Alcohol use disorder represents a tremendous burden on society. While our understanding of neuronal pathwaysand circuitry involved in addiction has grown of late, efficacy of available treatments has not seen the samesuccess. We uncovered a novel epigenetic process controlling neuronal plasticity that is key to long-termmemory formation, involving the metabolic enzyme ACSS21. ACSS2 generates acetyl-CoA, a key cofactor forhistone acetylation that is important for long-term memory2. We discovered that ACSS2 plays a critical role inalcohol-related learning by coordinating alcohol-induced histone acetylation and gene expression in thehippocampus, through conversion of alcohol-derived acetate to acetyl-CoA3. This new evidence furtherelucidates how ethanol may facilitate its rewarding properties via ACSS2-dependent histone acetylation. Thisradically new gene regulatory mechanism presents an attractive potential therapeutic strategy viapharmacological inhibition of ACSS2 to interfere with alcohol-related learning driving alcohol use disorder. In thisproposal, we will test small molecule inhibitors of catalytic ACSS2 (ACSS2i) for use in animal models of alcoholuse disorder (AUD). The proposed experiments will validate and establish ACSS2i as potential novelpharmacotherapies that may ultimately be used in the context of psychotherapy to treat alcohol use disorder.
Public Health Relevance Statement: NARRATIVE
Alcohol use disorder (AUD) is one of the most pervasive diseases in our society and conventional
pharmacotherapeutics fail to counteract the tremendous social, psychological and financial
burdens that this issue exacts on patients, families, and society. EpiVario will utilize our discovery
of a novel epigenetic regulatory mechanism in neurons by inhibiting key metabolic enzyme
ACSS2 to weaken drug-associated memory associations. EpiVario has generated 10 proprietary
ACSS2 inhibitors, and the proposed SBIR grant will determine which compound is the most
effective. By showing efficacy in industry-accepted preclinical animal models of AUD, we will
address a critical unmet medical need.
Project Terms: | 