ABSTRACT
BACKGROUND: Epigenetic changes, leading 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 qPCR 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-type medium spiny neurons (MSN) 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 histone 3 lysine 27 trimethylation (H3K27me3) levels. JMJD3 bidirectionally affected seeking: expression of the wild type increased whereas expression of a catalytic dead mutant decreased cue-induced seeking. JMJD3 expression was increased in D2+ but not D1+ MSNs. Expression of the mutant JMJD3 in D2+ neurons was sufficient to decrease cue-induced heroin seeking. CONCLUSIONS: JMJD3 mediates persistent cellular and behavioral adaptations underlying heroin relapse and this activity is regulated by the BMP pathway.
