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

Xavier Gallego, Susanna Molas, Alejandro Amador-Arjona, Michael J. Marks, Noemí Robles, Patricia Murtra, Llus Armengol, Ruben D. Fernandez-Montes, Monica Gratacòs, Mart Pumarola, Roberto Cabrera, Rafael Maldonado, Josefa Sabrià, Xavier Estivill, Mara Dierssen

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26 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)897-909
Number of pages13
JournalAmino Acids
Volume43
Issue number2
DOIs
Publication statusPublished - 1 Aug 2012

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Keywords

  • A3
  • A5
  • B4 Nicotinic receptor subunits
  • CHRNA5/A3/B4 genomic cluster
  • MHb
  • Nicotine addiction
  • VTA

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Gallego, X., Molas, S., Amador-Arjona, A., Marks, M. J., Robles, N., Murtra, P., Armengol, L., Fernandez-Montes, R. D., Gratacòs, M., Pumarola, M., Cabrera, R., Maldonado, R., Sabrià, J., Estivill, X., & Dierssen, M. (2012). Overexpression of the CHRNA5/A3/B4 genomic cluster in mice increases the sensitivity to nicotine and modifies its reinforcing effects. Amino Acids, 43(2), 897-909. https://doi.org/10.1007/s00726-011-1149-y