# ACSS2 inhibition in treating Alcohol Abuse

> **NIH NIH R41** · EPIVARIO, LLC · 2022 · $259,971

## Abstract

Alcohol use disorder represents a tremendous burden on society. While our understanding of neuronal pathways
and circuitry involved in addiction has grown of late, efficacy of available treatments has not seen the same
success. We uncovered a novel epigenetic process controlling neuronal plasticity that is key to long-term
memory formation, involving the metabolic enzyme ACSS21. ACSS2 generates acetyl-CoA, a key cofactor for
histone acetylation that is important for long-term memory2. We discovered that ACSS2 plays a critical role in
alcohol-related learning by coordinating alcohol-induced histone acetylation and gene expression in the
hippocampus, through conversion of alcohol-derived acetate to acetyl-CoA3. This new evidence further
elucidates how ethanol may facilitate its rewarding properties via ACSS2-dependent histone acetylation. This
radically new gene regulatory mechanism presents an attractive potential therapeutic strategy via
pharmacological inhibition of ACSS2 to interfere with alcohol-related learning driving alcohol use disorder. In this
proposal, we will test small molecule inhibitors of catalytic ACSS2 (ACSS2i) for use in animal models of alcohol
use disorder (AUD). The proposed experiments will validate and establish ACSS2i as potential novel
pharmacotherapies that may ultimately be used in the context of psychotherapy to treat alcohol use disorder.

## Key facts

- **NIH application ID:** 10546942
- **Project number:** 1R41AA030516-01
- **Recipient organization:** EPIVARIO, LLC
- **Principal Investigator:** HOWARD C. BECKER
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $259,971
- **Award type:** 1
- **Project period:** 2022-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10546942

## Citation

> US National Institutes of Health, RePORTER application 10546942, ACSS2 inhibition in treating Alcohol Abuse (1R41AA030516-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10546942. Licensed CC0.

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