# Reversing Cocaine-induced Neurobehavioral Deficits using a Combination Drug Approach

> **NIH NIH F30** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2021 · $2,500

## Abstract

Project Summary
Cocaine addiction is a chronic, relapsing brain disease that is intimately associated with dysregulations of the
dopamine and dynorphin systems, which contributes to the dysphoric syndrome seen during withdrawal from
cocaine. Furthermore, during abstinence, a negative affect persists, in addition to a reward deficiency,
heightened stress response, and an inability to feel pleasure—all contributing to a high risk of relapse. The
cycle from abstinence to withdrawal to subsequent escalation of drug use is far too common, and even though
ample therapeutics targeted at the dopamine and dynorphin systems have been created, none have yet been
proven effective and approved by the FDA to treat cocaine addiction. Due to the profound dysfunction of the
dopamine and dynorphin systems, we propose to use the dopamine transporter and kappa opioid receptor as
possible cellular targets in the development of therapeutics for cocaine addiction. Our overarching
hypothesis is to combine a dopamine releaser to enhance dopaminergic tone and a kappa opioid
receptor antagonist to produce anxiolytic and antidepressant effects, ultimately to reduce motivation
to take cocaine and normalize the dopamine and kappa opioid receptor systems after chronic cocaine
use in rats. Guided by our preliminary data showing promising results for combining two drugs that target the
dopamine and dynorphin systems, we propose to pursue the following specific aims: (1) To assess whether
phenmetrazine and LY2444296, both individually and in combination, will reduce the motivation to take
cocaine; and (2) To assess whether phenmetrazine and LY2444296, both individually and in combination, will
reverse long-term dysregulations in the dopamine and kappa opioid receptor systems. Collectively, our
proposed studies use a combination therapy approach, in which the dopamine releaser phenmetrazine and the
kappa opioid receptor antagonist LY2444296 may accentuate the beneficial effects of each individual drug,
with the advantage of targeting two dysregulated neurotransmitter systems post-chronic cocaine exposure, in a
cocaine self-administration rat model. These studies have the potential to uncover potential cellular interactions
that can be targeted for treatment of cocaine use disorder.

## Key facts

- **NIH application ID:** 10375061
- **Project number:** 3F30DA048575-03S1
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Paige Marie Estave
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $2,500
- **Award type:** 3
- **Project period:** 2019-01-15 → 2023-03-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10375061

## Citation

> US National Institutes of Health, RePORTER application 10375061, Reversing Cocaine-induced Neurobehavioral Deficits using a Combination Drug Approach (3F30DA048575-03S1). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10375061. Licensed CC0.

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