Mice lacking neuronal nicotinic acetylcholine receptor beta4-subunit and mice lacking both alpha5- and beta4-subunits are highly resistant to nicotine-induced seizures.
Nicotine, the main addictive component of tobacco, evokes a wide range of dose-dependent behaviors in rodents, and when administrated in high doses, it can induce clonic-tonic seizures. Nicotine acts through the nicotinic acetylcholine receptors (nAChRs). Mutations in the human alpha4- and the beta2-nAChR subunit genes cause autosomal dominant nocturnal frontal lobe epilepsy. Using transgenic mice with mutations in nAChR subunits, it was demonstrated previously that the alpha4-, alpha5-, and alpha7-subunits are involved in nicotine-induced seizures. To examine the possibility that the beta4-subunit is also involved in this phenotype, we tested mice with homozygous beta4-subunit deficiency. The beta4 null mice were remarkably resistant to nicotine-induced seizures compared with wild-type and alpha5 null mice. We also generated mice with double deficiency of both alpha5- and beta4-nAChR subunits and demonstrated that they were more resistant to nicotine's convulsant effect than either the alpha5 or the beta4 single mutant mice. In addition, the single alpha5 mutants and the double alpha5beta4-deficient mice exhibited a significantly shorter latency time to seizure than that of the wild-type mice. Our results thus show that beta4-containing nAChRs have a crucial role in the pathogenesis of nicotine-induced seizures. Furthermore, by comparing multiple mutant mice with single and double subunit deficiency, we suggest that nicotinic receptors containing either alpha5- or beta4-subunits are involved in nicotine-induced seizures and that receptors containing both subunits are likely to contribute to this phenomena as well. However, the alpha5-subunit, but not the beta4-subunit, regulates the rate of response to high doses of nicotine.
Kedmi
Merav
M
Genetic Institute, Tel Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Beaudet
Arthur L
AL
Orr-Urtreger
Avi
A
D000818:Animals; D001921:Brain / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D007700:Kinetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009538:Nicotine / Q000633:toxicity*; D018722:Nicotinic Agonists / Q000633:toxicity*; D021122:Protein Subunits / Q000235:genetics / Q000502:physiology; D011978:Receptors, Nicotinic / Q000235:genetics / Q000502:physiology*; D012640:Seizures / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism
D009538:Nicotine; D018722:Nicotinic Agonists; D021122:Protein Subunits; D011978:Receptors, Nicotinic