Wang Cheng Z, Johnson Kenneth M
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555-1031, USA.
J Neurosci Res. 2005 Jul 15;81(2):284-92. doi: 10.1002/jnr.20559.
Acute and subchronic administration of N-methyl-D-aspartate antagonists to rats in the early postnatal period has been reported to produce widespread and selectively cortical neurotoxicity, respectively. To resolve this apparent discrepancy, we sought to clarify these data by determining the dose and temporal and regional characteristics of acute and subchronic phencyclidine (PCP)-induced neurotoxicity. Measurement of degenerating neurons with the cupric silver technique following a single dose of PCP on postnatal day (PN) 7 revealed that neurodegeneration increased in all areas measured (frontal, parietal and cingulate cortices, striatum, hippocampus, subiculum, and thalamus) within 9 hr. Silver staining peaked at 9-16 hr and was then not detectable or was greatly reduced after 24 hr depending on the specific region. Dose-response analysis at 9 hr showed that the lowest effective dose was 1, 3, and 10 mg/kg for the frontal cortex, hippocampus, and striatum, respectively. However, repeated PCP administration (10 mg/kg) on PN 7, 9, and 11 elicited an increase in silver staining only in the frontal cortex. To determine whether the loss of effect in the striatum and hippocampus was due to a "tolerance" mechanism or to a developmental phenomenon, we compared the effects of PCP given on PN 7, 9, or 11 with those of two doses given on PN 7 and 9 or three doses administered on PN 7, 9, and 11. Analysis of these experiments shows that both developmental factors and unknown mechanisms of tolerance underlie the apparent selective cortical neurotoxicity observed following subchronic PCP administration in perinatal rat pups.
据报道，在出生后早期给大鼠急性和亚慢性给予N-甲基-D-天冬氨酸拮抗剂分别会产生广泛的和选择性的皮质神经毒性。为了解决这一明显的差异，我们试图通过确定急性和亚慢性苯环己哌啶（PCP）诱导的神经毒性的剂量、时间和区域特征来澄清这些数据。在出生后第7天（PN7）单次给予PCP后，用铜银技术测量退化神经元，结果显示在9小时内，所有测量区域（额叶、顶叶和扣带回皮质、纹状体、海马体、下托和丘脑）的神经变性均增加。银染色在9 - 16小时达到峰值，然后在24小时后根据特定区域检测不到或大大减少。9小时时的剂量反应分析表明，额叶皮质、海马体和纹状体的最低有效剂量分别为1、3和10 mg/kg。然而，在PN7、9和11重复给予PCP（10 mg/kg）仅引起额叶皮质银染色增加。为了确定纹状体和海马体中效应丧失是由于“耐受”机制还是发育现象，我们比较了在PN7、9或11给予PCP的效果与在PN7和9给予两剂或在PN7、9和11给予三剂的效果。对这些实验的分析表明，发育因素和未知的耐受机制是围产期大鼠幼崽亚慢性给予PCP后观察到的明显选择性皮质神经毒性的基础。
