Lilly Centre for Cognitive Neuroscience, Lilly Research Laboratories, Eli Lilly & Co. Ltd., Erl Wood Manor, Sunninghill Road, Windlesham, Surrey, GU20 6PH, UK.
Psychopharmacology (Berl). 2011 Sep;217(2):255-69. doi: 10.1007/s00213-011-2277-5. Epub 2011 Apr 12.
N-methyl-D: -Aspartate receptor (NMDAR) antagonists such as ketamine induce cognitive symptoms in man similar to those of schizophrenia and therefore might be useful as models of the disease in animals. However, it is unclear which NMDAR antagonist(s) offer the best means to produce cognitive deficits in attention and working memory and to what extent those deficits can be measured selectively in rats.
The present study systematically compared the effects of eight different NMDAR antagonists-MK-801, phencyclidine, (S)-(+)-ketamine, memantine, SDZ-220,581, Ro 25-6981, CP 101-606 and NVP-AAM077-in rats using standard tests of visual attention, the five-choice serial reaction time task (5CSRT), and working memory, the delayed matching to position task (DMTP).
Drug-induced responses varied qualitatively and quantitatively in both a compound- and a task-dependent manner. Effects were generally confounded by concomitant motor and motivational disruption, although individual doses of phencyclidine for example appeared to impair selectively cognitive functions. Interestingly, GluN2B selective antagonists were unique in their effects; inducing potential performance benefit in the 5CSRT.
Overall, the opportunity to induce a selective cognitive deficit in attention (5CSRT) or working memory (DMTP) in the rat is limited by both the NMDAR antagonist and the dose range used. The importance of a preclinical focus on ketamine, which is used more frequently in clinical settings, is limited by the extent to which cognitive effects can be both detected and quantified using this exposure regimen within these two operant assays.
N-甲基-D-天冬氨酸受体（NMDAR）拮抗剂，如氯胺酮，在人体内引起类似于精神分裂症的认知症状，因此可能作为动物疾病模型有用。然而，尚不清楚哪种 NMDAR 拮抗剂能最好地产生注意力和工作记忆的认知缺陷，以及这些缺陷在多大程度上可以在大鼠中选择性地测量。
本研究系统比较了八种不同的 NMDAR 拮抗剂-MK-801、苯环利定、(S)-(+)-氯胺酮、美金刚、SDZ-220581、Ro 25-6981、CP 101-606 和 NVP-AAM077-在大鼠中的作用，使用视觉注意力的标准测试、五选择连续反应时间任务（5CSRT）和工作记忆的延迟匹配位置任务（DMTP）。
药物诱导的反应在化合物和任务依赖性方面均具有定性和定量的差异。虽然例如苯环利定的个别剂量似乎选择性地损害认知功能，但效应通常与运动和动机障碍同时发生。有趣的是，GluN2B 选择性拮抗剂的作用独特；在 5CSRT 中诱导潜在的性能获益。
总的来说，在大鼠中诱导选择性注意力（5CSRT）或工作记忆（DMTP）认知缺陷的机会受到 NMDAR 拮抗剂和使用剂量范围的限制。在这两个操作性测定中，使用这种暴露方案可以检测和量化认知效应的程度，这限制了对临床环境中更频繁使用的氯胺酮进行临床前关注的重要性。
