The alpha3 and beta4 nicotinic acetylcholine receptor subunits are necessary for nicotine-induced seizures and hypolocomotion in mice

Neuropharmacology. 2004 Sep;47(3):401-7. doi: 10.1016/j.neuropharm.2004.05.002.


Binding of nicotine to nicotinic acetylcholine receptors (nAChRs) elicits a series of dose-dependent behaviors that go from altered exploration, sedation, and tremors, to seizures and death. nAChRs are pentameric ion channels usually composed of alpha and beta subunits. A gene cluster comprises the alpha3, alpha5 and beta4 subunits, which coassemble to form functional receptors. We examined the role of the beta4 subunits in nicotine-induced seizures and hypolocomotion in beta4 homozygous null (beta4 -/-) and alpha3 heterozygous (+/-) mice. beta4 -/- mice were less sensitive to the effects of nicotine both at low doses, measured as decreased exploration in an open field, and at high doses, measured as sensitivity to nicotine-induced seizures. Using in situ hybridization probes for the alpha3 and alpha5 subunits, we showed that alpha5 mRNA levels are unchanged, whereas alpha3 mRNA levels are selectively decreased in the mitral cell layer of the olfactory bulb, and the inferior and the superior colliculus of beta4 -/- brains. alpha3 +/- mice were partially resistant to nicotine-induced seizures when compared to wild-type littermates. mRNA levels for the alpha5 and the beta4 subunits were unchanged in alpha3 +/- brains. Together, these results suggest that the beta4 and the alpha3 subunits are mediators of nicotine-induced seizures and hypolocomotion.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Analysis of Variance
  • Animals
  • Dose-Response Relationship, Drug
  • Female
  • Gene Expression / genetics
  • In Situ Hybridization / methods
  • Locomotion / drug effects*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Nicotine / toxicity*
  • Nicotinic Agonists / toxicity*
  • Protein Subunits / chemistry
  • Protein Subunits / physiology*
  • RNA, Messenger / metabolism
  • Receptors, Nicotinic / chemistry
  • Receptors, Nicotinic / physiology*
  • Seizures / chemically induced*
  • Sex Factors


  • Nicotinic Agonists
  • Protein Subunits
  • RNA, Messenger
  • Receptors, Nicotinic
  • Nicotine