毒品成瘾记忆形成的痰证病位、兼杂特征及其与表观遗传分子机制研究

The drug relapse caused by the environmental clues has always been the treatment problem. At present, many researchers suppose that the problem is the long-term abnormal memory caused by the addictive drugs. The long-term stability of epigenetic variation can be considered as the important candidate mechanism of long-term addiction memory. The preliminary researches show that the dense phlegm is one core pathogenesis of "addiction" relapse, which goes through the entire process of drug addiction. On the basis of existing studies, the researchers in this application program intend to carry out the biofeedback technology to simulate environmental clues to induce relapses, to use visual analogue scale to divide groups and to adopt the method of combining clinical research and animal experiment: (1) Standardized collection of the four diagnostic information in different induction times and different craving periods; analysis on the syndrome location changes and miscellaneous characteristics of heroin group and methamphetamine group before and after the induced relapses; discusses on the phlegm syndrome features, miscellaneous laws and evolution tendency and phase transformation of the addiction memory forming. (2) Drug addicts' DNA methylation difference map and MiRNA differentiation expression map were established to differentiate the epigenetic molecular marker (group) which can predict drug addiction extent and ability, and to detect the genetic mutations relevant to drug addiction genetic susceptibility. This study is able to solve the problem of drug addiction memory forming. From the perspective of "phlegm", the research discussed the shortages in dialectical thinking, index screening, diagnostic assessment, etc, providing scientific basis for better taking full advantage of combining therapy of traditional Chinese and Western medicine.

环境线索诱发的复吸是毒品成瘾治疗难题。目前多认为成瘾药物导致的异常记忆长期存在所致。表观遗传变异的长时稳定性可为成瘾记忆长期性的重要候选机制。 申请人前期工作证实，顽痰是"毒瘾"复发的核心病机之一，贯穿毒品成瘾全过程。 本项目拟在原工作基础上，模拟环境线索诱发复吸，应用视觉模拟评分法分组，采用生物反馈结合线索暴露治疗法开展研究： （1）采集不同诱发时段、不同心理渴求海洛因与甲基苯丙胺成瘾者四诊信息，分析不同诱发时相的痰证病位和兼杂特征，阐释成瘾记忆形成的痰证病理特征、兼杂规律和演变趋势。 （2）建立药物成瘾者DNA甲基化差异图谱和miRNA差异表达图谱，区分预测毒品成瘾程度能力的表观遗传分子标志物（群），尝试找到与毒品成瘾遗传易感性相关的遗传变异。 可解决毒品成瘾记忆形成从"痰"论治在辨证思维、指标筛查、诊断评估等存在不足，为更好发挥中西医结合优势提供科学基础。

环境线索诱发的复吸是毒品成瘾治疗难题。表观遗传变异的长时稳定性可为成瘾记忆长期性的重要候选机制。申请人前期工作证实，顽痰是“毒瘾”复发的核心病机之一。本项目在原工作基础上，模拟环境线索诱发复吸，应用视觉模拟评分法分组，采用生物反馈结合线索暴露治疗法开展研究，主要内容（1）采集不同诱发时段、不同心理渴求海洛因成瘾者与甲基苯丙胺成瘾者四诊信息，分析不同诱发时相的痰证病位和兼杂特征，阐释成瘾记忆形成的痰证病理特征、兼杂规律和演变趋势。（2）建立药物成瘾者DNA甲基化差异图谱和miRNA差异表达图谱，区分预测毒品成瘾程度能力的表观遗传分子标志物（群），尝试找到与毒品成瘾遗传易感性相关的遗传变异。重要结果：（1）无论何种毒品成瘾者，多为多脏腑功能失调的表现，痰湿气滞是毒品成瘾的基本病性特征，痰是导致毒瘾缠绵难愈的根本原因，而痰作为其中最重要的病性因素贯穿始终，同时随着吸毒年限的增加，痰的病理因素也相应增加，复吸得次数也易随之提高。若戒毒人员还混合使用不同类型的毒品，会比单独使用一种类型毒品诱发痰证的可能性更大。（2）虚实夹杂是毒品成瘾的证候学特点，不同毒品成瘾者在证候表现上或许有不同侧重，如影响海洛因成瘾者主要病性为痰、阳虚，影响甲基苯丙胺成瘾者主要的病性为热、阴虚，但无论何种类型的毒品，突出表现都为本虚标实、因虚致实、因实致虚，即虚实夹杂是毒品成瘾普遍的证候学特点。（3）阿片类药物成瘾与OPRM1基因启动子区甲基化改变关联，主要表现为甲基化水平上调。同时本研究结果也发现OPRM1基因启动子区甲基化存在种族异质性，并提出5种与海洛因成瘾、甲基苯丙胺成瘾相关性最显著的GO。本课题证实“痰”是导致毒瘾缠绵难愈的根本原因，为中西医结合防治本病从“痰”论治提供新思路，提出5种与海洛因成瘾、甲基苯丙胺成瘾相关性最显著的GO，可为将来尝试找到与毒品成瘾遗传易感性相关的遗传变异提供科学基础数据。

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