Salas Ramiro, Pieri Fredalina, De Biasi Mariella
Division of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, USA.
J Neurosci. 2004 Nov 10;24(45):10035-9. doi: 10.1523/JNEUROSCI.1939-04.2004.
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 x kg(-1) x 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.
长期接触烟草的主要成瘾成分尼古丁后戒断，会在人体产生独特症状。这些症状的出现是人们试图戒烟时的主要阻碍。为了研究哪种类型的尼古丁受体与戒断综合征的发作相关，我们使用了尼古丁戒断的小鼠模型。对野生型小鼠以及β4（β4-/-）或β2（β2-/-）烟碱型乙酰胆碱受体亚基缺失的小鼠，植入渗透微型泵，持续13天给予24 mg·kg⁻¹·d⁻¹的尼古丁。随后，单次腹腔注射烟碱型受体拮抗剂美加明，诱发戒断行为症状，表现为梳理毛发、咀嚼、抓挠和颤抖增加，以及出现一些独特行为，如跳跃、腿部震颤和抓挠笼子。注射美加明在野生型和β2-/-小鼠中引发了类似的戒断症状，而β4-/-小鼠的躯体症状明显较轻。此外，尼古丁戒断在野生型小鼠而非β4-/-小鼠中产生了痛觉过敏。最后，慢性尼古丁给药使野生型和β4-/-小鼠大脑多个区域的埃博霉素结合增加，但这种受体上调与戒断症状的严重程度无关。我们的结果表明，含β4的烟碱型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，β2亚基似乎对这一现象影响不大。我们还表明，慢性尼古丁导致的埃博霉素结合位点上调，这一与含β2受体相关的效应，可能与戒断的潜在机制无关。
