白-1低表达减缓吗啡所致条件性位置偏爱的消退

发布时间：2018-05-14 03:10

  本文选题：吗啡 + 硫氧还蛋白-1　； 参考：《昆明理工大学》2017年硕士论文

【摘要】：吗啡是一种阿片类药物,长期使用导致依赖性和成瘾,吗啡成瘾已成为全球关注的公共卫生问题之一。中脑腹侧被盖区(ventral tegmental area,VTA),伏隔核(nucleus accumbens,NAc),前额叶皮层(prefrontal cortex,PFC),海马(hippocampus,HiP)是药物成瘾的中枢神经系统的重要组成部分。VTA区多巴胺系统参与奖赏效应,NAc接受VTA投射的多巴胺神经纤维以及海马和前额叶皮层传入的谷氨酸纤维,与复吸有关,海马在药物奖赏刺激与环境线索相关记忆形成中起重要作用。吗啡成瘾后停止给药则产生戒断行为,以及奖赏效应的消退,消退不是简单的遗忘或擦除原始的记忆,而是新的学习记忆形成,而NAc中谷氨酸的突触可塑性在药物奖赏消退中起重要的作用。硫氧还蛋白-1(Thioredoxin-1,Trx-1),是氧化还原调节蛋白,对细胞组织中氧化还原平衡的调节起重要作用,具有保护和抑制神经凋亡的作用。吗啡作用后可导致硫氧还蛋白-1表达改变,然而硫氧还蛋白-1是否参与了成瘾药物所致条件性位置偏爱(conditioned place preference,CPP)的消退还未有报道。本实验的目的是确定硫氧还蛋白-1是否通过调节NAc中谷氨酸信号通路改变吗啡诱导的CPP消退过程。我们利用CPP模型以及核团定位注射的技术,在吗啡诱导CPP形成后,在小鼠NAc双边注射Trx-1特异性的干扰RNA,构建NAc区Trx-1低表达小鼠,并比较对照组、阴性对照组和低表达组吗啡所诱导的小鼠CPP消退过程的时间差异。我们的研究结果表明NAc中Trx-1低表达减缓了吗啡所致CPP的消退。我们还检测了 NAc、VTA和HiP中相关蛋白的变化,发现吗啡CPP消退诱导NAc、VTA和HiP中α-氨基-3-羟基-5-甲基异恶唑-4-丙酸受体(a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors,AMPAR)的表达升高,而Trx-1低表达抑制了吗啡诱导的AMPAR的升高;吗啡CPP消退诱导NAc、VTA 和 HiP 中 N-甲基-D 天门冬氨酸(N-methyl-d-aspartate,NMDA)受体的 2B 亚型(NR2B)、突触后致密物质 95(postsynapticdensity-95,PSD95)、磷酸化钙调素依赖蛋白激酶 Ⅱ(phosphorylated Calcium/calmodulin-dependent protein kinase Ⅱ,p-CaMKⅡ)、磷酸化细胞外信号调节蛋白激酶1(phosphorylated extracellular signal-regulated protein kinasel,p-ERKl)及磷酸化 cAMP 反应元件结合蛋白(phosphorylated cAMP response element binding protein,p-CREB)表达水平的升高,而Trx-1 低表达进一步增加了 NR2B,PSD95,p-CaMKⅡ,p-ERKl,p-CREB的表达。总结:本研究表明吗啡诱导的CPP消退与NAc、VTA和HiP谷氨酸信号通路相关分子表达有关。NAc中Trx-1通过调节谷氨酸信号通路相关分子,延缓吗啡所诱导的CPP消退。该研究可为吗啡戒断治疗提出供新的思路和作用靶点。
[Abstract]:Morphine is an opioid drug, which leads to dependence and addiction. Morphine addiction has become one of the global public health problems. Ventral tegmental are VTAA in ventral tegmental area, nucleus accumbens in nucleus accumbens, prefrontal cortexa in prefrontal cortex, and hipppocampus in hippocampus are important components of the central nervous system of drug addiction. The dopamine system in VTA region is involved in the reward effect. NAC receives the dopamine neurofibrils projected by VTA. And the afferent glutamate fibers in the hippocampus and the prefrontal cortex, Hippocampus plays an important role in memory formation associated with drug reward stimulation and environmental cues. Withdrawal from morphine addiction results in abstinence and the regression of the reward effect, which is not simply forgetting or erasing the original memory, but the formation of new learning and memory. Synaptic plasticity of glutamate in NAc plays an important role in drug reward regression. Thioredoxin-1, a redox regulatory protein, plays an important role in the regulation of redox balance and protects and inhibits apoptosis. The expression of thioredoxin-1 was changed after morphine treatment. However, it has not been reported whether thioredoxin-1 is involved in the regression of conditioned place preference (CPP) induced by addictive drugs. The aim of this study was to determine whether thioredoxin-1 changes the morphine-induced CPP regression process by regulating the glutamate signaling pathway in NAc. Using CPP model and nucleocapsid injection technique, after morphine induced CPP formation and bilateral injection of Trx-1 specific interference RNAs into mice NAc, we constructed NAc region Trx-1 low expression mice, and compared the control group. The time of CPP regression induced by morphine in negative control group and low expression group was different. Our results suggest that the low expression of Trx-1 in NAc slows the regression of CPP induced by morphine. We also detected the changes of related proteins in HiP and HiP, and found that morphine CPP regression induced the increase of 伪 -amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptorsAMPAR in NAc-3-hydroxy-5-methylisoxazole-4-propionic acid receptorsAMPAR, but the low expression of Trx-1 inhibited the increase of AMPAR induced by morphine. Subtype 2B of N-methyl-D-aspartate NMDA-N-methyl-d-aspartate NMDAR induced by morphine CPP regression, 95 postsynaptic dense substance 95 postsynaptic density-95, phosphorylated calmodulin dependent protein kinase 鈪，

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