title: Evidence from mouse and man for a role of neuregulin 3 in nicotine dependence.
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.
authors.affiliation: Department of Pharmacology, Translational Research Laboratories, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Turner
authors.affiliation: Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Ray
authors.affiliation: Department of Pharmacology, Translational Research Laboratories, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Lee
authors.affiliation: Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Everett
authors.affiliation: Department of Pharmacology, Translational Research Laboratories, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Xiang
authors.affiliation: Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Jepson
authors.affiliation: Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: K H
authors.initials: KH
authors.lastname: Kaestner
authors.affiliation: Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Lerman
authors.affiliation: Department of Pharmacology, Translational Research Laboratories, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Blendy
mesh_terms: D000293:Adolescent; D000328:Adult; D000077716:Afatinib; D000368:Aged; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D020880:Neuregulins / Q000235:genetics* / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011799:Quinazolines / Q000494:pharmacology; D051381:Rats; D066247:Receptor, ErbB-4 / Q000037:antagonists & inhibitors; D012907:Smoking / Q000188:drug therapy / Q000235:genetics; D013375:Substance Withdrawal Syndrome / Q000235:genetics; D061485:Tobacco Use Cessation Devices; D014029:Tobacco Use Disorder / Q000235:genetics*; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D047908:Intracellular Signaling Peptides and Proteins; C486357:NRG3 protein, human; D020880:Neuregulins; C108113:Nrg3 protein, mouse; D011799:Quinazolines; D000077716:Afatinib; D009538:Nicotine; D004247:DNA; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4