RT Journal Article
SR Electronic
T1 Distribution and Pharmacology of α6-Containing Nicotinic Acetylcholine Receptors Analyzed with Mutant Mice
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 1208
OP 1217
DO 10.1523/JNEUROSCI.22-04-01208.2002
VO 22
IS 4
A1 Nicolas Champtiaux
A1 Zhi-Yan Han
A1 Alain Bessis
A1 Francesco Mattia Rossi
A1 Michele Zoli
A1 Lisa Marubio
A1 J. Michael McIntosh
A1 Jean-Pierre Changeux
YR 2002
UL http://www.jneurosci.org/content/22/4/1208.abstract
AB The α6 subunit of the nicotinic acetylcholine receptor (nAChR) is expressed at very high levels in dopaminergic (DA) neurons. However, because of the lack of pharmacological tools selective for α6-containing nAChRs, the role of this subunit in the etiology of nicotine addiction remains unknown. To provide new tools to investigate this issue, we generated an α6 nAChR knock-out mouse. Homozygous null mutants (α6−/−) did not exhibit any gross neurological or behavioral deficits. A careful anatomic and molecular examination of α6−/− mouse brains demonstrated the absence of developmental alterations in these animals, especially in the visual and dopaminergic pathways, where the α6 subunit is normally expressed at the highest levels. On the other hand, receptor autoradiography revealed a decrease in [3H]nicotine, [3H]epibatidine, and [3H]cytisine high-affinity binding in the terminal fields of retinal ganglion cells of α6−/− animals, whereas high-affinity [125I]α-conotoxinMII (αCtxMII) binding completely disappeared in the brain. Moreover, inhibition of [3H]epibatidine binding on striatal membranes, using unlabeled αCtxMII or cytisine, revealed the absence of αCtxMII-sensitive and cytisine-resistant [3H]epibatidine binding sites in α6−/− mice, although the total amount of binding was unchanged. Because αCtxMII, a toxin formerly thought to be specific for α3β2-containing nAChRs, is known to partially inhibit nicotine-induced dopamine release, these results support the conclusion that α6 rather than α3 is the partner of β2 in the nicotinic modulation of DA neurons. They further show that α6−/− mice might be useful tools to understand the mechanisms of nicotine addiction, although some developmental compensation might occur in these mice.