# The role of Phosphodiesterase type 4 in ethanol drinking

> **NIH NIH F32** · OREGON HEALTH & SCIENCE UNIVERSITY · 2021 · $66,390

## Abstract

Project Summary
Alcohol Use Disorders (AUD) have a devastating impact on individuals and their families, and exert a high cost
to society. Of the >88,000 annual deaths attributed to alcohol use, approximately half are due to binge
drinking, making it the third leading cause of preventable death in the United States. Binge drinking is a strong
predictor of AUD diagnosis and is associated with deleterious health consequences, including dysregulated
sleep/wake patterns and drastic changes in biological and circadian rhythms. Changes in these patterns, such
as mutations in circadian genes, are associated with both increased ethanol intake and the motivation to
consume ethanol. To help treat individuals with AUDs, our research focuses on understanding molecular
determinants of binge drinking and the motivation to drink ethanol. The goal of this application is to test the
importance of phosphodiesterase 4 (PDE4) as a molecular determinant in 1) the regulation of circadian genes
following chronic ethanol intake and 2) the motivational aspects of binge-like ethanol drinking. PDE4 inhibits
the activity of cyclic-AMP (cAMP), an important second messenger for both circadian- and motivation-related
cell signaling events. Pharmacotherapies which inhibit PDE4, such as apremilast (which is FDA approved to
treat psoriasis), have proven efficacious in reducing binge-like ethanol intake and ethanol preference,
suggesting a high translational value in the treatment of AUD. We have recently shown that two PDE4
inhibitors (rolipram and apremilast) reduce binge-like drinking in 3 high drinking strains of mice. Moreover,
apremilast reduced binge drinking when administered directly in the nucleus accumbens (NAc), a brain region
central to ethanol reinforcement. PDE4 inhibitors are also known to increase the amplitude of circadian gene
expression, suggesting therapeutic potential in rescuing the maladaptive loss of rhythmic circadian gene
expression following chronic ethanol drinking. Therefore, we propose to test whether the PDE4 inhibitor,
apremilast, can rescue the reduction in circadian gene expression in the NAc following chronic binge-like
ethanol drinking. Further, we will test whether apremilast treatment reduces the reinforcing effects of ethanol in
mice using operant self-administration. This approach directly tests a major component of human AUDs; the
motivation to drink. In
changes
the
progressive
inhibition
components
aim 1, we will determine whether treatment with apremilast ameliorates ethanol-induced
in rhythmic circadian gene expression in the NAc. In aim 2, we will t est whether apremilast educes
reinforcing and motivational effects of alcohol hrough the use of operant self-administration on a
order of reinforcement . These studies have the potential to determine mechanisms by which PDE4
decreases drinking behaviors and rescues maladaptive circadian gene changes, important
of alcohol use with face validity in human AUDs. 
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## Key facts

- **NIH application ID:** 10231547
- **Project number:** 1F32AA028686-01A1
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Kolter Grigsby
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $66,390
- **Award type:** 1
- **Project period:** 2021-06-26 → 2022-06-25

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10231547

## Citation

> US National Institutes of Health, RePORTER application 10231547, The role of Phosphodiesterase type 4 in ethanol drinking (1F32AA028686-01A1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10231547. Licensed CC0.

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