Comparison of methods for the assessment of locomotor activity in rodent safety pharmacology studies
Comparison of methods for the assessment of locomotor activity in rodent safety pharmacology studies
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DOI：
10.1016/j.vascn.2011.03.003
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发表时间：
2011-07-01
影响因子：
1.9
通讯作者：
Mittelstadt, Scott W.
中科院分区：
文献类型：
--
作者：
Lynch, James J., III;Castagne, Vincent;Mittelstadt, Scott W.
前言：临床前药物开发的靶点验证(早期发现)阶段接近尾声时，一般神经行为测试，如改良的欧文测试或功能观察组，是中枢神经系统(CNS)安全药理学测试所必需的。然而，在早期阶段，当必须对更多的测试化合物进行潜在的中枢神经系统副作用筛选时，运动活性评估可能是比较化合物的更好工具。方法：比较给予氯丙嗪(2-8 mg/kg)和咖啡因(3-24 mg/kg)的两种自动测试系统--红外射束活动仪(Actimeter)和机械振动仪(LABORAS)--所获得的自发活动计数。用改良的Irwin测验观察神经行为的影响。结果：在三种实验中，氯丙嗪和咖啡因分别观察到剂量依赖的镇静作用和兴奋相关作用。这两个自动活动检测系统在确定运动活动的变化方面表现出类似的灵敏度，但在检测咖啡因诱导的垂直活动(养育行为)方面，LABORAS比Actimeter更灵敏。讨论：基于红外线光束的活动检测系统和LABORAS提供了有关运动活动的相对可比的定量数据。在临床前药物开发的最早阶段，在决定使用哪种系统筛选测试化合物时，应考虑实际考虑因素，如相对成本与通用性程度。(C)2011 Elsevier Inc.保留所有权利。
Introduction: General neurobehavioral assays, like a modified Irwin test or a functional observational battery, are necessary for central nervous system (CNS) safety pharmacology testing near the end of the target validation (early discovery) stage of preclinical drug development. However, at earlier stages, when a greater number of test compounds must be screened for potential CNS side effects, locomotor activity assessment may be a better tool for the comparison of compounds. Methods: Spontaneous locomotor activity counts obtained from two automated test systems - an infrared beam-based activity meter (Actimeter) and the mechanical vibration-based LABORAS - were compared in rats dosed with chlorpromazine (2-8 mg/kg) or caffeine (3-24 mg/kg), p.o. A modified Irwin test was also performed to visually observe the neurobehavioral effects. Results: In all three assays, dose-dependent sedation- and excitation-related effects were observed with chlorpromazine and caffeine, respectively. The two automated activity-detection systems exhibited similar sensitivities in determining changes in locomotor activity, but with the LABORAS being more sensitive than the Actimeter in detecting caffeine-induced increases in vertical activity (rearing behavior). Discussion: Infrared beam-based activity detection systems and LABORAS provide relatively-comparable quantitative data regarding locomotor activity. Practical considerations, such as relative cost versus degree of versatility, should be considered when deciding which system to use for the screening of test compounds during the earliest stages of preclinical drug development. (C) 2011 Elsevier Inc. All rights reserved.