Nilsson Marie, Markinhuhta Katarina Rydén, Carlsson Maria L
The Arvid Carlsson Institute for Neuroscience at the Institute of Clinical Neuroscience, The Sahlgrenska Academy at Göteborg University, Medicinaregatan 11, Box 432, SE-405 30 Göteborg, Sweden.
Prog Neuropsychopharmacol Biol Psychiatry. 2006 May;30(3):521-30. doi: 10.1016/j.pnpbp.2005.11.010. Epub 2006 Jan 18.
Cognitive dysfunction plays an important role in mental disorders like schizophrenia and may involve inadequate glutamatergic signalling in different regions of the brain, mediated by e.g. glutamatergic N-methyl-D-aspartate (NMDA) receptors. In rodents, NMDA receptor antagonists often increase motor activity; in addition they induce a more primitive and undifferentiated behavioural pattern, which we believe may correspond to some of the cognitive defects seen in schizophrenia. In the present study, the movement pattern of mice treated with the uncompetitive NMDA receptor antagonist MK-801 in conjunction with six antipsychotic agents, some with reported clinical effects on cognition, was characterised and quantified. The classical neuroleptic drugs chlorpromazine and trifluoperazine, the atypical antipsychotic agents ziprasidone and olanzapine, the gamma-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-receptor potentiator CX516 and the serotonin (5-HT)2A-antagonist M100907 were tested. In accordance with previous observations, MK-801 was found to induce a primitive and monotonous behavioural pattern dominated by forward locomotion; spatial movements, the number of switches between the states moving and stationary, and rearing frequency were reduced. All test substances counteracted MK-801-induced hyperactivity, but differed in their ability to improve behavioural quality. Chlorpromazine and trifluoperazine were unable to restore behavioural diversity while ziprasidone, olanzapine, CX516 and M100907 restored it to varying degrees. A striking similarity in movement pattern was seen between the hypoglutamatergic mice treated with the AMPA-receptor agonist CX516, and those receiving the 5HT2A-antagonist M100907.
认知功能障碍在精神分裂症等精神疾病中起重要作用，可能涉及大脑不同区域谷氨酸能信号传导不足，例如由谷氨酸能N-甲基-D-天冬氨酸（NMDA）受体介导。在啮齿动物中，NMDA受体拮抗剂通常会增加运动活性；此外，它们会诱导出一种更原始、未分化的行为模式，我们认为这可能与精神分裂症中出现的一些认知缺陷相对应。在本研究中，对用非竞争性NMDA受体拮抗剂MK-801联合六种抗精神病药物治疗的小鼠的运动模式进行了表征和量化，其中一些抗精神病药物据报道对认知有临床作用。测试了经典抗精神病药物氯丙嗪和三氟拉嗪、非典型抗精神病药物齐拉西酮和奥氮平、γ-氨基-3-羟基-5-甲基异恶唑-4-丙酸（AMPA）受体增强剂CX516和5-羟色胺（5-HT）2A拮抗剂M100907。与先前的观察结果一致，发现MK-801会诱导出一种以向前运动为主的原始且单调的行为模式；空间运动、移动和静止状态之间的转换次数以及竖毛频率均降低。所有测试物质都抵消了MK-801诱导的多动，但在改善行为质量的能力方面存在差异。氯丙嗪和三氟拉嗪无法恢复行为多样性，而齐拉西酮、奥氮平、CX516和M100907在不同程度上恢复了行为多样性。在用AMPA受体激动剂CX516治疗的低谷氨酸能小鼠和接受5HT2A拮抗剂M100907的小鼠之间，观察到运动模式有惊人的相似性。
