# Nicotinic acetylcholine receptor function in the mesolimbic dopamine system

> **NIH NIH R01** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2021 · $378,936

## Abstract

PROJECT SUMMARY
Chronic exposure to nicotine in tobacco products results in numerous health consequences (lung cancer,
emphysema, hypertension, etc.) and accounts for over 6 million deaths per year. Relapse rates are high among
those who attempt to quit smoking, and pharmacotherapies that seek to foster smoking cessation have
moderate effectiveness. Thus, there is a significant unmet need for more effective strategies to treat nicotine
dependence. Development of such strategies requires a more detailed understanding of the biological
mechanisms leading to nicotine addiction. An essential goal related to mechanistic studies on nAChRs is
gaining a better understanding of the location and activity of nAChRs in discrete sites within individual nerve
cells. It is also critical that we connect this location/activity information to the various neurochemically-defined
(e.g. dopamine, GABA, glutamate) cell types within the brain reward pathways. For these specific cell types in
the reward pathway, recent research points to a highly complex input/output relationship. We identified
nAChR expression in glutamate-producing neurons in the ventral tegmental area (VTA), and have
demonstrated that these receptors enable nicotine- or ACh-mediated alterations in synaptic transmission
within the VTA. However, several gaps in knowledge remain, which we will address in this project. First (in
Aim 1), we will identify the location within VTA glutamate neurons where nAChRs show the greatest functional
activity. This will be done using electrophysiological recordings during 2-photon imaging of neurons in brain
slices. This approach will be coupled with studies using a novel photoactivatable nicotine, which we recently
introduced. Directly connecting this structural and functional information is critical to fully understanding how
nAChRs modulate glutamate transmission in the VTA. In Aim 2, we will answer questions related to nAChR
modulation of cell-cell communication within the VTA. Glutamate neurons in this nucleus directly impinge on
local DA/GABA neurons, activity which is modulated by nAChR activity on glutamate cells. We will investigate
the mechanisms underlying this synaptic communication using optogenetics, photostimulation techniques, and
2-photon microscopy. In Aim 3, we move our queries to the behaving animal to determine which of the
components investigated in Aims 1-2 are most important during animal behavior. Using fiber photometry, we
will image Ca2+ activity in VTA neurons during acute nicotine exposure and during acquisition/expression of
nicotine conditioned reward behavior. To complement these experiments, we will also use chemogenetics to
determine whether VTA glutamate neurons are important for nicotine reward-like behavior. By determining
how cholinergic mechanisms map onto the complexity (neurochemical and connectivity) of cell types in the
VTA, this project will significantly advance our understanding of cholinergic neurotransmission. These studi...

## Key facts

- **NIH application ID:** 10173732
- **Project number:** 5R01DA035942-08
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Ryan Michael Drenan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $378,936
- **Award type:** 5
- **Project period:** 2014-08-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10173732

## Citation

> US National Institutes of Health, RePORTER application 10173732, Nicotinic acetylcholine receptor function in the mesolimbic dopamine system (5R01DA035942-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10173732. Licensed CC0.

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