# PPARdelta receptors and alcohol use phenotypes

> **NIH NIH R21** · SCRIPPS RESEARCH INSTITUTE, THE · 2023 · $214,938

## Abstract

Abstract
New neurobiological understanding of and therapeutic targets for alcohol use disorder (AUD) are needed.
Advances in the biology of AUD indicate that lipid signaling is a key regulator of ethanol use and withdrawal
behavior via specialized G-protein coupled membrane receptors, transport proteins, and, more recently,
nuclear transcription factors. PPARs are lipid-sensing transcription factors encoded by 3 genes (PPAR,
PPAR, PPAR) that were identified for their roles in peripheral regulation of fuel homeostasis. PPAR and
PPAR have received intense attention for their anti-addiction-like actions. Yet, the central role of the more
abundantly expressed brain PPARreceptor isotype in the control of compulsive alcohol use behaviors is
entirely unknown. Here, we test the overarching hypothesis that brain peroxisome proliferator-activated
receptors-delta subtype (PPAR) inhibits compulsive ethanol use and negative emotional withdrawal. Studies
use the chronic intermittent ethanol vapor exposure model to elicit escalated and aversion-resistant ethanol
intake and withdrawal anxiety- and irritability-like behavior to yield new translational insights into AUD. We
combine novel brain-penetrant and translatable PPAR agonist (KD3010, T3D-959) and brain-restricted and
site-specific cre/lox conditional PPAR knockouts to test the causal role and central sites of PPARaction in
compulsive-like alcohol use phenotypes. The resulting data and novel genetic and translationally-relevant
pharmacological tools for this understudied PPARδ isotype will lay the groundwork for cell type- and
anatomically-specific mechanistic studies and may lead to interventions for people affected by compulsive
alcohol use and other forms of addiction.

## Key facts

- **NIH application ID:** 10682348
- **Project number:** 1R21AA029498-01A1
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** ERIC P ZORRILLA
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $214,938
- **Award type:** 1
- **Project period:** 2023-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10682348

## Citation

> US National Institutes of Health, RePORTER application 10682348, PPARdelta receptors and alcohol use phenotypes (1R21AA029498-01A1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10682348. Licensed CC0.

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