Decreased signs of nicotine withdrawal in mice null for the β4 nicotinic acetylcholine receptor subunit
Decreased signs of nicotine withdrawal in mice null for the β4 nicotinic acetylcholine receptor subunit
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DOI：
10.1523/jneurosci.1939-04.2004
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发表时间：
2004-11-10
影响因子：
5.3
通讯作者：
De Biasi, M
中科院分区：
文献类型：
--
作者：
Salas, R;Pieri, F;De Biasi, M
尼古丁是烟草的主要成瘾性成分，从尼古丁的长期接触中戒断后，人类会产生独特的症状。这些症状的出现是人们试图戒烟的主要障碍。为了研究哪种类型的尼古丁受体与戒断综合征的发作有关，我们使用了尼古丁戒断小鼠模型。野生型小鼠和β 4 （β 4 -/-）或β 2 （β 2 -/-）尼古丁乙酰胆碱受体亚基缺失的小鼠被植入渗透性微型泵，输送24 mg.kg（-1）。d（-1）尼古丁，持续13 d。随后，单次腹腔注射尼古丁受体拮抗剂甲胺诱导戒断行为症状，测量为增加梳理，咀嚼，抓挠和摇晃，以及一些独特行为的出现，如跳跃，腿部震颤和抓笼子。甲胺注射在野生型和β 2 -/-小鼠中引发了类似的戒断症状，而β 4 -/-小鼠表现出明显较轻的躯体症状。此外，尼古丁戒断在野生型小鼠中产生痛觉过敏，而在β 4 -/-小鼠中没有。最后，在野生型和β 4 -/-小鼠中，慢性尼古丁在大脑的几个区域产生了增加的依比替丁结合，但这种受体的上调与戒断症状的严重程度无关。我们的研究结果表明含有β 4的尼古丁乙酰胆碱受体在尼古丁戒断症状的出现中起主要作用。相比之下，β 2亚基似乎对这一现象影响不大。我们还表明，慢性尼古丁引起的依比替丁结合位点的上调，与含β 2受体有关，可能与戒断的机制无关。
Withdrawal from chronic exposure to nicotine, the main addictive component of tobacco, produces distinctive symptoms in humans. The appearance of these symptoms is a major deterrent when people try to quit smoking. To study which type of nicotine receptor is relevant for the onset of the withdrawal syndrome, we used a mouse model of nicotine withdrawal. Wild-type mice and mice null for the beta4 (beta4 -/-) or the beta2 (beta2 -/-) nicotinic acetylcholine receptor subunits were implanted with osmotic minipumps delivering 24 mg.kg(-1).d(-1) nicotine for 13 d. Subsequently, a single intraperitoneal injection of the nicotinic receptor antagonist mecamylamine induced behavioral symptoms of withdrawal measured as increased grooming, chewing, scratching, and shaking, plus the appearance of some unique behaviors such as jumping, leg tremors, and cage scratching. Mecamylamine injection triggered comparable withdrawal signs in wild-type and in beta2 -/- mice, whereas the beta4 -/- mice displayed significantly milder somatic symptoms. In addition, nicotine withdrawal produced hyperalgesia in wild-type but not beta4 -/- mice. Finally, chronic nicotine produced an increase in epibatidine binding in several areas of the brain in both wild-type and in beta4 -/- mice, but such receptor upregulation did not correlate with the severity of withdrawal signs.Our results demonstrate a major role for beta4-containing nicotinic acetylcholine receptors in the appearance of nicotine withdrawal symptoms. In contrast, the beta2 subunit does not seem to greatly influence this phenomenon. We also show that the upregulation of epibatidine binding sites attributable to chronic nicotine, an effect associated with beta2-containing receptors, is probably not related to the mechanisms underlying withdrawal.