Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Department of Pharmacology and Toxicology, Program in Neuroscience, State University of New York at Buffalo, Buffalo, NY 14214, USA.
Science. 2020 Apr 10;368(6487):197-201. doi: 10.1126/science.aaw8806.
Vulnerability to relapse during periods of attempted abstinence from cocaine use is hypothesized to result from the 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 the midbrain. Rats undergoing withdrawal from cocaine showed an accumulation of H3Q5dop in the VTA. By reducing H3Q5dop in the VTA during withdrawal, we reversed cocaine-mediated gene expression changes, attenuated dopamine release in the nucleus accumbens, and reduced cocaine-seeking behavior. These findings establish a neurotransmission-independent role for nuclear dopamine in relapse-related transcriptional plasticity in the VTA.
在试图戒除可卡因期间易复发的现象,据推测是由于大脑奖励回路的重连所致,尤其是腹侧被盖区(VTA)多巴胺神经元。可卡因暴露如何作用于中脑多巴胺神经元,从而引发与成瘾相关的基因表达变化尚不清楚。我们发现组蛋白 H3 谷氨酰胺 5 多巴胺化(H3Q5dop)在中脑可卡因诱导的转录可塑性中起关键作用。从可卡因戒断的大鼠中观察到 VTA 中 H3Q5dop 的积累。通过在戒断期间减少 VTA 中的 H3Q5dop,我们逆转了可卡因介导的基因表达变化,减弱了伏隔核中的多巴胺释放,并减少了可卡因觅药行为。这些发现确立了核多巴胺在 VTA 中与复发相关的转录可塑性中的神经传递独立性作用。