A growing body of evidence from the past 15 years implicates epigenetic mechanisms in the behavioral effects of addictive drugs. The main focus of these studies has been epigenetic mechanisms of psychomotor sensitization and drug reinforcement, as assessed by the conditioned place preference and drug self-administration procedures. Some of these studies have documented long-lasting changes in the expression of epigenetic enzymes and molecules that persist for weeks after the last drug exposure. These observations have inspired more recent investigations on the epigenetic mechanisms of relapse to drug seeking after prolonged abstinence. Here, we review studies that have examined epigenetic mechanisms (e.g., histone modifications, chromatin remodeler-associated modifications, and DNA methylation) that contribute to relapse to cocaine, amphetamine, methamphetamine, morphine, heroin, nicotine, or alcohol seeking, as assessed in rodent models. We first provide a brief overview of studies that have examined persistent epigenetic changes in the brain after prolonged abstinence from noncontingent drug exposure or drug self-administration. Next, we review studies on the effect of either systemic or brain site-specific epigenetic manipulations on the reinstatement of drug-conditioned place preference after extinction of the learned preference, the reinstatement of drug seeking after operant drug self-administration and extinction of the drug-reinforced responding, and the incubation of drug craving (the time-dependent increase in drug seeking after cessation of drug self-administration). We conclude by discussing the implications of these studies for understanding mechanisms contributing to persistent relapse vulnerability after prolonged abstinence. We also discuss the implications of these results for translational research on the potential use of systemically administered epigenetic enzyme inhibitors for relapse prevention in human drug users.

中文翻译：

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药物复发的表观遗传机制

过去 15 年中越来越多的证据表明，表观遗传机制与成瘾药物的行为影响有关。这些研究的主要焦点是精神运动致敏和药物强化的表观遗传机制，通过条件性位置偏好和药物自我给药程序进行评估。其中一些研究记录了表观遗传酶和分子表达的长期变化，这些变化在最后一次药物暴露后持续数周。这些观察结果激发了最近对长期禁欲后寻求药物复发的表观遗传机制的研究。在这里，我们回顾了一些研究，这些研究检查了导致可卡因、苯丙胺、苯丙胺、在啮齿动物模型中评估的甲基苯丙胺、吗啡、海洛因、尼古丁或酒精寻求。我们首先简要概述了在长期戒断非偶然药物暴露或药物自我给药后大脑中持续的表观遗传变化的研究。接下来，我们回顾了关于系统性或大脑位点特异性表观遗传操作对在习得性偏好消失后恢复药物条件位置偏好、在操作性药物自我给药和药物消失后恢复药物寻求的影响的研究。 -强化反应，以及药物渴望的孵化（药物自我给药停止后寻求药物的时间依赖性增加）。最后，我们讨论了这些研究对理解导致长期禁欲后持续复发易感性的机制的意义。我们还讨论了这些结果对转化研究的影响，即全身给药的表观遗传酶抑制剂可能用于预防人类吸毒者的复发。