# Alcohol-induced epigenetic reprogramming of PPAR-α affects allopregnanolone biosynthesis

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2024 · $359,775

## Abstract

Abstract. The neural substrates underlying alcohol use disorder (AUD), remain poorly understood in part due
to lack of translational models that recapitulate phenotypes from the human condition. Biosynthesis of the
GABAergic neurosteroid, allopregnanolone (Allo) in corticolimbic neurons, regulates stress sensitivity and
induces a potent anxiolytic action. In a rodent model of chronic intermittent ethanol (CIE) exposure, decreased
expression of Allo biosynthetic enzymes, 5α-reductase type I (5α-RI) and 3α-hydroxy-steroid dehydrogenase
(3α-HSD) is associated with Allo level downregulation in the hippocampus (HIP) and cerebellum. Consistently,
in AUD postmortem brain, cerebellum Allo levels and neurosteroidogenic proteins and enzymes, such as the
translocator protein (TSPO), 5α-RI and 3α-HSD expression decreased in association with aberrant epigenetic
marks. Alcohol-induced epigenetic modifications (e.g., DNA hyper/hypomethylation) on transcriptomics and
their impact on neurosteroidogenic gene expression, neurosteroid levels, and anxiety are poorly understood.
Allo biosynthesis can be upregulated in brain areas that modulate anxiety and alcohol reward by stimulating
the epigenetically modifiable nuclear receptor, peroxisome proliferator-regulated receptor (PPAR)-α by the
endogenous modulator, palmitoylethanolamide (PEA). Intriguingly, chronic alcohol exposure decreases PPAR-
α expression, while stimulation of PPAR-α by PEA decreases both anxiety and alcohol intake. The molecular
mechanisms underlying these effects remain unclear. Our preliminary and published results suggest that
alcohol-induced aberrant regulation of PPAR-α may affect anxiety via decreasing Allo content. Hypothesis:
Chronic alcohol exposure alters methylation/demethylation dynamics that downregulate corticolimbic PPAR-α
expression and allopregnanolone biosynthesis, and elevated anxiety. In male and female rats, we will: (AIM 1)
Examine the effect of 14-day CIE exposure (EtOH), ethanol acute (24h, W24h) and protracted (7 days, W7d)
withdrawal on the epigenetic regulation of PPAR-α expression and downstream effects on neurosteroidogenic
enzyme expression; (AIM 2) Investigate the effects of CIE exposure and ethanol acute and protracted
withdrawal on the brain content of Allo; and (AIM 3) Study the pharmacoepigenetics of PEA and fenofibrate on
Allo biosynthesis and anxiety after CIE exposure and acute and protracted ethanol withdrawal. This study may
unveil CIE-induced neurobiological alterations and suggest treatment targets for alcohol withdrawal symptoms.

## Key facts

- **NIH application ID:** 10930029
- **Project number:** 5R01AA030292-02
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** GRAZIANO PINNA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $359,775
- **Award type:** 5
- **Project period:** 2023-09-20 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10930029

## Citation

> US National Institutes of Health, RePORTER application 10930029, Alcohol-induced epigenetic reprogramming of PPAR-α affects allopregnanolone biosynthesis (5R01AA030292-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10930029. Licensed CC0.

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