Amino Acids

, Volume 43, Issue 2, pp 897–909

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

Authors

  • Xavier Gallego
    • Genes and Disease ProgramCenter for Genomic Regulation (CRG)
    • CIBER de Enfermedades Raras (CIBERER), CRG and UPF
    • Institute for Behavioral GeneticsUniversity of Colorado at Boulder
  • Susanna Molas
    • Genes and Disease ProgramCenter for Genomic Regulation (CRG)
    • CIBER de Enfermedades Raras (CIBERER), CRG and UPF
  • Alejandro Amador-Arjona
    • Genes and Disease ProgramCenter for Genomic Regulation (CRG)
    • CIBER de Enfermedades Raras (CIBERER), CRG and UPF
  • Michael J. Marks
    • Institute for Behavioral GeneticsUniversity of Colorado at Boulder
  • Noemí Robles
    • Department of BiochemistryAutonomous University of Barcelona (UAB)
  • Patricia Murtra
    • Unit of NeuropharmacologyPompeu Fabra University (UPF)
    • Institute of NeuroscienceMiguel Hernández University, Consejo Superior de Investigaciones Científicas (CSIC)
  • Lluís Armengol
    • Genes and Disease ProgramCenter for Genomic Regulation (CRG)
    • Unit of GeneticsPompeu Fabra University (UPF)
  • Rubén D. Fernández-Montes
    • Genes and Disease ProgramCenter for Genomic Regulation (CRG)
    • CIBER de Enfermedades Raras (CIBERER), CRG and UPF
  • Mònica Gratacòs
    • Genes and Disease ProgramCenter for Genomic Regulation (CRG)
    • Unit of GeneticsPompeu Fabra University (UPF)
  • Martí Pumarola
    • Department of Animal Medicine and SurgeryAutonomous University of Barcelona (UAB)
  • Roberto Cabrera
    • Unit of NeuropharmacologyPompeu Fabra University (UPF)
  • Rafael Maldonado
    • Unit of NeuropharmacologyPompeu Fabra University (UPF)
  • Josefa Sabrià
    • Department of BiochemistryAutonomous University of Barcelona (UAB)
  • Xavier Estivill
    • Genes and Disease ProgramCenter for Genomic Regulation (CRG)
    • Unit of GeneticsPompeu Fabra University (UPF)
    • Genes and Disease ProgramCenter for Genomic Regulation (CRG)
    • CIBER de Enfermedades Raras (CIBERER), CRG and UPF
Original Article

DOI: 10.1007/s00726-011-1149-y

Cite this article as:
Gallego, X., Molas, S., Amador-Arjona, A. et al. Amino Acids (2012) 43: 897. doi:10.1007/s00726-011-1149-y

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.

Keywords

α5α3β4 Nicotinic receptor subunitsCHRNA5/A3/B4 genomic clusterVTAMHbNicotine addiction

Copyright information

© Springer-Verlag 2011