Glutamate receptor subunits are altered in forebrain and cerebellum in rats chronically exposed to the NMDA receptor antagonist phencyclidine
Glutamate receptor subunits are altered in forebrain and cerebellum in rats chronically exposed to the NMDA receptor antagonist phencyclidine
复制标题
DOI：
10.1038/sj.npp.1300485
复制
发表时间：
2004-11-01
影响因子：
7.6
通讯作者：
Keifer, J
中科院分区：
文献类型：
--
作者：
Lindahl, JS;Keifer, J
苯环利定(PCP)是N-甲基-D-天冬氨酸(NMDA)谷氨酸受体亚型的非竞争性拮抗剂。它会在正常人中产生一过性精神病，并会加剧精神分裂症患者的精神病。当给啮齿动物注射五氯苯酚时，会引起刻板印象的行为，包括无情的摇头、多动症和社交退缩。在本研究中，我们检测了慢性染毒大鼠前脑、海马区和小脑中NMDA受体亚基及其调节受体α-氨基-3-羟基-5-甲基-4-异恶唑丙酸酯(AMPA)的相对分布。大鼠注射五氯苯酚(10 mg/kg)30d，年龄/性别匹配的对照组注射生理盐水30d。免疫细胞化学和Western印迹分析脑内NMDA和AMPA受体亚单位的分布模式和蛋白水平。慢性PCP处理的动物表现出显著的谷氨酸受体亚单位的变化，特别是NMDA受体的NR1、NR2B、NR2C和NR2D成分。AMPA受体亚基在亚基可利用性方面几乎没有显著变化。免疫印迹分析在很大程度上证实了免疫细胞化学的结果，这些结果支持慢性PCP拮抗作用选择性地改变NMDA受体亚基的结论，而AMPA受体亚基的变化很小或没有变化。我们的发现与以下解释是一致的，即功能失调的NMDA受体复合体可能介导了异常的谷氨酸能神经传递，并可能有助于认知障碍的复杂病因。
Phencyclidine (PCP) is a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) glutamate receptor subtype. It produces transient psychoses in normal individuals and exacerbates psychoses in schizophrenics. When administered to rodents, PCP elicits stereotypic behaviors including unrelenting head swaying, hyperlocomotion, and social withdrawal. In this study, we examined the relative distribution of the NMDA receptor subunits, as well as the subunits of its modulating receptor, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) in the forebrain, hippocampus, and cerebellum of rats chronically exposed to PCP. Rats were injected for 30 days with PCP (10 mg/kg) and age/sex-matched controls were injected for 30 days with saline vehicle. Brain NMDA and AMPA receptor subunit distribution patterns and protein levels were then analyzed by immunocytochemistry and Western blot analysis. Chronic PCP-treated animals showed significant alterations in glutamate receptor subunits, particularly for the NR1, NR2B, NR2C, and NR2D components of the NMDA receptor. AMPA receptor subunits demonstrated few significant changes in subunit availabilities. Western blot analysis largely confirmed the immunocytochemical findings, These results support the conclusion that subunits of the NMDA receptor are selectively altered by chronic PCP antagonism, with minimal to no changes observed in AMPA receptor subunits. Our findings are consistent with the interpretation that a dysfunctional NMDA receptor complex may mediate abnormal glutamatergic neurotransmission and potentially contribute to the complex etiology of cognitive disorders.