Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555-0617, USA.
Neuroscience. 2009 Nov 10;163(4):1181-91. doi: 10.1016/j.neuroscience.2009.07.058. Epub 2009 Aug 3.
The mechanism underlying phencyclidine (PCP)-induced apoptosis in perinatal rats and the development of schizophrenia-like behaviors is incompletely understood. We used antagonists for N-methyl-D-aspartate (NMDA) receptor subunit NR2A- and NR2B-containing NMDA receptor to test the hypothesis that the behavioral and apoptotic effects of PCP are mediated by blockade of NR1/NR2A-containing receptors, rather than NR1/NR2B-containing receptors. Sprague-Dawley rats were treated on PN7, PN9, and PN11 with PCP (10 mg/kg), PEAQX (NR2A-preferring antagonist; 10, 20, or 40 mg/kg), or ifenprodil (selective NR2B antagonist; 1, 5, or 10 mg/kg) and sacrificed for measurement of caspase-3 activity (an index of apoptosis) or allowed to age and tested for locomotor sensitization to PCP challenge on PN28-PN35. PCP or PEAQX on PN7, PN9, and PN11 markedly elevated caspase-3 activity in the cortex; ifenprodil showed no effect. Striatal apoptosis was evident only after subchronic treatment with a high dose of PEAQX (20 mg/kg). Animals treated with PCP or PEAQX on PN7, PN9, and PN11 showed a sensitized locomotor response to PCP challenge on PN28-PN35. Ifenprodil treatment had no effect on either measure. Therefore, PCP blockade of cortical NR1/NR2A, rather than NR1/NR2B, appears to be responsible for PCP-induced apoptosis and the development of long-lasting behavioral deficits.
苯环利定（PCP）诱导围生期大鼠凋亡和精神分裂样行为的机制尚不完全清楚。我们使用 N-甲基-D-天冬氨酸（NMDA）受体亚单位 NR2A 和 NR2B 含有 NMDA 受体的拮抗剂来检验以下假说，即 PCP 的行为和凋亡作用是由 NR1/NR2A 含有受体的阻断介导的，而不是由 NR1/NR2B 含有受体的阻断介导的。在 PN7、PN9 和 PN11 时，用 PCP（10mg/kg）、PEAQX（NR2A 偏好性拮抗剂；10、20 或 40mg/kg）或 ifenprodil（选择性 NR2B 拮抗剂；1、5 或 10mg/kg）处理 Sprague-Dawley 大鼠，并进行 caspase-3 活性（凋亡指标）的测量，或允许其生长并在 PN28-PN35 时测试对 PCP 挑战的运动敏化作用。PCP 或 PEAQX 在 PN7、PN9 和 PN11 时可显著提高皮质中的 caspase-3 活性；ifenprodil 则没有作用。纹状体的凋亡仅在亚慢性给予高剂量 PEAQX（20mg/kg）后才明显。在 PN7、PN9 和 PN11 时用 PCP 或 PEAQX 处理的动物在 PN28-PN35 时对 PCP 挑战的运动敏化反应增强。ifenprodil 处理对这两个指标均无影响。因此，PCP 阻断皮质 NR1/NR2A，而不是 NR1/NR2B，似乎是 PCP 诱导的凋亡和长期行为缺陷发展的原因。
