Damaj M I, Kao W, Martin B R
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Box 980613, Richmond, VA 23298-0613, USA.
J Pharmacol Exp Ther. 2003 Nov;307(2):526-34. doi: 10.1124/jpet.103.054908. Epub 2003 Sep 11.
The nicotine withdrawal syndrome was validated and characterized in the mouse using both somatic and affective measures after infusion with nicotine daily via subcutaneous minipumps. The influence of dose, duration of infusion, and repeated withdrawal as well as the contribution of genetic factors were investigated. We then characterized the contribution of nicotinic receptor and site mechanisms to withdrawal signs using various nicotinic antagonists. Our results showed that spontaneous nicotine withdrawal increased the number of somatic signs, decreased the time spent in open arms of the plus-maze test, and induced hyperalgesia. The effect was dose-dependent in all measures with no significant changes at the lowest dose of nicotine (6 mg/kg/day). Withdrawal signs were prominent shortly after pump removal and remained prominent through day 3 or 4. The results with the different antagonists (mecamylamine, dihydro-beta-erythroidine, and methyllycaconitine) suggest the involvement of several nicotinic subtypes such as alpha3beta4*, alpha4beta2*, and alpha7 in nicotine withdrawal. Increasing the duration of nicotine exposure (from 7 to 60 days) and the total nicotine exposure (increasing doses of infusing) augmented the severity of nicotine withdrawal signs. The withdrawal severity of nicotine differs between C57/BL and 129/SvEv inbred mice with nicotine withdrawal in C57 being more severe than in the 129 strain. In summary, our present results suggest that withdrawal from nicotine can be modulated by genetic factors, daily nicotine intake, duration of nicotine exposure, and withdrawal history. The present study demonstrates that our mouse nicotine withdrawal model will be useful for studying the pharmacological, biochemical, and genetic mechanisms involved in nicotine dependence.
通过皮下微型泵每日给小鼠输注尼古丁后，利用躯体和情感测量方法对尼古丁戒断综合征进行了验证和特征描述。研究了剂量、输注持续时间、反复戒断的影响以及遗传因素的作用。然后，我们使用各种烟碱拮抗剂来确定烟碱受体和位点机制对戒断症状的作用。我们的结果表明，自发尼古丁戒断增加了躯体症状的数量，减少了在十字迷宫试验开放臂中停留的时间，并诱发了痛觉过敏。在所有测量中，这种效应呈剂量依赖性，在最低尼古丁剂量（6毫克/千克/天）时无显著变化。戒断症状在移除泵后不久就很明显，并在第3天或第4天一直很明显。不同拮抗剂（美加明、二氢β-刺桐碱和甲基lycaconitine）的结果表明，几种烟碱亚型如α3β4*、α4β2*和α7参与了尼古丁戒断。增加尼古丁暴露的持续时间（从7天增加到60天）和总的尼古丁暴露量（增加输注剂量）会加剧尼古丁戒断症状的严重程度。C57/BL和129/SvEv近交系小鼠的尼古丁戒断严重程度不同，C57小鼠的尼古丁戒断比129品系更严重。总之，我们目前的结果表明，尼古丁戒断可受遗传因素、每日尼古丁摄入量、尼古丁暴露持续时间和戒断史的调节。本研究表明，我们的小鼠尼古丁戒断模型将有助于研究尼古丁依赖所涉及的药理、生化和遗传机制。
