毒品成瘾是困扰人类的重大社会问题之一，它不仅使成瘾者的身心健康受到伤害，且对家庭和社会造成沉重的负担。毒品的成瘾性表现为一种难以控制的渴求和依赖行为，呈慢性复发性依赖病程。目前对于毒品成瘾的治疗缺乏完全有效的方式，强制戒断后复吸率很高。因此，研究成瘾的生物学机制对于成瘾的治疗与干预具有非常重要的意义。
线粒体是机体能量工厂，与机体代谢息息相关。线粒体代谢异常与多种退行性神经系统疾病相关。为了阐明线粒体是否在毒品成瘾过程中扮演了重要角色，博士研究生冯月梅、贾云芳和硕士研究生苏凌燕等在姚永刚研究员和徐林研究员的悉心指导下，从细胞、啮齿类动物模型和海洛因成瘾病人三个层次开展了一系列的研究。他们发现海洛因成瘾者的血液、吗啡成瘾大鼠的海马组织和血液，以及吗啡处理的神经细胞株都存在线粒体DNA拷贝数显著降低的现象，进一步研究表明，这种降低由吗啡诱导的线粒体功能异常导致的自噬所致。采用线粒体抗氧化剂褪黑素处理，可以拯救吗啡诱导的线粒体功能异常，进而拮抗吗啡诱导的神经元自噬及其形态结构改变，恢复细胞中的线粒体DNA拷贝数。
在建立吗啡成瘾的小鼠模型过程中，预先给予低剂量的褪黑素处理，可以阻断吗啡诱导的小鼠运动行为敏感化和痛觉耐受，这一过程与褪黑素拮抗吗啡诱导的海马组织中的自噬发生直接相关，表现为自噬减少，线粒体DNA拷贝数恢复到接近对照个体水平。对海洛因成瘾者脱毒后为期6个月的跟踪观察发现，病人血浆中的褪黑素水平相对于开始脱毒时有所升高，相应的，病人血液中的线粒体DNA拷贝数在脱毒康复过程中也有所升高，但两者都没有恢复到在正常人群中观察到的水平。这些结果提示，线粒体DNA拷贝数降低和血浆褪黑素减少有望作为成瘾过程中的生物学标记，自噬是研究毒品成瘾机制的新视角。研究结果近期发表在国际期刊Autophagy。
该工作得到科技部、国家自然科学基金委、中科院和云南省的资助。（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.
