# A Novel Pharmacotherapy for Alcoholism: Evaluation of Reward, Aversion, Compulsivity, Withdrawal & Reinstatement

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2022 · $89,681

## Abstract

Project summary
 Alcohol use disorder (AUD) is an extremely common and serious condition that is associated with
numerous somatic diseases, early mortality, personal and interpersonal hardship, and direct and indirect
economic costs to society. Although there are several effective pharmacological treatments for AUD, their
limited effectiveness contributes to the ongoing burden of AUD on society. A major impediment to better
treatments for AUD is the lack of understanding surrounding fundamental molecular mechanisms associated
with alcohol’s acute and chronic effects on the brain. Ongoing work in our lab has demonstrated that genetic
and pharmacological manipulation of the enzyme Glyoxalase 1 (GLO1) can reduce ethanol drinking in mice
and rats. GLO1 is an evolutionarily conserved enzyme that metabolizes methylglyoxal (MG), which is a non-
enzymatic side product of glycolysis and is thus present in all animal cells. Transgenic overexpression of GLO1
decreases MG (GLO1’s substrate) in the brain. Reciprocally, direct administration of MG, genetic knockdown
of Glo1 or pharmacological inhibition of GLO1 increase MG concentrations in the brain. We showed that MG is
a selective agonist at GABA-A receptors. More recently, we discovered that GLO1 and MG modulate ethanol
drinking behavior, which we hypothesize is due to MG’s effects at GABA-A receptors.
 In this supplement request, we are extending on the studies funded by the parent R01 to pursue a
new line of experimentation. Specifically, we are exploring the possibility that ethanol may be directly converted
into MG on a timescale that is consistent with the acute effects of ethanol. This exciting possibility raises the
tantalizing possibility that some of ethanol’s effects on GABA-A receptors could be due to MG (rather than
ethanol), directly influencing GABA-A signaling. We will test this possibility by measuring MG levels at various
time points following administration of ethanol. In subsequent experiments, we will explore the possibility that
ethanol is directly converted into MG (as opposed to altering MG in an indirect manner) by administering
stable-labeled ethanol in which the hydrogen atoms have been replaced with deuterium. We will use mass-
spec to assess MG levels, which will allow us to distinguish unlabeled MG from MG labeled with one or more
deuterium atoms. These studies have the potential to greatly enhance our mechanistic understanding of
ethanol’s actions. The mentoring plan is also described; the primary goal is to prepare the trainee to enter a
Ph.D. program.

## Key facts

- **NIH application ID:** 10523383
- **Project number:** 3R01AA026281-05S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Abraham A. Palmer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $89,681
- **Award type:** 3
- **Project period:** 2018-07-05 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10523383

## Citation

> US National Institutes of Health, RePORTER application 10523383, A Novel Pharmacotherapy for Alcoholism: Evaluation of Reward, Aversion, Compulsivity, Withdrawal & Reinstatement (3R01AA026281-05S1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10523383. Licensed CC0.

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