# PARP-mediated gene regulation in alcohol drinking behavior

> **NIH VA I01** · JESSE BROWN VA MEDICAL CENTER · 2020 · —

## Abstract

Alcohol use disorder (AUD) is highly prevalent among U.S. military veterans. Excessive alcohol consumption,
defined as the acquisition of a blood alcohol concentration (BAC) ≥ 0.08 g/dl (binging) or ≥ 15 drinks/week for
men, is an important risk factor for many serious medical and psychiatric conditions, including AUD. The
medial prefrontal cortex (mPFC) is important for integrating various internal and external states in order to
determine approach/avoidant behavior to rewarding or aversive stimuli. Prior studies demonstrated that Poly-
ADP ribose Polymerase (PARP), through its ability to regulate synaptic plasticity gene expression, promotes
cocaine addictive behaviors. Whether PARP enzymatic activity plays a similar role in the addictive properties of
ethanol (EtOH) has yet to be studied. The hypothesis of this grant proposal is that EtOH increases PARP
activity causing reduced expression of certain neuronal synaptic plasticity genes in excitatory mPFC neurons
ultimately increasing alcohol drinking behavior. EtOH increases PARP enzymatic activity in cell culture, adult
binging animals, and during fetal development. PARP can silence gene expression by catalyzing reactions
adding PAR groups (PARylation) to downstream gene regulatory proteins, including the transcription factor
peroxisome proliferator-activated receptor-γ (PPARγ) and KDM4D, a demethylase of the transcriptionally
repressive dimethylated lysine 9 of histone 3 (H3K9me2). Examples of genes implicated in AUD that are well-
established to be regulated by H3K9me2 are Brain-derived Neurotrophic Factor (Bdnf) and Pparγ. BDNF and
PPARγ are expressed by excitatory neurons in the cortex, where both have roles in synaptic plasticity and
neuronal survival. Therefore, an alcohol induced suppression of BDNF and PPARγ expression would be
expected to alter mPFC excitatory outputs, promoting continued alcohol drinking behavior. This is supported by
reports indicating higher BDNF expression and PPARγ agonists reduce alcohol consumption. We reported that
PARP activity is in part responsible for EtOH-induced decreases in Bdnf IV and IXa mRNA expression in
primary cortical neuron cultures. We found several lines of evidence indicating that reduced PPARγ promoter
binding may serve as an intermediary step between increased PARP activity and decreased Bdnf expression.
We now propose to examine these same pathways in vivo. Our preliminary data indicate that mice that
voluntarily consumed EtOH in the binge-like drinking-in-the-dark (DID) paradigm had increased PARP mRNA
expression and enzymatic activity in the PFC. DID consumed EtOH reduced BDNF and PPARγ expression,
effects that were reversed by PARP inhibitor treatment. DID EtOH consumption decreased PPARγ DNA
binding ability generally and specifically at the Bdnf IXa promoter. Also, DID consumed EtOH increased global
levels of H3K9me2, and PARP inhibition decreased H3K9me2 at Pparγ and Bdnf IXa gene promoters. Finally,
we found that PARP inhibition reduc...

## Key facts

- **NIH application ID:** 9898316
- **Project number:** 5I01BX004091-03
- **Recipient organization:** JESSE BROWN VA MEDICAL CENTER
- **Principal Investigator:** Rajiv Pandit Sharma
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898316

## Citation

> US National Institutes of Health, RePORTER application 9898316, PARP-mediated gene regulation in alcohol drinking behavior (5I01BX004091-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9898316. Licensed CC0.

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