自噬在甲基苯丙胺渴求潜伏中的作用及机制研究

项目名称： 自噬在甲基苯丙胺渴求潜伏中的作用及机制研究

项目编号： No.81471355

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 王贵彬

作者单位： 中国医学科学院药物研究所

项目金额： 70万元

中文摘要： 新型毒品甲基苯丙胺滥用在我国已造成严重的社会公共卫生问题，其长期戒断后仍具有极高的复吸率，研究认为，药物相关环境线索诱导的渴求随戒断时间的延长而增加即渴求潜伏现象与其密切相关。中脑边缘多巴胺系统内的神经可塑性变化如缺少GluR2亚基的AMPA受体的形成参与调节这一现象。但其确切调控机制仍需深入研究。自噬作为一种主要的蛋白质降解通路，参与调节NMDA受体依赖的突触可塑性及多巴胺能神经末梢的结构和功能可塑性。自噬受到蛋白质乙酰化的调节，乙酰基转移酶Tip60通过乙酰化特异的自噬相关蛋白诱导自噬的发生。目前对自噬在甲基苯丙胺成瘾中的作用与机制的研究尚未见报道。因此，本课题旨在采用条件性位置偏爱和自我给药动物模型，结合行为学、分子生物学、形态学，遗传学和药理学方法，系统研究中脑边缘多巴胺通路各脑区的自噬在甲基苯丙胺渴求潜伏中的作用及乙酰化可能的调控作用，以期找到治疗甲基苯丙胺成瘾的新靶点。

中文关键词： 甲基苯丙胺；渴求潜伏；自噬；中脑边缘多巴胺系统；突触可塑性

英文摘要： Methamphetamine(METH) abuse greatly threatens the public health in China and has caused serious social problems.Relapse to METH use in humans can occur even after prolonged abstinence and is often precipitated by exposure to drug-associated cues that provoke drug craving.Time-dependent increases in cue-induced drug seeking, termed incubation of drug craving was identified in rats and humans with a history of multiple drugs including METH.Synaptic plasticity in mesocorticlimbic dopamine system such as formation of GluR2-lacking AMPA receptors are involved in the of incubation of craving. However, the underlying molecular events needs further study. As a major protein degradation pathway in vivo, autophagy is involved in the NMDAR-dependent synaptic plasticity, as well as the structural and functional plasticity of dopaminergic terminals. Protein acetylation represents an evolutionarily conserved mechanism tightly regulating autophagy,and acetyltransferase TIP60 stimulates autophagy via acetylating autophagy-related proteins (Atgs). However, no study has investigated the role of autophagy in the METH addiction. The present study aims to determine the role of autophagy within the mesocorticolimbic dopamine pathway in the incubation of METH craving (conditioned place preference and self- administration) and the underlying mechanisms, combining behavioral, morphological, molecular biological and pharmacological methods. This research will explore new molecular targets and provide further scientific evidence for the therapy of METH addiction and METH-induced psychosis.

英文关键词： methamphetamine;incubation of drug craving;autophagy;mesolimbic system;synaptic plasticity