A reversible model of the cognitive impairment associated with schizophrenia in monkeys: potential therapeutic effects of two nicotinic acetylcholine receptor agonists.
A reversible model of the cognitive impairment associated with schizophrenia in monkeys: potential therapeutic effects of two nicotinic acetylcholine receptor agonists.
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DOI：
10.1016/j.bcp.2009.06.102
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发表时间：
2009-10-01
影响因子：
5.8
通讯作者：
Terry, Alvin V., Jr.
中科院分区：
文献类型：
--
作者：
Buccafusco, Jerry J.;Terry, Alvin V., Jr.
在精通计算机辅助延迟反应任务的猴子中，在2 mg/kg剂量后，给予亚镇静剂量的氯胺酮显着损害了任务表现，导致所有四个延迟间隔的准确性下降。氯胺酮引起任务延迟的偶尔和不一致的增加。但总的来说，处理速度不受试验剂量的显著影响。α7烟碱受体激动剂GTS-21 (DMXB-A) [3-[(3E)-3-[（2,4-二甲氧基苯基）亚甲基]-5,6-二氢- 4h -吡啶-2-基]吡啶]预处理对氯胺酮引起的任务精度下降产生剂量依赖性衰减。事实上，最佳剂量的GTS-21完全逆转了氯胺酮的作用。尼古丁代谢物可替宁是一种认知增强剂，在预测抗精神病活性的模型中具有活性。可替宁预处理不能逆转氯胺酮产生的任务缺陷，选择最佳剂量是必要的，以显示可替宁的活性。然而，最佳剂量的可替宁，如GTS-21，完全逆转了氯胺酮引起的任务缺陷。在24小时后进行的会议中，相对于非氯胺酮基线，任务准确性有所提高。可替宁-氯胺酮的给药顺序被颠倒，以提供一个更具有临床相关性的模型，可替宁治疗后方案产生了氯胺酮诱导的任务缺陷的明显逆转。长期任务的改善也很明显。氯胺酮引起的DMTS任务损伤能够被两种已知能改善工作记忆和认知的化合物完全逆转。该模型可以为解决与主要精神疾病相关的认知障碍的新化合物的晚期临床前评估提供一种手段。
In monkeys proficient in the performance of a computer-assisted delayed response task, administration of sub-sedative doses of ketamine significantly impaired task performance after the 2 mg/kg dose, producing a decrease in accuracies across all four delay intervals. Ketamine elicited occasional and inconsistent increases in task latencies. But in general processing speed was not dramatically affected by the test dose. Pretreatment with the α7 nicotinic receptor agonist GTS-21 (DMXB-A) [3-[(3E)-3-[(2,4-dimethoxyphenyl) methylidene]-5,6-dihydro-4H-pyridin-2-yl]pyridine] produced a dose-dependent attenuation of ketamine-induced decreases in task accuracies. In fact, the best dose of GTS-21 completely reversed the effects of ketamine. The nicotine metabolite cotinine is a cognitive-enhancer, and active in models predictive of antipsychotic activity. Pretreatment with cotinine did not reverse the task deficits produced by ketamine, and selection of a best dose was necessary to show the activity of cotinine. However, the best dose of cotinine, like GTS-21, completely reversed the ketamine-induced task deficits. Task accuracies were increased relative to their non-ketamine baselines during sessions run 24 hr later. The cotinine-ketamine order of administration was reversed to provide a more clinically relevant model, and cotinine post-treatment regimen produced a clear reversal of the ketamine-induced task deficits. The protracted task improvement also was still evident. The DMTS task impairment induced by ketamine was capable of being completely reversed by two compounds that are known to improve working memory and cognition. The model could provide a means of late stage preclinical evaluation of new compounds that address the cognitive impairment associated with major psychotic disease.
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