# Viral vectors for desensitization-resistant nAChRs

> **NIH NIH R21** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2024 · $232,500

## Abstract

PROJECT SUMMARY
Tobacco dependence represents a major public health challenge, and novel treatment approaches are urgently
needed. Nicotinic acetylcholine receptors (nAChRs) are known to mediate the addictive action of nicotine, but it
has been difficult to know which aspects of nAChR function are involved in the behavioral and physiological
response to nicotine. In particular, the contribution of nAChR activation vs. desensitization to the establishment
and maintenance of nicotine reinforcement has remained unclear. We will leverage our unique experience with
nAChR molecular pharmacology and self-administration assays to address this issue. In Aim 1, we will design,
produce, and validate AAV vectors for expression of desensitization-resistant β2 and β4 nAChR subunits. We
will test several β2 and β4 variants with specific mutations at a conserved leucine residue in the 2nd
transmembrane ⍺-helix (i.e. the “pore-forming” ⍺-helix). Patch clamp electrophysiology will be used to
characterize the biophysical change induced by the mutation, and 2-photon laser scanning microscopy and
nicotine uncaging will verify proper trafficking of variant subunits in neurons. In Aim 2, we will study how
removal of β2 desensitization in VTA impacts nicotine self-administration and dopamine release. We will test
the hypothesis that a lack of desensitization will fundamentally alter nicotine's action as a reinforcer. We will
also determine how removal of desensitization from VTA β2* nAChRs impacts evoked dopamine release using
electrochemical methods. Together, these Aims will 1) produce/validate novel tools for nAChR research and 2)
help us understand how nAChR desensitization normally modulates nicotine reinforcement and associated DA
release. These vectors and their characterization in behavioral assays will lay the groundwork for future projects
related to nAChR physiology and pharmacology, and may also facilitate the development of novel tobacco
cessation treatments.

## Key facts

- **NIH application ID:** 10818742
- **Project number:** 1R21DA058419-01A1
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Ryan Michael Drenan
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $232,500
- **Award type:** 1
- **Project period:** 2024-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10818742

## Citation

> US National Institutes of Health, RePORTER application 10818742, Viral vectors for desensitization-resistant nAChRs (1R21DA058419-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10818742. Licensed CC0.

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