# COCA: Project 1. Drug-induced ROS and Epigenetic Mechanisms

> **NIH NIH P50** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2022 · $273,823

## Abstract

PROJECT SUMMARY – Project 1 Cowan
A major challenge for treating drug addiction is the poor understanding of the molecular mechanisms by which
drug use produces persistent changes in brain function that facilitate drug seeking even after long periods of
abstinence. Chronic drug use engages an epigenetic process, involving the chromatin-remodeling enzyme,
histone deacetylase 5 (HDAC5), in striatal medium spiny neurons that functions to limit the development of
multiple addiction-related behaviors, including reinstatement of cocaine and heroin seeking. However,
HDAC5’s regulation and function during and after drug taking is complex and poorly understood. Cocaine and
heroin produce reactive oxygen and nitrogen species (ROS/RNS) that alter the redox state of the cell, and
redox-mediated cysteine thiol modifications alter the structure/function of target proteins, including class IIa
HDACs. Repeated treatment of animals or humans with the antioxidant and glutathione precursor, N-
acetylcysteine (NAC), reduces the vulnerability to reinstatement of cocaine and heroin seeking, and NAC
blocks ROS-promoted HDAC5 nuclear export. The long-term goal of Project 1 is to understand the redox
protein signaling and epigenetic mechanisms by which HDAC5 and NAC regulate heroin and cocaine relapse
behaviors in hopes of identifying better therapeutic strategies for the treatment of drug addiction. We
hypothesize that: (1) cocaine- and heroin-produced oxidative stress modifies HDAC5 cysteine thiol groups in
the nucleus accumbens, which promotes nuclear export and reduces the anti-relapse actions of HDAC5, and
(2) the anti-relapse effects of repeated NAC treatment are due, at least in part, to its ability to protect HDAC5
from ROS signaling events that promote nuclear exclusion and changes in gene expression. We will use
cutting-edge mouse genetics and cre-dependent viral tools that allow for time-delimited and cell-type specific
manipulation of nucleus accumbens core neurons during drug taking and relapse events.
Aim 1. Molecular and Cellular Mechanisms: In this aim, we will determine how cocaine and heroin SA
regulate HDAC5’s redox-sensitive posttranslational modifications, subcellular distribution, genomic binding and
regulation of gene expression.
Aim 2. Circuit Specificity: In this aim, we will take a cutting-edge molecular genetic approach to dissect the
cell-type specific roles for HDAC5 to negatively-regulate cocaine and heroin drug seeking.
Aim 3. Treatment: In this aim, we will analyze the regulation of HDAC5 by NAC, and test the role of HDAC5
in the long-lasting ability of NAC to reduce reinstatement of heroin and cocaine seeking.

## Key facts

- **NIH application ID:** 10404584
- **Project number:** 5P50DA046373-04
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Christopher W Cowan
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $273,823
- **Award type:** 5
- **Project period:** 2019-09-15 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10404584

## Citation

> US National Institutes of Health, RePORTER application 10404584, COCA: Project 1. Drug-induced ROS and Epigenetic Mechanisms (5P50DA046373-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10404584. Licensed CC0.

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