【摘要】：甲基苯丙胺(methamphetamine, METH)是一種被廣泛使用的神經(jīng)興奮劑,它可以使人興奮,產(chǎn)生欣快感并引起幻覺。這主要是由于甲基苯丙胺導(dǎo)致的腦內(nèi)的多巴胺和五羥色胺急劇大量增加所致。然而,甲基苯丙胺的持續(xù)作用,會導(dǎo)致依賴,復(fù)吸等成癮行為。 甲基苯丙胺成癮引起的復(fù)吸與腹側(cè)被蓋區(qū)(Ventral Tegmental Area, VTA)/伏隔核(nucleus accumbens, NAc)/前額葉皮質(zhì)(prefrontal cortex, PFC)構(gòu)成的獎賞通路以及VTA/NAc/海馬(Hippocampus, HiP)構(gòu)成的強(qiáng)化學(xué)習(xí)記憶回路被激活有關(guān)。細(xì)胞外調(diào)節(jié)蛋白激酶(extracellular regulated protein kinase, ERK)信號轉(zhuǎn)導(dǎo)通路與成癮密切相關(guān)。細(xì)胞內(nèi)多條途徑可激活ERK,活化的ERK從多方面參與甲基苯丙胺的作用過程。有關(guān)ERK信號轉(zhuǎn)導(dǎo)通路的研究有助于了解甲基苯丙胺成癮所導(dǎo)致的成癮現(xiàn)象。 本研究采用甲基苯丙胺1mM短時程(0、10、20、30、45、60分鐘)刺激PC12細(xì)胞,用蛋白免疫印跡(Western Blot)法檢測p-ERK、ERK。結(jié)果發(fā)現(xiàn)p-ERK的表達(dá)量明顯增高。 在小鼠身上也進(jìn)行了相同的實驗,使用2.5mg/kg/d的METH注射小鼠4小時,之后檢測了小鼠大腦VTA/NAc/PFC/HiP區(qū)的ERK通路的變化,且ERK通路下游分子細(xì)胞周期依賴蛋白激酶5(cyclin-dependent kinase5, CDK5), cAMP應(yīng)答元件結(jié)合蛋白(cAMP-responsive element-binding protein, CREB)蛋白也發(fā)生了相應(yīng)的變化。并比較了硫氧還蛋白轉(zhuǎn)基因小鼠與野生型的差異,發(fā)現(xiàn)硫氧還蛋白高表達(dá)在不同的腦區(qū)可翻轉(zhuǎn)以上部分分子的變化。 本研究證明了ERK通路確實參與了甲基苯丙胺引起的急性作用,且ERK通路與這些作用有關(guān),這為甲基苯丙胺成癮的研究提供了新的理論基礎(chǔ)。雖然ERK信號通路在甲基苯丙胺成癮中所起的作用還需要進(jìn)一步的研究與探索,但ERK通路可能是METH成癮治療的潛在靶點。
[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.
【學(xué)位授予單位】：昆明理工大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2014
【分類號】：R96

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