# FMRP in the striatum: mechanisms of early drug reward

> **NIH NIH R36** · TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR · 2021 · $53,422

## Abstract

Project Summary/Abstract
Substance use disorders, affecting approximately 20.1 million individuals in the U.S., are characterized by a
shift in voluntary drug-taking to compulsive drug-seeking and -taking behaviors, which persist despite negative
consequences and remain prone to relapse after periods of abstinence. Though environmental influences have
been identified as risk factors, there are major gaps in understanding of biological factors that contribute to the
development of substance use disorders, limiting our ability to provide effective and lasting treatments.
Previous work suggests that the fragile X mental retardation protein (FMRP), an RNA-binding protein that
regulates synaptic plasticity, is required for cocaine-induced synapse elimination in the striatum, a brain region
critical to reward function. Moreover, loss of FMRP, either broadly or in the ventral striatum (nucleus
accumbens; NAc), is capable of dampening cocaine-induced behaviors that are considered indicative of higher
addiction-related risk. The main objective of this R36 application is to determine the mechanism by which
FMRP facilitates operant self-administration of intravenous cocaine and reinstatement of drug-seeking
behavior. The central hypothesis, based on published and preliminary data, is that FMRP positively mediates
cocaine intravenous self-administration and reinstatement of drug-seeking via its regulation of the activity-
regulated cytoskeleton-associated protein (Arc) in D1-receptor (D1R) expressing cells of the NAc. This
hypothesis will be tested in two specific aims, each utilizing conditional knockdown approaches and an
extensive self-administration assay that includes cue- and drug-induced reinstatement paradigms. Aim 1 will
determine whether FMRP mediates these phenotypes via its function in specifically D1R or D2R cells of the
NAc, while Aim 2 will determine whether FMRP’s regulation of Arc contributes to these phenotypes. This work
will complete the applicant’s dissertation, as part of her training for a career in addiction-related science,
provide insight into the mechanism by which FMRP mediates drug-related behaviors, providing critical direction
for future studies aimed at identifying downstream targets for therapeutic intervention.

## Key facts

- **NIH application ID:** 10128740
- **Project number:** 1R36DA051727-01A1
- **Recipient organization:** TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
- **Principal Investigator:** Jessica Huebschman
- **Activity code:** R36 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $53,422
- **Award type:** 1
- **Project period:** 2021-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10128740

## Citation

> US National Institutes of Health, RePORTER application 10128740, FMRP in the striatum: mechanisms of early drug reward (1R36DA051727-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10128740. Licensed CC0.

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