甲基苯丙胺调节细胞外信号激酶（ERK）表达的研究
发布时间：2018-11-17 07:13
【摘要】：甲基苯丙胺(methamphetamine, METH)是一种被广泛使用的神经兴奋剂,它可以使人兴奋,产生欣快感并引起幻觉。这主要是由于甲基苯丙胺导致的脑内的多巴胺和五羟色胺急剧大量增加所致。然而,甲基苯丙胺的持续作用,会导致依赖,复吸等成瘾行为。 甲基苯丙胺成瘾引起的复吸与腹侧被盖区(Ventral Tegmental Area, VTA)/伏隔核(nucleus accumbens, NAc)/前额叶皮质(prefrontal cortex, PFC)构成的奖赏通路以及VTA/NAc/海马(Hippocampus, HiP)构成的强化学习记忆回路被激活有关。细胞外调节蛋白激酶(extracellular regulated protein kinase, ERK)信号转导通路与成瘾密切相关。细胞内多条途径可激活ERK,活化的ERK从多方面参与甲基苯丙胺的作用过程。有关ERK信号转导通路的研究有助于了解甲基苯丙胺成瘾所导致的成瘾现象。 本研究采用甲基苯丙胺1mM短时程(0、10、20、30、45、60分钟)刺激PC12细胞,用蛋白免疫印迹(Western Blot)法检测p-ERK、ERK。结果发现p-ERK的表达量明显增高。 在小鼠身上也进行了相同的实验,使用2.5mg/kg/d的METH注射小鼠4小时,之后检测了小鼠大脑VTA/NAc/PFC/HiP区的ERK通路的变化,且ERK通路下游分子细胞周期依赖蛋白激酶5(cyclin-dependent kinase5, CDK5), cAMP应答元件结合蛋白(cAMP-responsive element-binding protein, CREB)蛋白也发生了相应的变化。并比较了硫氧还蛋白转基因小鼠与野生型的差异,发现硫氧还蛋白高表达在不同的脑区可翻转以上部分分子的变化。 本研究证明了ERK通路确实参与了甲基苯丙胺引起的急性作用,且ERK通路与这些作用有关,这为甲基苯丙胺成瘾的研究提供了新的理论基础。虽然ERK信号通路在甲基苯丙胺成瘾中所起的作用还需要进一步的研究与探索,但ERK通路可能是METH成瘾治疗的潜在靶点。
[Abstract]:Methamphetamine (methamphetamine, METH) is a widely used neurostimulant that can cause excitement, pleasure and hallucinations. This is mainly due to a sharp increase in dopamine and serotonin in the brain caused by methamphetamine. However, the persistence of methamphetamine can lead to addictive behaviors such as dependence and relapse. Relapse induced by methamphetamine addiction and reward pathway of (Ventral Tegmental Area, VTA) / (nucleus accumbens, NAc) / (prefrontal cortex, PFC) in ventral tegmental area and VTA/NAc/ hippocampus (Hippocampus,) HiP) is related to the activation of the enhanced learning and memory circuit. Extracellular regulated protein kinase (extracellular regulated protein kinase, ERK) signal transduction pathway is closely related to addiction. Multiple intracellular pathways activate ERK,-activated ERK involved in methamphetamine in many ways. The study of ERK signal transduction pathway is helpful to understand the addiction caused by methamphetamine addiction. In this study, PC12 cells were stimulated with methamphetamine 1mM for 60 minutes (0 10 / 20) and p-ERK / ERK was detected by Western blot (Western Blot). The results showed that the expression of p-ERK was significantly increased. The same experiment was carried out in mice. The mice were injected with METH of 2.5mg/kg/d for 4 hours, and then the changes of ERK pathway in the VTA/NAc/PFC/HiP region of the mouse brain were detected. And the downstream molecular cell cycle dependent protein kinase 5 (cyclin-dependent kinase5, CDK5), cAMP response element binding protein (cAMP-responsive element-binding protein, CREB) protein of ERK pathway has also changed accordingly. The differences between thioredoxin transgenic mice and wild-type mice were compared. It was found that the high expression of thioredoxin in different brain regions could reverse the changes of some of the above molecules. This study demonstrated that the ERK pathway is indeed involved in the acute effects induced by methamphetamine, and the ERK pathway is related to these effects, which provides a new theoretical basis for the study of methamphetamine addiction. Although the role of ERK signaling pathway in methamphetamine addiction needs further study and exploration, ERK pathway may be a potential target for the treatment of METH addiction.
【学位授予单位】：昆明理工大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R96
本文编号：2336922
[Abstract]:Methamphetamine (methamphetamine, METH) is a widely used neurostimulant that can cause excitement, pleasure and hallucinations. This is mainly due to a sharp increase in dopamine and serotonin in the brain caused by methamphetamine. However, the persistence of methamphetamine can lead to addictive behaviors such as dependence and relapse. Relapse induced by methamphetamine addiction and reward pathway of (Ventral Tegmental Area, VTA) / (nucleus accumbens, NAc) / (prefrontal cortex, PFC) in ventral tegmental area and VTA/NAc/ hippocampus (Hippocampus,) HiP) is related to the activation of the enhanced learning and memory circuit. Extracellular regulated protein kinase (extracellular regulated protein kinase, ERK) signal transduction pathway is closely related to addiction. Multiple intracellular pathways activate ERK,-activated ERK involved in methamphetamine in many ways. The study of ERK signal transduction pathway is helpful to understand the addiction caused by methamphetamine addiction. In this study, PC12 cells were stimulated with methamphetamine 1mM for 60 minutes (0 10 / 20) and p-ERK / ERK was detected by Western blot (Western Blot). The results showed that the expression of p-ERK was significantly increased. The same experiment was carried out in mice. The mice were injected with METH of 2.5mg/kg/d for 4 hours, and then the changes of ERK pathway in the VTA/NAc/PFC/HiP region of the mouse brain were detected. And the downstream molecular cell cycle dependent protein kinase 5 (cyclin-dependent kinase5, CDK5), cAMP response element binding protein (cAMP-responsive element-binding protein, CREB) protein of ERK pathway has also changed accordingly. The differences between thioredoxin transgenic mice and wild-type mice were compared. It was found that the high expression of thioredoxin in different brain regions could reverse the changes of some of the above molecules. This study demonstrated that the ERK pathway is indeed involved in the acute effects induced by methamphetamine, and the ERK pathway is related to these effects, which provides a new theoretical basis for the study of methamphetamine addiction. Although the role of ERK signaling pathway in methamphetamine addiction needs further study and exploration, ERK pathway may be a potential target for the treatment of METH addiction.
【学位授予单位】：昆明理工大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R96
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