Effects of 5-HT6 receptor antagonism and cholinesterase inhibition in models of cognitive impairment in the rat
Effects of 5-HT6 receptor antagonism and cholinesterase inhibition in models of cognitive impairment in the rat
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DOI：
10.1038/bjp.2008.281
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发表时间：
2008-10-01
影响因子：
7.3
通讯作者：
Ramirez, M. J.
中科院分区：
文献类型：
--
作者：
Marcos, B.;Chuang, T. T.;Ramirez, M. J.
背景和目的：5-HT6受体拮抗剂在认知方面的有益作用仍存在争议。本研究旨在重新评估选择性5-羟色胺受体拮抗剂SB-271046急性治疗与亚慢性治疗对未受损大鼠的认知增强特性，以及针对东莨菪碱(胆碱能)或MK-801(谷氨酸介导的)缺陷的治疗。实验方法：使用Morris水迷宫，测量行为获得和保持以及游泳速度。其他行为测量包括打哈欠和运动。SB-271046在每次试验前急性给药或在试验前亚慢性给药7天。乙酰胆碱酯酶抑制剂加兰他敏单独或与SB-271046联合应用。关键结果：SB-271046亚慢性治疗可改善Morris水迷宫中的获得，而急性治疗仅改善保持能力。急性或亚慢性SB-271046治疗均不能逆转东莨菪碱所致的学习障碍。MK-801引起的学习障碍与行为综合征有关，可通过急性但不是亚慢性的SB-271046治疗而逆转。有趣的是，加兰他明和SB-271046的联合治疗逆转了东莨菪碱或MK-801诱导的学习障碍。SB-271046的亚慢性治疗并未改变单次使用SB-271046引起的运动活动或打哈欠次数的增加，这是一种胆碱能介导的行为。结论和意义：这些数据表明，5-HT6受体拮抗剂如SB-271046单独或与加兰他明联合使用，在治疗认知功能障碍方面具有潜在的治疗作用，如阿尔茨海默病和精神分裂症。
Background and purpose: The beneficial effect of 5-HT6 receptor antagonism in cognition remains controversial. This study has been undertaken to reassess the cognition enhancing properties of acute vs subchronic treatment with the selective 5-HT6 receptor antagonist SB-271046 in unimpaired rats, as well as against scopolamine (cholinergic-) or MK-801 (glutamatergicmediated) deficits.Experimental approach: The Morris water maze was used, measuring behaviour acquisition and retention, and swim speed. Other behavioural measures included yawning and motor activity. SB-271046 was given acutely before each trial or subchronically for 7 days before the trials. The AChE inhibitor galanthamine was also used alone or in combination with SB-271046.Key results: Subchronic treatment with SB-271046 improved acquisition in the Morris water maze, while the acute treatment only improved retention. Neither acute nor subchronic SB-271046 treatment reversed scopolamine-induced learning deficits. MK-801 induced learning impairment associated with a behavioural syndrome, reversed by acute, but not subchronic, SB-271046 treatment. Interestingly, combined treatment with galanthamine and SB-271046 reversed the scopolamine- or MK-801-induced learning impairments. Subchronic treatment with SB-271046 did not modify motor activity or the increased number of yawns, a cholinergic-mediated behaviour, induced by single administration of SB-271046.Conclusions and implications: These data suggest a potential therapeutic role of 5-HT6 receptor antagonists such as SB-271046, alone or in combination with galanthamine, in the treatment of cognitive dysfunction, such as those seen in Alzheimer's disease and schizophrenia.