Evidence from Mouse and Man for a Role of Neuregulin 3 in Nicotine Dependence

Department of Pharmacology, Translational Research Laboratories, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Molecular Psychiatry (Impact Factor: 14.5). 09/2013; 19(7). DOI: 10.1038/mp.2013.104
Source: PubMed


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.Molecular Psychiatry advance online publication, 3 September 2013; doi:10.1038/mp.2013.104.

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Available from: Bridgin Lee, May 12, 2014
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    • "With continual technological advancements, genetic studies have helped scientists identify common genetic variation within the human population that may underlie nicotine dependence and co-morbid disorders, such as schizophrenia. For example, SNPs on genes encoding the NRG– ErbB signaling pathway have been shown to influence nicotine dependence and withdrawal (Turner et al., 2014), as well as the pathophysiology of schizophrenia (Badner & Gershon, 2002; Gurling et al., 2001), providing researchers new insight into the potential benefits of examining the NRG–ErbB4 pathway for novel therapeutic targets not only for smoking cessation but also for treating symptoms seen in schizophrenia as well. Furthermore , due to such high demand for novel therapeutics targeted at treating co-morbid disorders such as tobacco smoking and schizophrenia, understanding common cellular processes that link these disorders is worth investigating and the NRG–ErbB pathway may represent a promising place to start. "
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