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Long-Term Exposure to Nicotine Modulates the Level and Activity of Acetylcholine Receptors in White Blood Cells of Smokers and Model Mice

Récepteurs et Cognition, Unité de Recherche Associée D1284, Centre National de la Recherche Scientifique, Institut Pasteur, Paris, France (A.C., Y.P., J.-P.C., R.G.); Laboratoire de Pharmacologie, Faculté de Médecine de Paris XII, Créteil, France (R.Z., J.-P.T.); and Centre de Tabacologie, Albert Chenevier Hospital, Créteil, France (G.L.)

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 -bungarotoxin binding site, which corresponds to the homomeric 7 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 60% in knockout mice lacking the genes encoding either the 2 or the 4 receptor subunits. Additional analysis of knockout mice revealed that the remaining 40% do not undergo up-regulation, indicating that the 4/2 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.

Address correspondence to: Dr. Régis Grailhe, Institut Pasteur, 25 rue du Dr. Roux, 75724 Paris, France. E-mail: regis{at}grailhe.com

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