Distribution and pharmacology of α6-containing nicotinic acetylcholine receptors analyzed with mutant mice
Distribution and pharmacology of α6-containing nicotinic acetylcholine receptors analyzed with mutant mice
复制标题
DOI：
10.1523/jneurosci.22-04-01208.2002
复制
发表时间：
2002-02-15
影响因子：
5.3
通讯作者：
Changeux, JP
中科院分区：
文献类型：
--
作者：
Champtiaux, N;Han, ZY;Changeux, JP
烟碱乙酰胆碱受体（nAChR）的α 6亚基在多巴胺能（DA）神经元中表达水平非常高。然而，由于缺乏选择性含有alpha6的nachr的药理学工具，该亚基在尼古丁成瘾病因学中的作用仍然未知。为了提供新的工具来研究这个问题，我们生成了一个alpha6 nAChR敲除小鼠。纯合子零突变体（alpha6-/-）没有表现出任何严重的神经或行为缺陷。对alpha6-/-小鼠大脑的仔细解剖和分子检查表明，在这些动物中没有发育改变，特别是在视觉和多巴胺能通路中，alpha6亚基通常以最高水平表达。另一方面，受体放射自显像显示α 6-/-动物视网膜神经节细胞终末区[H-3]尼古丁、[H-3]依比替丁和[H-3]胞氨酸高亲和力结合减少，而脑区高亲和力[I-125] α - conotoxxinmii （alphaCtxMII）结合完全消失。此外，使用未标记的alphaCtxMII或cytisine抑制纹状体膜上的[H-3]依巴替丁结合，发现在alpha6-/-小鼠中，虽然结合总量不变，但缺乏对alphaCtxMII敏感和对cytisine耐药的[H-3]依巴替丁结合位点。由于先前认为含有alpha3beta2的nAChRs特异性毒素alphaactxmii可以部分抑制尼古丁诱导的多巴胺释放，因此这些结果支持了alpha6而不是alpha3在DA神经元的尼古丁调节中是beta2的伴侣的结论。他们进一步表明，alpha6-/-小鼠可能是了解尼古丁成瘾机制的有用工具，尽管这些小鼠可能会发生一些发育补偿。
The alpha6 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 alpha6-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 alpha6 nAChR knock-out mouse. Homozygous null mutants (alpha6-/-) did not exhibit any gross neurological or behavioral deficits. A careful anatomic and molecular examination of alpha6-/- mouse brains demonstrated the absence of developmental alterations in these animals, especially in the visual and dopaminergic pathways, where the alpha6 subunit is normally expressed at the highest levels. On the other hand, receptor autoradiography revealed a decrease in [H-3] nicotine, [H-3] epibatidine, and [H-3] cytisine high-affinity binding in the terminal fields of retinal ganglion cells of alpha6-/- animals, whereas high-affinity [I-125]alpha-conotoxinMII (alphaCtxMII) binding completely disappeared in the brain. Moreover, inhibition of [H-3] epibatidine binding on striatal membranes, using unlabeled alphaCtxMII or cytisine, revealed the absence of alphaCtxMII-sensitive and cytisine-resistant [H-3] epibatidine binding sites in alpha6-/- mice, although the total amount of binding was unchanged. Because alphaCtxMII, a toxin formerly thought to be specific for alpha3beta2-containing nAChRs, is known to partially inhibit nicotine-induced dopamine release, these results support the conclusion that alpha6 rather than alpha3 is the partner of beta2 in the nicotinic modulation of DA neurons. They further show that alpha6-/- mice might be useful tools to understand the mechanisms of nicotine addiction, although some developmental compensation might occur in these mice.