# Cocaine self-administration and cholesterol metabolism

> **NIH NIH R21** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2022 · $232,500

## Abstract

Project Summary
The Center for Disease Control and Prevention reports that death rates involving cocaine are on the rise.
There is still no effective pharmacological treatment for cocaine use disorder (CUD). Cocaine binds to the
dopamine transporter (DAT), inhibiting dopamine (DA) reuptake and thus elevating extracellular DA levels in
the striatum. Striatal DA elevation is associated with subjective experience of euphoria in humans. Recent
meta-analysis of neuroimaging in patients with CUD indicates that acute cocaine-induced elevation of DA is
blunted. This dysregulation likely contributes to repeated cycles of cocaine-seeking and taking behavior and
accidental overdoses. A critical knowledge gap is how cocaine-DAT interactions are disrupted by chronic
cocaine exposure. DAT adopts an outward-facing conformation in a cholesterol-enriched membrane
environment to accommodate high-affinity cocaine binding. Perturbation of cholesterol homeostasis in cultured
cells and ex vivo disrupts cocaine-DAT interactions. Our preliminary data show that cocaine SA reduces
striatal cholesterol content and importantly, ex vivo cholesterol replenishment to striatal synaptosomes
improves the ability of cocaine to inhibit DA reuptake. Based on these observations, this proposal will
investigate a previously unknown molecular mechanism whereby cocaine modulation of brain cholesterol
metabolism mediates cocaine-DAT interactions. We will explore whether pharmacological and genetic
modulation of cholesterol content is a new avenue to mitigate disrupted cocaine-DAT interactions and
attenuate cocaine self-administration.

## Key facts

- **NIH application ID:** 10509798
- **Project number:** 1R21DA056857-01
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Rong Chen
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $232,500
- **Award type:** 1
- **Project period:** 2022-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10509798

## Citation

> US National Institutes of Health, RePORTER application 10509798, Cocaine self-administration and cholesterol metabolism (1R21DA056857-01). Retrieved via AI Analytics 2026-06-16 from https://api.ai-analytics.org/grant/nih/10509798. Licensed CC0.

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