Selective serotonin 5-HT2A receptor antagonist EMD 281014 improves delayed matching performance in young and aged rhesus monkeys
Selective serotonin 5-HT2A receptor antagonist EMD 281014 improves delayed matching performance in young and aged rhesus monkeys
复制标题
DOI：
10.1007/s00213-004-2114-1
复制
发表时间：
2005-06-01
影响因子：
3.4
通讯作者：
Bartoszyk, GD
中科院分区：
文献类型：
--
作者：
Terry, AV;Buccafusco, JJ;Bartoszyk, GD
基本原理：精神分裂症文献中报道的非典型精神抑制剂的上级认知作用优于典型药物，这通常归因于非典型药物对5-羟色胺（2A）受体的更突出的拮抗剂活性。然而，非典型神经安定药也对许多其他神经递质受体具有活性，并且很少有研究专门（和前瞻性）测试了单独的5 HT 2A拮抗作用导致认知功能增强的假设。目的：本研究的目的是评价选择性5-HT 2A拮抗剂7-{4-[ 2-（4-氟-苯基）-乙基]-哌嗪-1-羰基}-1H-吲哚-3-腈盐酸盐（EMD 281014）在年轻和老年猴中的工作记忆功能测试。研究方法：在6只年轻成年猕猴（平均年龄= 9.2岁）和8只老年恒河猴（平均年龄= 24.9岁）中评价了4种经口给药（0.1、1.0、3.0和10.0 mg/kg）的EMD 281014，这些猕猴接受了计算机辅助延迟样本匹配（DMTS）任务的培训。结果：根据剂量，EMD 281014主要在中等或长保留时间间隔内改善了年轻和老年猴的DMTS准确性。虽然在基线条件下，与不正确的颜色选择相关的潜伏期（选择潜伏期）往往长于与正确选择相关的潜伏期（特别是在老年受试者中），但EMD 281014对两个年龄组的样本或选择潜伏期均无显著影响。此外，在两个动物队列中评价的剂量范围内均未观察到不良反应。结论：这些在非人灵长类动物模型中进行的实验表明，选择性5 HT（2A）拮抗剂如EMD 281014可以通过改善工作记忆功能为年轻和老年精神病患者提供治疗益处。
Rationale: The superior cognitive effects of atypical neuroleptics over typical agents reported in the schizophrenia literature are often attributed to the more prominent antagonist activity of the atypical drugs at serotonin 5HT(2A) receptors. However, atypical neuroleptics also have activity at many additional neurotransmitter receptors and few studies have specifically ( and prospectively) tested the hypothesis that 5HT2A antagonism alone results in enhanced cognitive function. Objectives: The purpose of this study was to evaluate the selective 5-HT2A antagonist, 7-{4-[ 2-(4-fluoro-phenyl)-ethyl]-piperazine-1-carbonyl}-1H-indole-3-carbonitrile HCl (EMD 281014) in young and aged monkeys in a test designed to assess working memory function. Methods: Four oral doses (0.1, 1.0, 3.0, and 10.0 mg/kg) of EMD 281014 were evaluated in six young adult (mean age = 9.2 years) and eight aged rhesus macaques (mean age = 24.9 years) trained to perform a computer-assisted delayed matching-to-sample (DMTS) task. Results: Depending on dose, EMD281014 improved DMTS accuracy in young and aged monkeys primarily at either the medium or long retention intervals. While the latencies associated with incorrect color selections (choices latencies) tended to be longer than those associated with correct selections (particularly in the aged subjects) under baseline conditions, there were no significant effects of EMD 281014 on either sample or choice latencies in either age group. In addition, no adverse effects were observed across the range of doses evaluated in either cohort of animals. Conclusion: These experiments, conducted in a non-human primate model, suggest that selective 5HT(2A) antagonists such as EMD 281014 could offer therapeutic benefit to younger and older psychiatric patients by improving working memory function.