Gallaher E J, Henauer S A, Jacques C J, Hollister L E
J Pharmacol Exp Ther. 1986 May;237(2):462-7.
Diazepam was administered to Swiss-Webster mice for 53 days as a mixture of drug in laboratory chow, leading to consumption as high as 1000 mg/kg/day. Low plasma concentrations of diazepam, but very high levels (generally between 5,000 and 10,000 ng/ml) of the active metabolites nordiazepam and oxazepam, were found. Animals appeared healthy throughout drug administration, but some died because of apparent drug-induced aggression. Withdrawal was precipitated by omitting drug from the food. The behavior and physiological state of each animal were observed in detail during treatment and withdrawal phases. Tests that showed stable results in control animals and changes during abstinence were used to measure the withdrawal syndrome. These changes included piloerection, tremor, pelvic elevation and tail elevation, as well as changes in body tone, abdominal tone and pupil size. A composite withdrawal score was plotted against time; this score increased significantly (P less than .01) 1 day after withdrawal and remained significantly elevated for 17 days. This technique provides a quantitative method to study the effect of withdrawal from benzodiazepines in mice.
将地西泮混入实验室饲料中，连续53天喂给瑞士韦伯斯特小鼠，导致其摄入量高达1000毫克/千克/天。结果发现小鼠血浆中的地西泮浓度较低，但活性代谢产物去甲地西泮和奥沙西泮的水平非常高（一般在5000至10000纳克/毫升之间）。在给药期间动物看起来健康，但有些因明显的药物诱发攻击行为而死亡。通过从食物中撤药引发戒断反应。在治疗和戒断阶段详细观察每只动物的行为和生理状态。采用在对照动物中结果稳定且在禁欲期间有变化的测试来衡量戒断综合征。这些变化包括竖毛、震颤、骨盆抬高和尾巴抬高，以及身体张力、腹部张力和瞳孔大小的变化。绘制了综合戒断评分随时间的变化图；该评分在撤药后1天显著增加（P小于0.01），并在17天内一直显著升高。该技术提供了一种定量方法来研究小鼠中苯二氮䓬类药物戒断的影响。
