# Alcohol-Induced Neuroinflammation and AUD Therapeutic Mechanisms

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2023 · $407,250

## Abstract

Abstract
 Alcohol use disorder (AUD) is a heterogeneous condition resulting from the interplay of neurobiological,
genetic, and environmental factors. There is pressing need to develop new and, potentially, broadly effective
medications. Alcohol is a highly pro-inflammatory molecule, which is key in the pathogenesis of alcohol-
induced tissue damage. Work by the applicants and collaborators has identified 3 candidate drugs for
repositioning for AUD that are likely to act at least in part via reduction of neuroinflammation. They include
inhibitors of the pannexin1 channel, which has emerged as a major driver of neuroinflammation, and
modulators of glucocorticoid signaling, that has a complex action on inflammation. In fact, chronic
glucocorticoids result in neuroinflammation and neuronal damage that contribute to both AUD and
neurodegenerative diseases. Collectively, these considerations support targeting inflammation and the
associated tissue damage for AUD. However, some inflammatory signaling mechanisms recruited by alcohol,
such as the Toll-like receptor 4, have proven not to modify alcohol intake. Thus, it is paramount to delineate the
inflammatory mechanisms of motivational and therapeutic significance. To this end, Specific Aim 1 in the
present proposal will test the effects of representative anti-inflammatory drugs including direct and indirect
inflammasome inhibitors with different mechanisms of action in an established rat paradigm of non-dependent
and dependent alcohol intake, which is characterized by escalated alcohol drinking and is highly translational
as it proved sensitive to the action of virtually all drugs that have shown promise in human AUD. Interlinked
studies in Specific Aim 2 will dissect the effects of alcohol and the therapeutics under study on
neuroinflammation, inflammasome regulation and astrocyte and microglia regulation to identify key indicators
of alcohol-induced neuroinflammation as well as the mechanisms of action of the drugs under testing to
determine the molecular bases of their effectiveness or lack thereof as well as to uncover potential new
therapeutic targets for AUD.
 Altogether, the results of this study will advance our understanding of the mechanisms behind treatment
responsiveness or lack thereof as well as of alcohol-induced tissue damage of therapeutic significance, and
will point to new therapeutic targets for more specific and effective medications to ameliorate
neuroinflammation and tissue damage in the setting of AUD and reduce excessive alcohol consumption.

## Key facts

- **NIH application ID:** 10580663
- **Project number:** 5R01AA028982-02
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Vez REPUNTE-CANONIGO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $407,250
- **Award type:** 5
- **Project period:** 2022-03-01 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10580663

## Citation

> US National Institutes of Health, RePORTER application 10580663, Alcohol-Induced Neuroinflammation and AUD Therapeutic Mechanisms (5R01AA028982-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10580663. Licensed CC0.

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