Epigenetic changes that lead to long-term neuroadaptations following opioid exposure are not well understood. We examined how histone demethylase JMJD3 in the nucleus accumbens (NAc) influences heroin seeking after abstinence from self-administration. Male Sprague Dawley rats were trained to self-administer heroin. Western blotting and quantitative polymerase chain reaction were performed to quantify JMJD3 and bone morphogenetic protein (BMP) pathway expression in the NAc ( = 7–11/group). Pharmacological inhibitors or viral expression vectors were microinfused into the NAc to manipulate JMJD3 or the BMP pathway member SMAD1 ( = 9–11/group). The RiboTag capture method ( = 3–5/group) and viral vectors ( = 7–8/group) were used in male transgenic rats to identify the contributions of D1- and D2-expressing medium spiny neurons in the NAc. Drug seeking was tested by cue-induced response previously paired with drug infusion. Levels of JMJD3 and phosphorylated SMAD1/5 in the NAc were increased after 14 days of abstinence from heroin self-administration. Pharmacological and virus-mediated inhibition of JMJD3 or the BMP pathway attenuated cue-induced seeking. Pharmacological inhibition of BMP signaling reduced JMJD3 expression and H3K27me3 levels. JMJD3 bidirectionally affected seeking: expression of the wild-type increased cue-induced seeking whereas expression of a catalytic dead mutant decreased it. JMJD3 expression was increased in D2 but not D1 medium spiny neurons. Expression of the mutant JMJD3 in D2 neurons was sufficient to decrease cue-induced heroin seeking. JMJD3 mediates persistent cellular and behavioral adaptations that underlie heroin relapse, and this activity is regulated by the BMP pathway.

中文翻译：

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组蛋白去甲基化酶 JMJD3 在介导海洛因诱导的复发样行为中的新作用


导致阿片类药物暴露后长期神经适应的表观遗传变化尚不清楚。我们研究了伏隔核 （NAc） 中的组蛋白去甲基化酶 JMJD3 如何影响自我禁欲后的海洛因寻求。雄性 Sprague Dawley 大鼠被训练自我服用海洛因。进行蛋白质印迹和定量聚合酶链反应以定量 NAc 中 JMJD3 和骨形态发生蛋白 （BMP） 通路的表达 （ = 7-11/组）。将药理学抑制剂或病毒表达载体微量注入 NAc 中以操纵 JMJD3 或 BMP 通路成员 SMAD1 （ = 9–11/组）。在雄性转基因大鼠中使用 RiboTag 捕获方法 （ = 3-5/组） 和病毒载体 （ = 7-8/组） 来确定表达 D1 和 D2 的中等棘神经元在 NAc 中的贡献。通过先前与药物输注配对的线索诱导反应来测试药物寻求。戒断海洛因自我给药 14 天后，NAc 中 JMJD3 和磷酸化 SMAD1/5 的水平升高。药理学和病毒介导的对 JMJD3 或 BMP 通路的抑制减弱了线索诱导的寻求。BMP 信号传导的药理学抑制降低了 JMJD3 表达和 H3K27me3 水平。JMJD3 双向影响寻找：野生型的表达增加了线索诱导的寻找，而催化性死亡突变体的表达降低了它。JMJD3 表达在 D2 中增加，但在 D1 中等棘状神经元中未增加。突变体 JMJD3 在 D2 神经元中的表达足以减少线索诱导的海洛因寻找。JMJD3 介导海洛因复发的持续细胞和行为适应，这种活性受 BMP 通路调节。