# Cholinergic mechanisms of cocaine reinforcement probed with nicotinic receptor gene editing

> **NIH NIH R21** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2022 · $193,750

## Abstract

PROJECT SUMMARY
Cocaine use disorder represents a major public health challenge, and novel treatment approaches are urgently
needed. Tobacco usage is highly co-morbid with cocaine use disorder, and at present, it is not known
whether/how nicotinic signal transduction modulates the brain's response to cocaine. We hypothesize that
tobacco usage contributes to cocaine use, and we will model this research question using a rat model system. We
will probe the mechanistic underpinnings of nicotinic modulation of cocaine reinforcement, focusing on
identifying key nicotine receptors and nerve cell types in the brain's reward circuit. In the R21 phase, we will
validate a set of molecular tools that we developed in a previously funded project. These tools allow us to reduce
or eliminate the expression of specific nicotine receptors in precise cell types in the brain. We'll verify that these
tools work for their purpose in this project, examining how well they reduce nicotine receptor function in cellular
assays (Aim 1). This involves single-cell patch-clamp recordings and fiber photometry. In R21 Aim 2, we will
determine whether/how nicotine receptor functional attenuation impacts cocaine self-administration behavior.
Specific manipulations that impact cocaine reinforcement will be confirmed with replication studies and other
control experiments then advanced to the R33 phase for further investigation. In the R33, we will further probe
the mechanisms by which nicotine receptors modulate cocaine reinforcement. R33 Aim 3 will probe the circuits
involved in nicotine receptor modulation of cocaine self-administration. R33 Aim 4 will use a biophysical
approach to examine the novel hypothesis that cocaine has direct acute and long-term interactions with nicotine
receptors. Together, these AIMs will help us understand how nicotine receptor activity modulates cocaine intake.
Associated neurobiological mechanisms will be identified, potentially leading to novel approaches to treat
tobacco and/or cocaine dependence.

## Key facts

- **NIH application ID:** 10436486
- **Project number:** 1R21DA054819-01A1
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Ryan Michael Drenan
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $193,750
- **Award type:** 1
- **Project period:** 2022-09-15 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10436486

## Citation

> US National Institutes of Health, RePORTER application 10436486, Cholinergic mechanisms of cocaine reinforcement probed with nicotinic receptor gene editing (1R21DA054819-01A1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10436486. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*