A Novel Role for the Histone Demethylase JMJD3 in Mediating Heroin-Induced Relapse-Like Behaviors

Background: 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. Methods: 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 (n = 7–11/group). Pharmacological inhibitors or viral expression vectors were microinfused into the NAc to manipulate JMJD3 or the BMP pathway member SMAD1 (n = 9–11/group). The RiboTag capture method (n = 3–5/group) and viral vectors (n = 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. Results: 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. Conclusions: JMJD3 mediates persistent cellular and behavioral adaptations that underlie heroin relapse, and this activity is regulated by the BMP pathway.