Witkin Jeffrey M, Morrow Denise, Li Xia
Neuroscience Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285-0510, USA.
Psychopharmacology (Berl). 2004 Feb;172(1):52-7. doi: 10.1007/s00213-003-1618-4. Epub 2003 Sep 18.
Effects of compounds on punished responding have been predictive of anxiolytic efficacy in humans. The use of mice in these tests has been limited, but the utility of this species in drug discovery and for neurobiological inquiry would benefit from a rapid, reliable method.
The present experiments were designed to validate a new procedure in mice.
Male, NIH Swiss mice were food deprived and placed in an experimental chamber with two nose-poke holes. Every nose poke (FR1) produced a 20 mg food pellet. On the following day, a drug vehicle was administered and the mice were again exposed to the FR1 schedule. On day 3, a compound was given and the mice were run under a mixed FR1 (food), FR1 (food+shock) schedule in alternating, unsignalled periods of 4 and 10 min for three cycles. In the 10-min periods, nose-pokes produced both food plus brief electrification of the grid floor (0.5 mA for 100 ms). Effects of compounds on food intake were also evaluated in separate groups of mice.
The introduction of shock substantially decreased responding during the 10-min punishment periods without significantly affecting responding during the non-punishment periods. The clinically effective anxiolytic agents chlordiazepoxide, pentobarbital, and bretazenil, but not buspirone, produced dose-dependent increases in suppressed responding, whereas d-amphetamine, chlorpromazine, and morphine were not effective. Chlordiazepoxide and bretazenil increased food consumption.
The present method enables rapid and reliable evaluation of potential anxiolytic agents in mice with minimal training. Increases in food intake are not necessary for anxiolytic-like effects under these conditions.
化合物对受惩罚反应的影响已被证明可预测其在人类中的抗焦虑功效。在这些测试中使用小鼠的情况有限，但该物种在药物发现和神经生物学研究中的实用性将受益于一种快速、可靠的方法。
本实验旨在验证一种小鼠新程序。
雄性NIH瑞士小鼠禁食后置于带有两个鼻触孔的实验箱中。每次鼻触（固定比率1）会产生一粒20毫克的食物颗粒。第二天，给予药物载体，小鼠再次接受固定比率1的程序。第三天，给予一种化合物，小鼠在固定比率1（食物）、固定比率1（食物+电击）的混合程序下交替进行，无信号提示的4分钟和10分钟周期各进行三个循环。在10分钟周期内，鼻触既会产生食物，同时网格地板会短暂通电（0.5毫安，持续100毫秒）。还在单独的小鼠组中评估了化合物对食物摄入量的影响。
电击的引入在10分钟惩罚期内显著减少了反应，而对非惩罚期的反应没有显著影响。临床有效的抗焦虑药物氯氮卓、戊巴比妥和布立哌唑，但不包括丁螺环酮，产生了剂量依赖性的被抑制反应增加，而右旋苯丙胺、氯丙嗪和吗啡则无效。氯氮卓和布立哌唑增加了食物消耗。
本方法能够在最少训练的情况下对小鼠潜在的抗焦虑药物进行快速可靠的评估。在这些条件下，抗焦虑样效应并不一定需要食物摄入量增加。
