# Epigenetic mechanisms of sustained transcription across cocaine abstinence

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $686,803

## Abstract

PROJECT SUMMARY
Cocaine addiction is characterized by compulsive drug seeking and high vulnerability to relapse
even after prolonged abstinence. A major focus of the field of addiction research has therefore
been to identify stable, cocaine-induced neuroadaptations occurring in brain reward circuits.
Transcriptional changes are known to persist throughout abstinence, yet the underlying molecular
mechanisms of such persistence remain elusive.
We recently discovered that the transcription factor, Nr4a1 (nuclear receptor subfamily 4)
represses cocaine reward and seeking behavior. Our preliminary data show that Nr4a1 is a
central regulator of cocaine-induced transcription, including target gene expression in late
abstinence. The significance of this study is strengthened by the utility of therapeutic agents that
regulate Nr4a1 and block mouse cocaine self-administration, underscoring the enormous
potential of this basic research program in combating drug addiction.
Given that histone posttranslational modifications (hPTMs) confer long-lasting changes in gene
expression necessary for stable cellular phenotypes, histone modifications acquired during
abstinence may explain how individual genes “remember” prior drug exposure. We have
previously found that Nr4a1 regulates hPTMs at individual target genes at late abstinence. This
proposal aims to define the mechanism(s) of persistent gene expression in the nucleus
accumbens (NAc) of male and female mice following volitional cocaine self-administration. We
apply novel methods for cell-type specific quantification of both chromatin and gene expression
in a single sample. We then validate the causal mechanism of Nr4a1 action using epigenetic
editing in vivo. At the conclusion of this study we will have defined the cell-type specific
mechanism by which Nr4a1 regulates stable gene expression across cocaine abstinence. Beyond
this, we will apply machine learning to identify novel regulators of persistent gene expression
relevant to cocaine addiction.

## Key facts

- **NIH application ID:** 10434147
- **Project number:** 5R01DA052465-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Elizabeth A Heller
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $686,803
- **Award type:** 5
- **Project period:** 2021-07-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10434147

## Citation

> US National Institutes of Health, RePORTER application 10434147, Epigenetic mechanisms of sustained transcription across cocaine abstinence (5R01DA052465-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10434147. Licensed CC0.

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