The overall goal of this proposal is to characterize a lead compound with a novel mode of action (MOA) thatreduces both stress- and dependence-related alcohol drinking in a preclinical model of Alcohol Use Disorder(AUD). AUD is a major problem in the U.S. as approximately 13.9% of adults meet AUD criteria per year. Theannual economic burden of AUD is estimated at >$200 billion and AUD is a leading cause of preventable deathsin the USA. Persistent alcohol abuse and dependence is difficult to treat in part because alcohol increases thereactivity of the body's stress systems. The influence of stress systems facilitates the "the dark side of addiction",and stress is a primary factor that triggers relapse. Therefore, pharmacotherapies that can reduce stress- anddependence-associated alcohol drinking could reduce both heavy drinking and stress-triggered relapse inindividuals suffering from AUD. We recently discovered that systemic administration of an epigenetic enzymeinhibitor reduced both stress- and dependence-potentiated alcohol drinking in a preclinical model. We have filedfor patent protection of this entirely novel MOA to treat AUD, which provides a commercial path forward. In thisPhase I STTR application, we will evaluate oral bioavailability of our lead compound to examine whether thepreferred oral method of delivery is feasible for AUD treatment. We will also examine maximum tolerated dose(MTD) and behavioral toxicity measures. We will then determine optimal dosing conditions, and we seek toestablish strong proof-of-principle data that these compounds reduce dependence- and stress-related alcoholdrinking in multiple preclinical models and multiple mouse strains in both male and female mice. At the conclusionof these aims, we expect to have sufficient pre-clinical information for subsequent Phase II STTR studiestargeting a future Investigational New Drug (IND) application.
Public Health Relevance Statement: Project Narrative
We have identified a lead compound with a novel mode of action that is capable of reducing both stress- and
dependence-related alcohol drinking in a preclinical model of alcohol use disorder (AUD). NeuroEpigenix will
extend these initial studies to further develop the lead compound for potential treatment of AUD.
Project Terms: <21+ years old><κ opiate><κ opioid><κ opioid receptors><κ-OR><κOR>
