# Epitranscriptomic Regulation of Synaptic Responses to Drugs of Abuse

> **NIH NIH DP1** · DUKE UNIVERSITY · 2022 · $477,378

## Abstract

ABSTRACT
Chronic exposure to drugs of abuse leads to persistent changes in synaptic connectivity which underlie the
complex behaviors that characterize addiction. Thus, uncovering the factors that regulate synaptic plasticity is
critical for understanding the molecular underpinnings of drug-induced neural adaptation and improving our
ability to treat addiction. Several studies to date have focused on epigenetic mechanisms of gene expression that
regulate the genome, whereas modifications to the transcriptome have been largely overlooked. Methylation of
adenosine residues (m6A) has recently been shown to be a widespread RNA modification found in thousands of
cellular mRNAs. Furthermore, m6A is particularly abundant within the brain, and its regulation has been
implicated in the behavioral and electrophysiological response to cocaine. Recent studies have begun to reveal
that m6A regulates gene expression changes during synaptic activity. However, whether m6A contributes to
synaptic changes in gene expression that underlie drug-induced plasticity remains unknown. Here, we will
explore the novel hypothesis that m6A-mediated changes in local protein production at the synapse regulate gene
expression changes caused by drugs of abuse. First, we will identify cocaine-induced changes to the local
methylome within the mouse brain and identify potential synaptic mRNAs which are regulated through mRNA
methylation. Second, we will develop novel tools for the in vivo identification of transient m6A:protein
interactions to identify both new m6A binding proteins as well as dynamic m6A binding events induced by cocaine
exposure. Third, we will use a combination of global gene expression profiling and gene targeting approaches to
determine how m6A regulates local gene expression following cocaine exposure. Collectively, these studies will
explore novel roles of the epitranscriptome in controlling drug-induced gene expression changes and will likely
reveal new mechanisms that regulate long-term synaptic changes that occur during addiction.

## Key facts

- **NIH application ID:** 10433956
- **Project number:** 5DP1DA046584-05
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Kathryn D Meyer
- **Activity code:** DP1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $477,378
- **Award type:** 5
- **Project period:** 2018-07-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10433956

## Citation

> US National Institutes of Health, RePORTER application 10433956, Epitranscriptomic Regulation of Synaptic Responses to Drugs of Abuse (5DP1DA046584-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10433956. Licensed CC0.

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