# Translational study on CHRNA5 variation and alcohol reward mechanisms

> **NIH NIH U01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $362,250

## Abstract

Alcohol use disorder (AUD) is the third leading cause of preventable death in the United States. This
disease has a negative impact on health, work, and relationships of the affected individuals. Research on the
genetic and environmental determinants of the response to alcohol, and their relationship to the risk of
developing AUD is critical to reducing the substantial societal burden of AUD. Genetic studies have shown
association of AUD with gene variation in several loci. However, due to the heterogeneity in the AUD clinical
phenotype and small effect sizes, there has been an increasing interest in examining the influence of gene
variation on quantitative endophenotypes such as alcohol seeking, consumption, and brain circuit alterations.
 The present application focuses on the potential influence of gene variation in CHRNA5, the gene
encoding the α5 subunit of nicotinic acetylcholine receptors, on alcohol self-administration and brain circuit
alterations. The rs16969968 missense single-nucleotide polymorphism (SNP) in CHRNA5 is associated with
nicotine addiction and smoking-related consequences. However, despite the widely prevalent co-abuse of
tobacco and alcohol, little work has been done to examine the effect of this SNP on alcohol use, dependence, or
alcohol response. The goal of this proposal is to examine the influence of CHRNA5 variation on alcohol
responses using an integrated translational pharmacogenetic approach that leverages the expertise of
investigators at the NIAAA and NIDA intramural programs with the project PI to combine clinical research on
human subjects and pre-clinical analyses in rodent models. A prospective study will compare alcohol self-
administration behavior and neuroimaging responses in humans that are homozygous for the G-allele and those
that are A-allele carriers of the CHRNA5 rs16969968 SNP. We will study the potential interaction of alcohol and
nicotine by comparing smoking and non-smoking drinkers. To better understand the mechanistic link between
CHRNA5 and alcohol response, we will conduct behavioral and functional studies in genetically modified
animals expressing the α5 gene variants or an α5 null mutation. Similar to the human studies, we will study
alcohol self-administration in nicotine-naïve vs. nicotine-treated animals. Furthermore, we will study how
CHRNA5 variation influences the effects of alcohol on the dopaminergic system by measuring ethanol-induced
electrophysiological responses and dopamine release.
 Examination of the role of CHRNA5 variation in alcohol response will provide a greater understanding of
the cholinergic mechanisms underlying the neurobiology of alcohol, with the goal of providing an expanded
etiological spectrum for alcohol reward response phenotypes.

## Key facts

- **NIH application ID:** 10177822
- **Project number:** 5U01AA025931-04
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Mariella De Biasi
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $362,250
- **Award type:** 5
- **Project period:** 2018-06-20 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10177822

## Citation

> US National Institutes of Health, RePORTER application 10177822, Translational study on CHRNA5 variation and alcohol reward mechanisms (5U01AA025931-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10177822. Licensed CC0.

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