Developing a novel epigenetic regulator as a treatment for opioid use disorder Project Summary/Abstract Opioid Use Disorder (OUD) has become a public health emergency of unique proportion that cripples entire communities and the health care system, killing over tens of thousands of Americans each year. FDA approved pharmacotherapeutics for OUD target opioid receptors and provide partial relief, but available treatments remain inadequate and typically result in relapse. Challenges are posed by the medications’ drug-abuse liability, barriers to accessibility, and treatment retention. Crucially, the drug-related cue and contextual memory that are linked to craving responses and, ultimately, relapse are not targeted with current treatment approaches. The encoding of drug-related memory involves histone acetylation and gene transcription in memory-processing brain regions over a sensitive time window. We discovered that this process is reliant on the metabolic enzyme ACSS2, which is bound to key memory genes and promotes histone acetylation and the gene transcription needed for neuroplasticity. Inhibition of ACSS2 through genetic or pharmacologic approaches leads to severe but precise defects in long-term associative learning and decreases drug-related cue memory in a rat model of opioid (oxycodone) use disorder. EpiVario has developed next generation ACSS2 inhibitors with improved drug-like properties and potency. In this proposal, we will screen these new compounds using in vitro assays and ADME assays. The top compound will then be tested in our rat model of opioid addiction. Additionally, we will test for adverse side-effects in memory and learning. Together, these experiments will identify a next generation ACSS2i to further develop as a potential novel pharmacotherapy for OUD.