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

Amino Acids. 2012 Aug;43(2):897-909. doi: 10.1007/s00726-011-1149-y. Epub 2011 Nov 19.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Binding Sites
  • Cerebral Cortex / diagnostic imaging
  • Cerebral Cortex / metabolism
  • Cloning, Molecular
  • Corpus Striatum / metabolism
  • Dose-Response Relationship, Drug
  • Female
  • Gene Expression
  • Genetic Engineering
  • Hippocampus / diagnostic imaging
  • Hippocampus / metabolism
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Motor Activity / drug effects
  • Multigene Family*
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Nicotine / adverse effects
  • Nicotine / pharmacology*
  • Phenotype
  • Proto-Oncogene Proteins c-fos / genetics
  • Proto-Oncogene Proteins c-fos / metabolism
  • Radionuclide Imaging
  • Receptors, Nicotinic / genetics*
  • Receptors, Nicotinic / metabolism
  • Seizures / chemically induced
  • Self Administration
  • Tobacco Use Disorder / genetics*


  • CHRNA5 protein, human
  • CHRNB4 protein, human
  • Nerve Tissue Proteins
  • Proto-Oncogene Proteins c-fos
  • Receptors, Nicotinic
  • nicotinic receptor subunit alpha3
  • Nicotine