Long-term exposure to nicotine modulates the level and activity of acetylcholine receptors in white blood cells of smokers and model mice.
Long-term consumption of tobacco by smokers causes addiction and increases the level of neuronal nicotinic acetylcholine receptors (nAChRs) in the brain, a phenomenon known as up-regulation. Here, we show that up-regulation of specific nAChR subunits takes place in white blood cells (WBCs) of smokers and mice subjected to long-term administration of nicotine. The basal level of alpha-bungarotoxin binding site, which corresponds to the homomeric alpha7 nAChR subtype, was not affected in WBCs of both smokers and mice administered nicotine. In contrast, epibatidine (EB) binding sites, which correspond to heteromeric nAChR subtypes, were detected in WBCs of smokers but not in WBCs of nonsmokers. The number of EB binding sites significantly decreased after incubation of the smokers' WBCs for 3 days in nicotine-free culture medium. In WBCs of wild-type mice, basal level of EB binding sites was detected before nicotine administration. This basal level is reduced by approximately 60% in knockout mice lacking the genes encoding either the beta2 or the alpha4 receptor subunits. Additional analysis of knockout mice revealed that the remaining approximately 40% do not undergo up-regulation, indicating that the alpha4/beta2 subunits comprise the up-regulated nAChRs. We further found that upregulation in mouse WBCs is accompanied by a significant decrease in the capacity of the up-regulated receptor channels to convey calcium ions. The phenomenon of nAChR up-regulation in WBCs provides a simple tool to evaluate and study tobacco addiction.
Cormier
Anne
A
Récepteurs et Cognition, Unité de REecherche Associée D1284, Centre National de la Recherche Scientifique, Institut Pasteur, Paris, France.
Paas
Yoav
Y
Zini
Roland
R
Tillement
Jean-Paul
JP
Lagrue
Gilbert
G
Changeux
Jean-Pierre
JP
Grailhe
Régis
R
D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D007700:Kinetics; D051379:Mice; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D009538:Nicotine / Q000494:pharmacology*; D011950:Receptors, Cholinergic / Q000097:blood* / Q000187:drug effects; D012907:Smoking / Q000503:physiopathology*; D015854:Up-Regulation
D011950:Receptors, Cholinergic; D009538:Nicotine