Novel Epigenetic Therapeutics for the Treatment of Opioid Use Disorder

Epigenetic-based therapeutics are promising treatment options for Substance Use Disorder (SUD) due to their ability to influence gene expression and reverse behavioral responses associated with addiction. For example, previous studies have shown that 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 reduced cocaine- seeking behaviors in animal models, a role for BET proteins in animal models of Opioid Use Disorder (OUD) remains unknown. To identify a 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 ad lib 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 were 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 polymerase chain reaction (qPCR). Results showed that mice consumed more oxycodone water compared to regular water and that oxycodone consumption (mg/kg and ml/g) in females was higher compared to males. In qPCR studies, time-dependent changes in BET mRNA expression in PFC, NAc, and DS was observed following abstinence. In naloxone-precipitated withdrawal behavioral experiments, global withdrawal scores were significantly elevated in mice that consumed oxycodone. Ongoing research will determine if BET inhibitors reduce oxycodone consumption and/or oxycodone- induced withdrawal-like behaviors. Results from these experiments may lead to more effective therapies for the treatment of OUD