毒品成癮是困擾人類(lèi)的重大社會(huì)問(wèn)題之一,，它不僅使成癮者的身心健康受到傷害,，且對(duì)家庭和社會(huì)造成沉重的負(fù)擔(dān)。毒品的成癮性表現(xiàn)為一種難以控制的渴求和依賴(lài)行為,，呈慢性復(fù)發(fā)性依賴(lài)病程,。目前對(duì)于毒品成癮的治療缺乏完全有效的方式，強(qiáng)制戒斷后復(fù)吸率很高,。因此,，研究成癮的生物學(xué)機(jī)制對(duì)于成癮的治療與干預(yù)具有非常重要的意義。
線(xiàn)粒體是機(jī)體能量工廠(chǎng),，與機(jī)體代謝息息相關(guān),。線(xiàn)粒體代謝異常與多種退行性神經(jīng)系統(tǒng)疾病相關(guān)。為了闡明線(xiàn)粒體是否在毒品成癮過(guò)程中扮演了重要角色,，博士研究生馮月梅,、賈云芳和碩士研究生蘇凌燕等在姚永剛研究員和徐林研究員的悉心指導(dǎo)下，從細(xì)胞,、嚙齒類(lèi)動(dòng)物模型和海洛因成癮病人三個(gè)層次開(kāi)展了一系列的研究,。他們發(fā)現(xiàn)海洛因成癮者的血液、嗎啡成癮大鼠的海馬組織和血液,，以及嗎啡處理的神經(jīng)細(xì)胞株都存在線(xiàn)粒體DNA拷貝數(shù)顯著降低的現(xiàn)象,，進(jìn)一步研究表明,，這種降低由嗎啡誘導(dǎo)的線(xiàn)粒體功能異常導(dǎo)致的自噬所致,。采用線(xiàn)粒體抗氧化劑褪黑素處理，可以拯救嗎啡誘導(dǎo)的線(xiàn)粒體功能異常,，進(jìn)而拮抗嗎啡誘導(dǎo)的神經(jīng)元自噬及其形態(tài)結(jié)構(gòu)改變,，恢復(fù)細(xì)胞中的線(xiàn)粒體DNA拷貝數(shù)。
在建立嗎啡成癮的小鼠模型過(guò)程中,，預(yù)先給予低劑量的褪黑素處理,，可以阻斷嗎啡誘導(dǎo)的小鼠運(yùn)動(dòng)行為敏感化和痛覺(jué)耐受，這一過(guò)程與褪黑素拮抗嗎啡誘導(dǎo)的海馬組織中的自噬發(fā)生直接相關(guān),，表現(xiàn)為自噬減少,，線(xiàn)粒體DNA拷貝數(shù)恢復(fù)到接近對(duì)照個(gè)體水平。對(duì)海洛因成癮者脫毒后為期6個(gè)月的跟蹤觀(guān)察發(fā)現(xiàn),，病人血漿中的褪黑素水平相對(duì)于開(kāi)始脫毒時(shí)有所升高,，相應(yīng)的，病人血液中的線(xiàn)粒體DNA拷貝數(shù)在脫毒康復(fù)過(guò)程中也有所升高,，但兩者都沒(méi)有恢復(fù)到在正常人群中觀(guān)察到的水平,。這些結(jié)果提示,，線(xiàn)粒體DNA拷貝數(shù)降低和血漿褪黑素減少有望作為成癮過(guò)程中的生物學(xué)標(biāo)記，自噬是研究毒品成癮機(jī)制的新視角,。研究結(jié)果近期發(fā)表在國(guó)際期刊Autophagy,。
該工作得到科技部、國(guó)家自然科學(xué)基金委,、中科院和云南省的資助,。（生物谷Bioon.com）
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Decreased mitochondrial DNA copy number in the hippocampus and peripheral blood during opiate addiction is mediated by autophagy and can be salvaged by melatonin
Yue-Mei Feng, Yun-Fang Jia, Ling-Yan Su, Dong Wang, Li Lv, *Lin Xu, *Yong-Gang Yao
Drug addiction is a chronic brain disease that is a serious social problem and causes enormous financial burden. Because mitochondrial abnormalities have been associated with opiate addiction, we examined the effect of morphine on mtDNA levels in rat and mouse models of addiction and in cultured cells. We found that mtDNA copy number was significantly reduced in the hippocampus and peripheral blood of morphine-addicted rats and mice compared with control animals. Concordantly, decreased mtDNA copy number and elevated mtDNA damage were observed in the peripheral blood from opiate-addicted patients, indicating detrimental effects of drug abuse and stress. In cultured rat pheochromocytoma (PC12) cells and mouse neurons, morphine treatment caused many mitochondrial defects, including a reduction in mtDNA copy number that was mediated by autophagy. Knockdown of the Atg7 gene was able to counteract the loss of mtDNA copy number induced by morphine. The mitochondria-targeted antioxidant melatonin restored mtDNA content and neuronal outgrowth and prevented the increase in autophagy upon morphine treatment. In mice, coadministration of melatonin with morphine ameliorated morphine-induced behavioral sensitization, analgesic tolerance and mtDNA content reduction. During drug withdrawal in opiate-addicted patients and improvement of protracted abstinence syndrome, we observed an increase of serum melatonin level. Taken together, our study indicates that opioid addiction is associated with mtDNA copy number reduction and neurostructural remodeling. These effects appear to be mediated by autophagy and can be salvaged by melatonin.
