Dopaminylation of Histone H3 in Ventral Tegmental Area Regulates Cocaine-seeking

Vulnerability to relapse during periods of attempted abstinence from cocaine use is hypothesized to result from rewiring of brain reward circuitries, particularly ventral tegmental area (VTA) dopamine neurons. How cocaine exposures act on midbrain dopamine neurons to precipitate addiction-relevant changes in gene expression is unclear. We found that histone H3 glutamine 5 dopaminylation (H3Q5dop) plays a critical role in cocaine-induced transcriptional plasticity in midbrain. Rats undergoing withdrawal from cocaine showed an accumulation of H3Q5dop in VTA. By reducing H3Q5dop in VTA during withdrawal, we reversed cocaine-mediated gene expression changes, attenuated cue-induced dopamine release in nucleus accumbens and reduced cocaine-seeking behavior. These findings establish a neurotransmission-independent role for nuclear dopamine in relapse-related transcriptional plasticity in VTA.现有假说认为，尝试戒除可卡因使用期间的复吸易感性，源于大脑奖赏回路的重塑，尤其是腹侧被盖区（ventral tegmental area, VTA）多巴胺能神经元。目前尚不清楚可卡因暴露如何作用于中脑多巴胺能神经元，进而引发与成瘾相关的基因表达改变。本研究发现，组蛋白H3谷氨酰胺5多巴胺化（histone H3 glutamine 5 dopaminylation, H3Q5dop）在中脑可卡因诱导的转录可塑性中发挥关键作用。经可卡因戒断处理的大鼠在腹侧被盖区内出现了H3Q5dop的积累。通过在戒断期间降低腹侧被盖区内的H3Q5dop水平，本研究团队逆转了可卡因介导的基因表达改变，减弱了伏隔核（nucleus accumbens）内由线索诱导的多巴胺释放，并降低了可卡因寻求行为。本研究结果证实，核内多巴胺在腹侧被盖区复吸相关转录可塑性中具有不依赖于神经递质传递的调控功能。