The nicotinic acetylcholine receptor subunit α5 mediates short-term effects of nicotine in vivo
The nicotinic acetylcholine receptor subunit α5 mediates short-term effects of nicotine in vivo
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DOI：
10.1124/mol.63.5.1059
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发表时间：
2003-05-01
影响因子：
3.6
通讯作者：
De Biasi, M
中科院分区：
文献类型：
--
作者：
Salas, R;Orr-Urtreger, A;De Biasi, M
尼古丁作用于五聚体神经元烟碱型乙酰胆碱受体(NAChRs)，是烟草中主要的成瘾成分。在低剂量时，它会影响注意力、学习、记忆、焦虑、心血管反应、体温调节和伤害感。在高剂量下，尼古丁会产生更剧烈的行为，最终导致啮齿类动物的强直-阵挛发作。在哺乳动物中，已经克隆了nAChRs的几个亚基，包括八个阿尔法亚基和三个贝塔亚基。为了研究alpha5亚单位的生理作用，我们培育了alpha5缺陷小鼠。这些小鼠的外表总体上是健康的，在标准的行为测试中也是正常的。然而，与野生型小鼠相比，alpha5突变小鼠对尼古丁诱导的行为和癫痫发作的敏感度显著降低。这些动物具有正常的脑解剖结构和其他nAChR亚单位的正常mRNA水平，即α4、α6、α7、β2和β4。此外，在Alpha5缺陷小鼠的大脑中，I-125-epbatidine和[I-125]α-银环蛇毒素的结合是正常的。综上所述，这些结果表明Alpha5亚基直接参与了观察到的表型。
Nicotine, acting at pentameric neuronal nicotinic acetylcholine receptors (nAChRs), is the primary addictive component in tobacco. At low doses, it affects attention, learning, memory, anxiety, cardiovascular responses, thermoregulation, and nociception. At high doses, nicotine produces more drastic behaviors and eventually induces tonic-clonic seizures in rodents. In mammals, several subunits of the nAChRs have been cloned, including eight alpha and three beta subunits. To study the physiological role of the alpha5 subunit, we have generated alpha5-deficient mice. These mice have a generally healthy appearance and are normal in a standard battery of behavioral tests. However, the sensitivity of alpha5 mutant mice to nicotine-induced behaviors and seizures is dramatically reduced compared with their wild-type littermates. These animals have a normal brain anatomy and normal levels of mRNA for other nAChR subunits, namely alpha4, alpha6, alpha7, beta2, and beta4. In addition, I-125-epibatidine and [I-125]alpha-bungarotoxin binding in the brains of alpha5-deficient mice is normal. Together, these results suggest a direct involvement of the alpha5 subunit in the observed phenotypes.