Long-term effects of chronic nicotine exposure on brain nicotinic receptors

^†“Récepteurs et Cognition,” Centre National de la Recherche Scientifique Unité de Recherche Associée 2182, “Unité de Neurobiologie Intégrative des Systémes Cholinergiques,” Institut Pasteur, 75724 Paris, France;
^§Department of Physiology and Pharmacology, Karolinska Institute, S-171 77 Stockholm, Sweden;
^¶Centre National de la Recherche Scientifique Unité Mixte de Recherche 5106, Neurosciences Cognitives, Université Bordeaux 1, 33405 Talence, France

Contributed by Jean-Pierre Changeux, March 27, 2007 (received for review March 2, 2007)

Abstract

Chronic nicotine exposure results in long-term homeostatic regulation of nicotinic acetylcholine receptors (nAChRs) that play a key role in the adaptative cellular processes leading to addiction. However, the relative contribution of the different nAChR subunits in this process is unclear. Using genetically modified mice and pharmacological manipulations, we provide behavioral, electrophysiological, and pharmacological evidence for a long-term mechanism by which chronic nicotine triggers opposing processes differentially mediated by β2*- vs. α7*nAChRs. These data offer previously undescribed insights into the understanding of nicotine addiction and the treatment of several human pathologies by nicotine-like agents chronically acting on β2*- or α7*nAChRs.

Footnotes

^‡To whom correspondence may be addressed. E-mail: granon{at}pasteur.fr, changeux{at}pasteur.fr, and phfaure{at}pasteur.fr
Author contributions: M.B. and S.G. contributed equally to this work; M.B., S.G., J.-P.C., and P.F. designed research; M.B., S.G., M.M.-E., I.C.-T., N.M., A.C., P.C., and V.D. performed research; M.B., I.C.-T., and P.F. analyzed data; and M.B., S.G., I.C.-T., J.-P.C., and P.F. wrote the paper.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/cgi/content/full/0702698104/DC1.
Abbreviations:

nAChR,

nicotinic acetylcholine receptor;

β2*nAChR,

β2-subunit containing nAChR;

CA,

activity in the central zone;

CI,

inactivity in the central zone;

DA,

dopamine;

MLA,

methyllycaconitine;

PA,

activity in the peripheral zone;

VTA,

ventral tegmental area.
Freely available online through the PNAS open access option.