Calcium mobilization elicited by two types of nicotinic acetylcholine receptors in mouse substantia nigra pars compacta

被引:92
作者
Tsuneki, H
Klink, R
Léna, C
Korn, H
Changeux, JP
机构
[1] Inst Pasteur, CNRS UA Neurobiol Mol D1284, F-75724 Paris 15, France
[2] Inst Pasteur, INSERM, U261, Unite Neurobiol Cellulaire, F-75724 Paris 15, France
关键词
Ca2+; choline; dopaminergic neurons; mesencephalon; nicotine;
D O I
10.1046/j.1460-9568.2000.00138.x
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Nicotinic acetylcholine receptors (nAChRs) are expressed in the midbrain ascending dopaminergic system, a target of many addictive drugs. Here we assessed the intracellular Ca2+ level by imaging fura-2-loaded cells in substantia nigra pars compacta in mouse brain slices, and we examined the influence on this level of prolonged exposures to nicotine using mice lacking the nAChR beta 2-subunit. In control cells, superfusion with nicotine (10-100 mu m) caused a long-lasting rise of intracellular Ca2+ level which depended on extracellular Ca2+. This nicotinic response was almost completely absent in beta 2-/- mutant mice, leaving a small residual response to a high concentration (100 mu m) of nicotine which was inhibited by the alpha 7-subunit-selective antagonist, methyllycaconitine. Conversely, the alpha 7-subunit-selective agonist choline (10 mm) caused a methyllycaconitine-sensitive increase in intracellular Ca2+ level both in wild-type and beta 2-/- mutant mice. Nicotine-elicited Ca2+ mobilization was reduced by the Na+ channel blocker tetrodotoxin (TTX) and by T-type Ca2+ channel blocking agents, whereas the choline-elicited Ca2+ increase was insensitive to TTX. Neither nicotine nor choline produced Ca2+ increase following inhibition of the release of Ca2+ from intracellular stores by dantrolene. These results demonstrate that in nigral dopaminergic neurons, nicotine can elicit Ca2+ mobilization via activation of two distinct nAChR subtypes: that of beta 2-subunit-containing nAChR followed by activation of Na+ channel and T-type Ca2+ channels, and/or activation of alpha 7-subunit-containing nAChR. The Ca2+ influx due to nAChR activation is subsequently amplified by the recruitment of intracellular Ca2+ stores. This Ca2+ mobilization may possibly contribute to the long-term effects of nicotine on the dopaminergic system.
引用
收藏
页码:2475 / 2485
页数:11
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