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Evidence from mouse and man for a role of neuregulin 3 in nicotine dependence

Molecular Psychiatry volume 19, pages 801–810 (2014)Cite this article

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Abstract

Addiction to nicotine and the ability to quit smoking are influenced by genetic factors. We used functional genomic approaches (chromatin immunoprecipitation (ChIP) and whole-genome sequencing) to identify cAMP response element-binding protein (CREB) targets following chronic nicotine administration and withdrawal (WD) in rodents. We found that chronic nicotine and WD differentially modulate CREB binding to the gene for neuregulin 3 (NRG3). Quantitative analysis of saline, nicotine and nicotine WD in two biological replicates corroborate this finding, with NRG3 increases in both mRNA and protein following WD from chronic nicotine treatment. To translate these data for human relevance, single-nucleotide polymorphisms (SNPs) across NRG3 were examined for association with prospective smoking cessation among smokers of European ancestry treated with transdermal nicotine in two independent cohorts. Individual SNP and haplotype analysis support the association of NRG3 SNPs and smoking cessation success. NRG3 is a neural-enriched member of the epidermal growth factor family, and a specific ligand for the receptor tyrosine kinase ErbB4, which is also upregulated following nicotine treatment and WD. Mice with significantly reduced levels of NRG3 or pharmacological inhibition of ErbB4 show similar reductions in anxiety following nicotine WD compared with control animals, suggesting a role for NRG3 in nicotine dependence. Although the function of the SNP in NRG3 in humans is not known, these data suggest that Nrg3/ErbB4 signaling may be an important factor in nicotine dependence.

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Acknowledgements

This research was funded by grants from the National Cancer Institute and National Institute on Drug Abuse, P50-CA143187, 1-F32-DA026236, K01-DA031747, 1-K99-DA032681, and U01-DA020830. We thank the Next Generation Sequencing Core at the University of Pennsylvania for sequencing support and technical assistance.

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  1. R Ray

    Present address: 4Current address: GlaxoSmithKline Biologicals, Brussels, Belgium.,

Authors and Affiliations

  1. Department of Pharmacology, Translational Research Laboratories, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    J R Turner, B Lee, J Xiang & J A Blendy

  2. Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    R Ray, C Jepson & C Lerman

  3. Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    L Everett & K H Kaestner

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Turner, J., Ray, R., Lee, B. et al. Evidence from mouse and man for a role of neuregulin 3 in nicotine dependence. Mol Psychiatry 19, 801–810 (2014). https://doi.org/10.1038/mp.2013.104

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