# Nr4a1 activation suppresses cocaine-induced behavior via epigenetic regulation of homeostatic target genes

> **NIH NIH R36** · UNIVERSITY OF PENNSYLVANIA · 2020 · $53,999

## Abstract

PROJECT SUMMARY
Endogenous homeostatic mechanisms can restore normal neuronal function following cocaine-induced
neurotoxicity. Such mechanisms may be exploited in developing novel therapies for cocaine addiction, but a
molecular target has not yet been identified. Here we profiled mouse gene expression in the nucleus accumbes
(NAc), during early and late cocaine abstinence to identify putative regulators of neural homeostasis. Cocaine
regulated expression of the transcription factor, Nuclear Receptor Subfamily 4 Group A Member 1 (Nr4a1), and
its target gene, cocaine and amphetamine-regulated transcript peptide (Cartpt), a key molecule in mitigating
dopamine toxicity. Sustained activation of Cartpt at late abstinence was coupled with depletion of the repressive
histone modification, H3 lysine 27 tri-methylation (H3K27me3), and enrichment of activating mark, H3 lysine 27
acetylation (H3K27ac). Using both CRISPR-mediated and small molecule Nr4a1 activation, we demonstrate the
direct causal role of Nr4a1 in this epigenetic mechanism of sustained gene expression and in repression of
cocaine-evoked behavior. Our findings provide evidence that targeting endogenous changes in homeostatic
gene expression across abstinence is a potential strategy to combat cocaine addiction.
The overall goal of this study is to determine the pathways responsible for observed changes in Nr4a1 and target
gene expression by isolation of tagged nuclei in specific cell types (INTACT). To this end, we will measure
cocaine-induced gene expression and histone post translational modifications in direct (D1-expressing) and
indirect pathway (A2A-expressing) medium spiny neurons (MSNs) during abstinence. Additionally, will extend
our findings using contingent models of drugs of abuse, namely, cocaine self-administration to evaluate Nr4a1
epigenetic regulation of target genes in male and female mice. Finally, we will determine co-factors involved in
the epigenetic regulation of Nr4a1 target genes. Taken together, this proposal will improve our understanding of
the precise epigenetic mechanisms by which individual genes “remember” prior drug exposure.

## Key facts

- **NIH application ID:** 9957423
- **Project number:** 1R36DA050877-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Marco Devaughn Carpenter
- **Activity code:** R36 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $53,999
- **Award type:** 1
- **Project period:** 2020-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9957423

## Citation

> US National Institutes of Health, RePORTER application 9957423, Nr4a1 activation suppresses cocaine-induced behavior via epigenetic regulation of homeostatic target genes (1R36DA050877-01). Retrieved via AI Analytics 2026-06-16 from https://api.ai-analytics.org/grant/nih/9957423. Licensed CC0.

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