# Dissecting nicotinic receptor contributions to alcohol aversion

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2020 · $344,949

## Abstract

PROJECT SUMMARY
Alcohol produces rewarding and aversive subjective effects. People with increased sensitivity to the aversive
effects of alcohol consume lower levels of alcohol and have lower preference for alcohol. These data suggest
that enhancing the aversive effects of alcohol may be a useful strategy to reduce alcohol consumption.
Currently, the molecular mechanisms of alcohol aversion are poorly understood. Our preliminary data are the
first to implicate the nicotinic acetylcholine receptors (nAChRs) in alcohol aversion. The nAChRs are ligand-
gated cation channels that enhance neuronal excitability. We found that systemic injection of a pre-clinical
nAChR agonist increases alcohol aversion and decreases alcohol consumption in mice. To begin identifying
the neural circuits that are important for nAChR-mediated alcohol aversion, we targeted the rostromedial
tegmental nucleus (RMTg), which has been recently implicated in aversion. The RMTg is a GABAergic
structure that receives glutamatergic input from the lateral habenula and projects to dopamine neurons in the
ventral tegmental area (VTA). Micro-injection of a nAChR agonist into the RMTg and VTA reduced alcohol
consumption in mice, implicating nAChRs in this projection. Importantly, our data suggest that targeting
nAChRs in an aversive neural circuit can reduce alcohol consumption. Our application addresses critical gaps
in knowledge in the neural circuitry and molecular mechanisms of alcohol aversion: Does activation of the
RMTg-VTA projection increase alcohol aversion and decrease alcohol consumption? Which nAChR subunits
are critical for alcohol aversion and on which neurons are they located? To address these questions, we have
designed two specific aims. In AIM 1, we will chemogenetically modulate RMTg GABA and VTA dopamine
neuron activity using DREADDs to evaluate the contribution of these neuronal populations to alcohol aversion
and alcohol consumption in mice. In AIM 2, we will determine which nAChR subunits are important for alcohol
aversion and alcohol consumption, and whether they are located on RMTg GABA or VTA dopamine neurons
by reducing the expression of specific nAChR subunits in these neuronal populations using genetically
targeted RNA interference in transgenic mice. This project will generate new, fundamental knowledge on the
molecular mechanisms of alcohol aversion that will inform drug development efforts for alcohol addiction
treatment.

## Key facts

- **NIH application ID:** 9878727
- **Project number:** 5R01AA026598-03
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Anna M. Lee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $344,949
- **Award type:** 5
- **Project period:** 2018-05-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9878727

## Citation

> US National Institutes of Health, RePORTER application 9878727, Dissecting nicotinic receptor contributions to alcohol aversion (5R01AA026598-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9878727. Licensed CC0.

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