BET proteins as novel epigenetic targets for the treatment of Opioid Use Disorder.

Recent research has revealed that targeting epigenetic proteins is an effective strategy to reduce drug-seeking behaviors in animal models of addiction. We have found that expression of epigenetic reader proteins, called Bromodomains and Extra terminal Domain (BET), are increased in the nucleus accumbens following cocaine self-administration and that pharmacological inhibition of BET proteins reduced cocaine-seeking behaviors in rodents. Although BET inhibitors show promise in animal models of cocaine use disorder, the effectiveness of BET inhibitors in animal models of Opioid Use Disorder (OUD) remains unknown. To assess a potential role for BET proteins in OUD, we measured time-dependent changes in BET mRNA expression in the prefrontal cortex (PFC), nucleus accumbens (NAc), and dorsal striatum (DS), following oral oxycodone self-administration. In these experiments, female and male mice received home cage water bottles with or without oxycodone (0.5 mg/ml) for 10 consecutive days. The volume consumed and the weight of the mice was recorded at the same time each day. At the end of the 10th day, all mice were given regular drinking water. After 4 h, 24 h, or 7 days of abstinence, expression of BET genes (Brd2, Brd3, and Brd4) were measured via quantitative PCR (qPCR). Our results showed that mice consumed more oxycodone water compared to regular water and that oxycodone consumption (mg/kg and ml/g) in females were higher compared to males. In qPCR studies, expression of Brd2 was significantly increased in the NAc after 4 h of abstinence; Brd3 was significantly increased in the NAc after 24 h and 7 days of abstinence and Brd4 was significantly increased in the NAc after 7 days of abstinence and after 24 h in the PFC. These data indicate that BET genes are altered following abstinence from oxycodone. Ongoing studies are exploring a functional role for BETs in oxycodone consumption and oxycodone-induced withdrawal-like behaviors. Together, these experiments may lead to more effective therapies for the treatment of opioid use disorder.