The scopolamine-reversal paradigm in rats and monkeys: the importance of computer-assisted operant-conditioning memory tasks for screening drug candidates
The scopolamine-reversal paradigm in rats and monkeys: the importance of computer-assisted operant-conditioning memory tasks for screening drug candidates
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DOI：
10.1007/s00213-007-0887-8
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发表时间：
2008-08-01
影响因子：
3.4
通讯作者：
Warner, Samantha E.
中科院分区：
文献类型：
--
作者：
Buccafusco, Jerry J.;Terry, Alvin V., Jr.;Warner, Samantha E.
东莨菪碱逆转模型作为阿尔茨海默病（AD）的可逆药理学模型，在临床研究中重新引起了人们的兴趣。与东莨菪碱相关的认知损害与AD相似。东莨菪碱模型是不是简单的胆碱能模型，因为它可以被逆转的药物，是noncholinergic cognition-enhancing agents.Objectives本研究的目的是确定相关的计算机辅助操作条件反射任务在东莨菪碱逆转模型大鼠和猴子。材料与方法在Morris水迷宫中观察大鼠空间参考记忆任务的获得情况。一个单独的队列是熟练的自动延迟刺激辨别任务（DSDT）的性能。恒河猴熟练的自动延迟匹配到样本的任务（DMTS）的性能。结果AD药物多奈哌齐进行了评估，其能力，以扭转东莨菪碱管理在所有三个任务的准确性下降。在DSDT和DMTS任务中，多奈哌齐的作用是延迟（保留间隔）依赖性的，主要影响短延迟试验。多奈哌齐产生了显着的，但部分逆转东莨菪碱诱导的损害后，2毫克/公斤的水迷宫中，1毫克/公斤后，在DSDT，和50微克/公斤后，在DMTS task.Conclusions的任务（DSDT和DMTS）提供的数据最符合这些药物的临床研究报告。应用于非人灵长类动物的模型为临床试验前的新认知增强药物提供了一个很好的过渡模型。
Rationale The scopolamine-reversal model is enjoying a resurgence of interest in clinical studies as a reversible pharmacological model for Alzheimer's disease (AD). The cognitive impairment associated with scopolamine is similar to that in AD. The scopolamine model is not simply a cholinergic model, as it can be reversed by drugs that are noncholinergic cognition-enhancing agents.Objectives The objective of the study was to determine relevance of computer-assisted operant-conditioning tasks in the scopolamine-reversal model in rats and monkeys. Materials and methods Rats were evaluated for their acquisition of a spatial reference memory task in the Morris water maze. A separate cohort was proficient in performance of an automated delayed stimulus discrimination task (DSDT). Rhesus monkeys were proficient in the performance of an automated delayed matching-to-sample task (DMTS).Results The AD drug donepezil was evaluated for its ability to reverse the decrements in accuracy induced by scopolamine administration in all three tasks. In the DSDT and DMTS tasks, the effects of donepezil were delay (retention interval)-dependent, affecting primarily short delay trials. Donepezil produced significant but partial reversals of the scopolamine-induced impairment in task accuracies after 2 mg/kg in the water maze, after 1 mg/kg in the DSDT, and after 50 mu g/kg in the DMTS task.Conclusions The two operant-conditioning tasks (DSDT and DMTS) provided data most in keeping with those reported in clinical studies with these drugs. The model applied to nonhuman primates provides an excellent transitional model for new cognition-enhancing drugs before clinical trials.