PP2A调控吗啡渴求淬灭-引燃大鼠伏隔核Ras-Raf-MEK-ERK 信号通路的研究

The reinstatement of morphine-seeking behavior after extinction are the most important physiological and psychological mechanisms of drug elapse, however the molecular mechanisms underlying reinstatement induced by addictive drugs still remain unclear. Our group first used proteomic analysis on searching specific proteins of opioid induced drug self-administration. The nucleus accumbens (NAc), ventral tegmental area (VTA), prefrontal cortex (PFC), hippocampus (HIP) were closely related to psychological dependence of opioid abuse, and we did the research in the four areas supported by previous National Natural Science Funds, forty-eight proteins expression were discovered in difference. We found that the expression of protein phosphatase type 2A (PP2A) identified to be changed in nucleus accumbens, and PP2A have been regarded as a multifunctional enzyme with many transcription factors and protein kinases as its substrates. The phosphorylation and dephosphorylation to activate and inactivate phosphorylation reaction of the intracellular signal transduction pathway could be adjusted by PP2A comprehensively. The Ras-Raf-MEK-ERK, one of the intracellular signal transduction pathways associated with morphine induced psychological dependence was adjusted by phosphorylation of PP2A on these key proteins of Raf and ERK.However,if PP2A take part in morphine-seeking -rextinction-reinstatement course during morphine psychological dependence by signal transduction pathway Ras-Raf-MEK-ERK is not yet clear. Therefore，we will perform the study on protein quantitative and functional analysis of PP2A on the basis of previous research. Furthermore, developing research were taken on enhancement and inhibition of PP2A expression to figure out the influence on Ras-Raf-MEK-ERK pathway adjusting and morphine induced behaviors of drug-seeking, withdrawal and relapse. The results might demonstrate the mechanism of signal transduction on opioid induced drug addiction, and the aim of the study was to confirm the possibility and theoretical foundation on prevention and cure of drug addiction by gene regulation.

药物渴求淬灭后再度引燃是复吸最重要的生理心理机制，但其分子机制迄今未明。本课题组在前一基金项目中运用蛋白组学方法首次在阿片类精神依赖密切相关的伏隔核中发现差异表达的蛋白磷酸酶2A（PP2A）。PP2A是一种底物为众多转录因子和蛋白激酶的多功能酶，能通过磷酸化与去磷酸化来开启或关闭细胞信号传导通路RaS-Raf-MEK-ERK，该通路是吗啡成瘾密切相关的信号传导通路，其中的关键蛋白 Raf和ERK均为PP2A的底物。但在阿片类精神依赖中，PP2A是否通过调控信号通路RaS-Raf-MEK-ERK参与吗啡渴求淬灭-引燃过程，以及调控的具体机制和关键靶点是什么，至今未明，国内外均无相关研究报道。因此，本课题在前一研究工作的基础上首次对这些关键问题进行深入研究，以阐明阿片类渴求淬灭-引燃的新的信号传导机制，为寻求通过基因调控防治药物成瘾后复吸行为探索可能性和奠定理论基础。