Overexpression of the CHRNA5/A3/B4 genomic cluster in mice increases the sensitivity to nicotine and modifies its reinforcing effects

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 a3b4-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. © Springer-Verlag 2011.This work was funded by the Catalan Government (2009SGR1313) Spanish Ministry of Education and Sciences SAF2007-60827, SAF2007-31093-E, SAF2010-16427; Phecomp (EU LSHM-CT-2007-037669), EU/FIS PS09102673, ERARare, Ministerio de Salud y Consumo (RTA G03/005, PI05/0513 and PI082038), University of the Basque Country (1/UPV 0026.327-E-15924/2004) and Plan Nacional sobre Drogas (PNDMSC 2005), Fundacion Ramón Areces, Reina Sofía, Marató TV3, and CIBERER. P. M. is a scientific researcher supported by the Juan de la Cierva program of Ministerio de Ciencia e Innovación, and a grant from the National Institutes on Drug Abuse (R01 DA003194 to MJM).Peer Reviewe