Histone H3 dopaminylation in nucleus accumbens, but not medial prefrontal cortex, contributes to cocaine-seeking following prolonged abstinence

Enduring patterns of epigenomic and transcriptional plasticity within the mesolimbic dopamine system contribute importantly to persistent behavioral adaptations that characterize substance use disorders (SUD). While drug addiction has long been thought of as a disorder of dopamine (DA) neurotransmission, therapeutic interventions targeting receptor mediated DA-signaling have not yet resulted in efficacious treatments. Our laboratory recently identified a non-canonical, neurotransmission-independent signaling moiety for DA in brain, termed dopaminylation, whereby DA itself acts as a donor source for the establishment of post-translational modifications (PTM) on substrate proteins (e.g., histone H3 at glutamine 5; H3Q5dop). In our previous studies, we demonstrated that H3Q5dop plays a critical role in the regulation of neuronal transcription and, when perturbed within monoaminergic neurons of the ventral tegmental area (VTA), critically contribute to pathological states, including relapse vulnerability to both psychostimulants (e.g., cocaine) and opiates (e.g., heroin). Importantly, H3Q5dop is also observed throughout the mesolimbic DA reward pathway (e.g., in nucleus accumbens/NAc and medial prefrontal cortex/mPFC, which receive DA input from VTA). As such, we investigated whether H3Q5dop may similarly be altered in its expression in response to drugs of abuse in these non-dopamine-producing regions. In rats undergoing extended abstinence from cocaine self-administration (SA), we observed both acute and prolonged accumulation of H3Q5dop in NAc, but not mPFC. Attenuation of H3Q5dop in NAc during drug abstinence reduced cocaine-seeking and affected cocaine-induced gene expression programs associated with altered dopamine signaling and neuronal function. These findings thus establish H3Q5dop in NAc, but not mPFC, as an important mediator of cocaine-induced behavioral and transcriptional plasticity during extended cocaine abstinence.中脑边缘多巴胺系统（mesolimbic dopamine system）内表观基因组与转录组可塑性的持久模式，是介导物质使用障碍（substance use disorders, SUD）特征性持续性行为适应的关键因素。长期以来，药物成瘾被认为是多巴胺（dopamine, DA）神经传递紊乱引发的疾病，但靶向受体介导的DA信号传导的治疗干预手段至今尚未取得有效的治疗方案。本课题组近期在脑中发现了一种非经典、不依赖神经传递的多巴胺信号组分，将其命名为多巴胺修饰化（dopaminylation）——即DA本身作为供体来源，在底物蛋白上建立翻译后修饰（post-translational modifications, PTM），例如谷氨酰胺5位点组蛋白H3（H3Q5dop）。在既往研究中，我们证实H3Q5dop在神经元转录调控中发挥核心作用；当其在腹侧被盖区（ventral tegmental area, VTA）的单胺能神经元中出现异常时，会诱发多种病理状态，包括对精神兴奋剂（如可卡因）与阿片类物质（如海洛因）的复吸易感性升高。值得注意的是，H3Q5dop在整条中脑边缘多巴胺奖赏通路中均有表达，例如接受VTA多巴胺输入的伏隔核（nucleus accumbens, NAc）与内侧前额叶皮层（medial prefrontal cortex, mPFC）。据此，我们探究了在这些非多巴胺能神经元区域中，H3Q5dop的表达是否会因精神活性药物暴露而发生类似改变。在经历可卡因自身给药（cocaine self-administration, SA）延长戒断阶段的大鼠中，我们观察到NAc内H3Q5dop出现急性与持续性积累，而mPFC则无此现象。在药物戒断期间下调NAc内的H3Q5dop水平，可减少可卡因觅药行为，并影响与DA信号传导改变及神经元功能异常相关的可卡因诱导基因表达程序。综上，本研究证实NAc内的H3Q5dop而非mPFC的H3Q5dop，是延长可卡因戒断阶段中可卡因诱导的行为与转录组可塑性的重要介导因子。