title: Overexpression of the CHRNA5/A3/B4 genomic cluster in mice increases the sensitivity to nicotine and modifies its reinforcing effects.
abstract: Nicotinic acetylcholine receptors (nAChRs) are ligand-gated pentameric ion channels that account for the effects of nicotine. Recent genetic studies have highlighted the importance of variants of the CHRNA5/A3/B4 genomic cluster in human nicotine dependence. Among these genetic variants those found in non-coding segments of the cluster may contribute to the pathophysiology of tobacco use through alterations in the expression of these genes. To discern the in vivo effects of the cluster, we generated a transgenic mouse overexpressing the human CHRNA5/A3/B4 cluster using a bacterial artificial chromosome. Transgenic mice showed increased functional α3β4-nAChRs in brain regions where these subunits are highly expressed under normal physiological conditions. Moreover, they exhibited increased sensitivity to the pharmacological effects of nicotine along with higher activation of the medial habenula and reduced activation of dopaminergic neurons in the ventral tegmental area after acute nicotine administration. Importantly, transgenic mice showed increased acquisition of nicotine self-administration (0.015 mg/kg per infusion) and a differential response in the progressive ratio test. Our study provides the first in vivo evidence of the involvement of the CHRNA5/A3/B4 genomic cluster in nicotine addiction through modifying the activity of brain regions responsible for the balance between the rewarding and the aversive properties of this drug.
authors.affiliation: Genes and Disease Program, Center for Genomic Regulation, Barcelona Biomedical Research Park, 08003 Barcelona, Catalonia, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Gallego
authors.forename: Susanna
authors.initials: S
authors.lastname: Molas
authors.forename: Alejandro
authors.initials: A
authors.lastname: Amador-Arjona
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Marks
authors.forename: Noemí
authors.initials: N
authors.lastname: Robles
authors.forename: Patricia
authors.initials: P
authors.lastname: Murtra
authors.forename: Lluís
authors.initials: L
authors.lastname: Armengol
authors.forename: Rubén D
authors.initials: RD
authors.lastname: Fernández-Montes
authors.forename: Mònica
authors.initials: M
authors.lastname: Gratacòs
authors.forename: Martí
authors.initials: M
authors.lastname: Pumarola
authors.forename: Roberto
authors.initials: R
authors.lastname: Cabrera
authors.forename: Rafael
authors.initials: R
authors.lastname: Maldonado
authors.forename: Josefa
authors.initials: J
authors.lastname: Sabrià
authors.forename: Xavier
authors.initials: X
authors.lastname: Estivill
authors.forename: Mara
authors.initials: M
authors.lastname: Dierssen
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001665:Binding Sites; D002540:Cerebral Cortex / Q000000981:diagnostic imaging / Q000378:metabolism; D003001:Cloning, Molecular; D003342:Corpus Striatum / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D015870:Gene Expression; D005818:Genetic Engineering; D006624:Hippocampus / Q000000981:diagnostic imaging / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D005810:Multigene Family; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009538:Nicotine / Q000009:adverse effects / Q000494:pharmacology*; D010641:Phenotype; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D011877:Radionuclide Imaging; D011978:Receptors, Nicotinic / Q000235:genetics* / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced; D012646:Self Administration; D014029:Tobacco Use Disorder / Q000235:genetics*
chemical_list: D009419:Nerve Tissue Proteins; D009538:Nicotine; D016760:Proto-Oncogene Proteins c-fos; D011978:Receptors, Nicotinic; C447158:CHRNA5 protein, human; C447159:CHRNB4 protein, human