Beacon Discovery Inc, 6118 Nancy Ridge Drive, San Diego, CA, 92121, USA.
Department of Psychiatry, School of Medicine, University of California San Diego, 9500 Gilman Drive MC 0804, La Jolla, CA, 92093-0804, USA.
Psychopharmacology (Berl). 2021 Apr;238(4):979-990. doi: 10.1007/s00213-020-05744-0. Epub 2021 Jan 6.
Cognitive function is closely linked to functional outcomes in psychiatric disorders such as schizophrenia, however developing effective treatments for cognitive dysfunction have proven elusive. Potential reasons for this may include the complexity of diseases, the absence of appropriate and translatable animal tests of cognitive dysfunction, and the reproducibility of findings. Attention is a key component of cognitive function traditionally assessed in the clinic using a variant of the continuous performance test (CPT). The 5-choice (5C)-CPT was developed as a translational cross-species version of this task. Given the association between glutamatergic abnormalities and cognitive dysfunction in schizophrenia, we hypothesized that the NMDA receptor antagonist MK-801 would impair 5C-CPT in rats across different laboratories, and determined whether the dopamine D receptor agonist SKF38393 or the nonspecific nicotinic agonist nicotine would remediate such deficits.
Rats were trained in the 5C-CPT at Beacon Discovery and UCSD. These rats were then treated with MK-801, agonist treatment, and combinations of the two.
MK-801 produced 5C-CPT deficits in the same domains of rats across sites at similar doses. Neither nicotine nor SKF38393 treatment alone improved performance. Importantly, SKF38393, but not nicotine, remediated the MK-801-induced deficits.
Convergent observation of MK-801-induced deficits in 5C-CPT was seen across laboratories, resulting in deficits consistent with those seen in people with schizophrenia. Treatment with SKF38393 but not nicotine reversed these deficits. More work is needed, but the 5C-CPT is a reliable method for detecting NMDA receptor disruption-induced deficits in attention.
认知功能与精神疾病（如精神分裂症）的功能结果密切相关，然而，开发认知功能障碍的有效治疗方法一直难以实现。造成这种情况的潜在原因可能包括疾病的复杂性、缺乏适当和可转化的认知功能障碍动物测试，以及研究结果的可重复性。注意力是认知功能的一个关键组成部分，传统上在临床上使用连续作业测试（CPT）的变体进行评估。5 选择（5C）-CPT 是作为该任务的跨物种转化版本而开发的。鉴于谷氨酸能异常与精神分裂症认知功能障碍之间的关联，我们假设 NMDA 受体拮抗剂 MK-801 会损害不同实验室大鼠的 5C-CPT，并确定多巴胺 D 受体激动剂 SKF38393 或非特异性烟碱激动剂尼古丁是否会纠正这种缺陷。
大鼠在 Beacon Discovery 和 UCSD 接受 5C-CPT 训练。然后，这些大鼠接受 MK-801、激动剂治疗以及两者的组合治疗。
MK-801 在相似剂量下在不同地点的大鼠中产生了 5C-CPT 缺陷。单独使用尼古丁或 SKF38393 治疗均不能改善性能。重要的是，只有 SKF38393，而不是尼古丁，纠正了 MK-801 引起的缺陷。
在不同实验室中观察到 5C-CPT 中 MK-801 诱导的缺陷具有趋同观察结果，导致与精神分裂症患者所见的缺陷一致。用 SKF38393 治疗而不是尼古丁治疗可逆转这些缺陷。还需要做更多的工作，但 5C-CPT 是一种可靠的方法，可用于检测 NMDA 受体破坏引起的注意力缺陷。
