Histone H3 dopaminylation in ventral tegmental area underlies heroin-induced maladaptive plasticity

Persistent transcriptional events in ventral tegmental area (VTA) and other reward relevant brain regions contribute to enduring behavioral adaptations that characterize substance use disorder (SUD). Recent data from our laboratory indicate that aberrant accumulation of the newly discovered histone post-translational modification (PTM), H3 dopaminylation at glutamine 5 (H3Q5dop), contributes significantly to cocaine-seeking behavior following prolonged periods of abstinence. It remained unclear, however, whether this modification is important for relapse vulnerability in the context of other drugs of abuse, such as opioids. Here, we showed that H3Q5dop plays a critical role in heroin-mediated transcriptional plasticity in midbrain. In rats undergoing abstinence from heroin self-administration (SA), we found acute and persistent accumulation of H3Q5dop in VTA. By attenuating H3Q5dop during abstinence, we both altered gene expression programs associated with heroin withdrawal and reduced heroin-primed reinstatement behavior. These findings thus establish an essential role for H3Q5dop, and its downstream transcriptional consequences, in opioid-induced plasticity in VTA.腹侧被盖区（ventral tegmental area, VTA）及其他奖赏相关脑区内的持续性转录事件，可介导物质使用障碍（substance use disorder, SUD）特征性的持久行为适应。本实验室近期的研究数据表明，新发现的组蛋白翻译后修饰（histone post-translational modification, PTM）——组蛋白H3第5位谷氨酰胺多巴胺化修饰（H3Q5dop）——的异常蓄积，在长期戒断后的可卡因觅药行为中发挥关键调控作用。然而目前仍不清楚，该修饰在阿片类等其他滥用药物的情境下，是否对复吸易感性具有重要影响。本研究证实，H3Q5dop在中脑内海洛因介导的转录可塑性中扮演关键角色。在经历海洛因自身给药（heroin self-administration, SA）戒断的大鼠中，我们于腹侧被盖区内检测到H3Q5dop的急性且持续性蓄积。通过在戒断期减弱H3Q5dop的蓄积水平，我们不仅改变了与海洛因戒断相关的基因表达程序，还降低了海洛因引发的行为复燃率。综上，本研究确立了H3Q5dop及其下游转录调控效应在腹侧被盖区阿片类物质诱导的神经可塑性中的核心地位。