# System genetics of menthol and nicotine addiction

> **NIH NIH U01** · UNIVERSITY OF TENNESSEE HEALTH SCI CTR · 2022 · $657,702

## Abstract

The rat is the most commonly used model organism for behavioral studies of addiction. We propose to
establish an innovative hybrid rat diversity panel (HRDP) in this work. The HRDP is unique in that it integrates:
1) a high level of genetic diversity similar to that of admixed human populations; 2) a way to control drug
exposures and to systematically study gene-by-environment and gene-by-drug interactions; and 3) a way to
integrate "addictome" data across scale: from genetics, genomics, and other molecular data together with key
addiction related risks. This work will be a step toward developing experimental resources for precision
medicine. The HRDP consists of 91 highly diverse genomes of rats that are all open access and can be used
by any investigators to study facet of addiction and in different environments or under different treatments. We
will use the HRDP to identify sequence variants that control motivational effects of nicotine with a menthol cue.
Approximately 25% of smokers prefer mentholated cigarettes. Clinical studies have shown that menthol
facilitates initiation, enhances dependence and makes quitting more difficult. Given the large sample size
needed in human studies to identify key sequence variants associated with drug addiction, we argue that
animal models provide an efficient means to define and test genetic and molecular mechanisms that contribute
to the addiction-enhancing effects of menthol. We developed a rat model of nicotine i.v. self-administration
(IVSA) with an oral menthol cue. We found that 1) menthol facilitates the acquisition of nicotine IVSA, 2) rats
that receive the menthol cue for nicotine show a strong extinction burst, a model for drug craving, and 3) these
rats also demonstrate a strong cue-induced reinstatement, a model of relapse. We also showed that the
cooling sensation of menthol functions as a conditioned cue for nicotine reward, and that oral menthol
treatment increases brain nicotine accumulation. Critically, in the context of this U01 mechanism, we estimate
that heritability of these traits are greater than 0.6. We have three aims: In Aim 1 we conduct whole genome
sequencing of the HRDP. We will define all sequence variants that underlie heritable variation using innovative
linked-read libraries and de novo assemblies. In Aim 2 we phenotype nicotine IVSA with a menthol cue in
adolescent HRDP animals of both sexes with deep replication. We will phenotype nicotine IVSA with a visual
cue as a control. Effects of oral menthol on brain nicotine level will be measured. In Aim 3 we use systems
genetics methods to map and integrated behavioral phenotypes. Both forward (QTL) and reverse (PheWAS)
genetic methods will be used. We will use new linear mixed models to map and test candidate genes with key
cofactors (i.e., different cues). Finally, we evaluate the translational relevance of candidate genes and
biomarkers by comparison to GWAS cohorts and longitudinal reports of addiction in humans. This U01 w...

## Key facts

- **NIH application ID:** 10317100
- **Project number:** 5U01DA047638-04
- **Recipient organization:** UNIVERSITY OF TENNESSEE HEALTH SCI CTR
- **Principal Investigator:** Hao Chen
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $657,702
- **Award type:** 5
- **Project period:** 2019-04-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10317100

## Citation

> US National Institutes of Health, RePORTER application 10317100, System genetics of menthol and nicotine addiction (5U01DA047638-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10317100. Licensed CC0.

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