# Transcriptional Mechanisms of Addiction-related Neural Plasticity

> **NIH NIH R01** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2021 · $396,226

## Abstract

Project Summary/Abstract
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 compulsive drug seeking and taking
behaviors even after long periods of abstinence. We showed that MEF2 transcription factors regulate
excitatory synapse density by promoting structural and functional synapse elimination in a process involving
the Fragile X Mental Retardation Protein (FMRP) – an RNA-binding protein that regulates dendritic protein
synthesis and glutamatergic synaptic strength and density in the brain. FMRP acts to regulate multiple
cocaine-induced behaviors and glutamatergic synapses on medium spiny neurons (MSNs) of the nucleus
accumbens (NAc) shell. FMRP associates with hundreds of neuronal mRNAs, including the mRNA for the
activity-regulated cytoskeleton-associated protein (Arc). In our preliminary studies, we find that Arc is induced
in the NAc by cocaine and is a negative-regulator of NAc MSN glutamatergic synaptic transmission, and loss of
Arc enables the development of sensitized cocaine bheaviors, including motor, reward and possibly sensitivity
to low-dose cocaine in the mouse IV self-administration model. As such, our central hypothesis is that Arc RNA
and protein synthesis in the NAc functions to antagonize glutamatergic synaptic plasticity on MSNs, and loss of
Arc produces a synapse plasticity environment that facilitates sensitized cocaine behaviors. We will test and
refine our central hypothesis with the following specific aims:
Specific Aim 1: Analyze the regulation of Arc by cocaine in the adult NAc. In this aim, we will investigate
the dynamic, cell-type specific regulation of Arc mRNA and protein in the adult NAc after acute and chronic
cocaine (non-contingent and contingent) administration.
Specific Aim 2: Determine the role of Arc in sensitized cocaine behaviors. In this aim, we will build upon
our recent preliminary data to test for the role of Arc in the adult NAc for the development of non-contingent
and contingent drug behaviors.
Specific Aim 3: Determine the role of Arc in regulating cocaine-modulated NAc MSN excitatory
synaptic transmission. Using a cell type-specific approach, we will investigate the role of Arc in mediating
cocaine-induced (non-contingent and contingent) MSN glutamatergic synaptic strength and number with the
hypothesis that Arc limits the sensitized cocaine behaviors by promoting AMPAR endocytosis of D1R+ MSNs
in the adult NAc.

## Key facts

- **NIH application ID:** 10139009
- **Project number:** 5R01DA027664-12
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Christopher W Cowan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $396,226
- **Award type:** 5
- **Project period:** 2011-03-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10139009

## Citation

> US National Institutes of Health, RePORTER application 10139009, Transcriptional Mechanisms of Addiction-related Neural Plasticity (5R01DA027664-12). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10139009. Licensed CC0.

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