Neurobehavioural deficits associated with apoptotic neurodegeneration and vulnerability for ADHD
Neurobehavioural deficits associated with apoptotic neurodegeneration and vulnerability for ADHD
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DOI：
10.1007/bf03033280
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发表时间：
2004-01-01
影响因子：
3.7
通讯作者：
Archer, T
中科院分区：
文献类型：
--
作者：
Fredriksson, A;Archer, T
本文报道了N-甲基-D-天冬氨酸(NMDA)拮抗剂地佐西平(MK-801；3×0.5 mg/kg，分别于出生后11天8：00、16：00和24：00)，或氯胺酮(1×50 mg/kg)或乙醇(1×2.5 g/kg，乙醇低，或2 x 2.5 g/kg，间隔2小时，乙醇高)在出生后10天给药的几项研究。NMDA拮抗剂处理后24小时处死各处理组/赋形剂组小鼠，取脑组织作荧光染色分析。从60日龄开始进行功能分析。所有三种对NMDA受体、MK-801、氯胺酮和乙醇-High产生拮抗作用的处理都在运动活动测试室中诱导了类似的初始低活动模式，随后是显著和持久的高活动状态。在每个病例中，基础多动水平都被小剂量D-苯丙胺(0.25 mg/kg)急性治疗所消除。MK-801、氯胺酮和乙醇-高三种处理均导致在仪器学习的放射臂迷宫测试中的获得性成绩下降。小剂量D-苯丙胺可消除MK-801所致的出生后缺陷。MK-801、氯胺酮和乙醇-高三个处理组在环游的前三个试验日中，潜水平台保持不变的位置，但在第四个试验日，由于平台位置移动到不同的“象限”，导致了显著的缺陷。荧光翡翠染色分析表明，出生后服用NMDA拮抗剂的小鼠几个脑区出现毁灭性的细胞变性，包括海马区、额叶皮质、顶叶皮质和小脑。乙醇或安定(5 mg/kg)引起的丘脑外侧背侧神经元严重变性似乎不影响不同方面的功能。出生后NMDA拮抗剂治疗后的功能障碍结局和凋亡细胞丢失的模式提供了一个看似合理的相似的主要方面，在ADHD，多动，注意力不集中和冲动，从而提供了一个有趣的动物模型的障碍。
Several studies involving postnatal administration of the N-methyl-D-aspartate (NMDA) antagonists, dizocilpine (MK-801; 3 x 0.5 mg/kg, at 08.00, 16.00 and 24.00h) on Postnatal day 11, or Ketamine (1 x 50 mg/kg) or Ethanol (1 x 2.5 g/kg, Ethanol-Low, or 2 x 2.5 g/kg, 2-h interval, Ethanol-High) on Postnatal day 10, are described. Some mice from each treatment/vehicle group were sacrificed 24h after NMDA antagonist treatment and brain regions were taken for fluoro-jade staining analysis. Functional analysis was initiated at 60 days of age. All three treatments inducing an antagonistic action at NMDA receptors, MK-801, Ketamine and Ethanol-High induced a similar pattern of initial hypoactivity followed by marked and lasting hyperactivity in the motor activity test chambers. In each case, the basal hyperactivity level was abolished by acute treatment with a low dose of D-amphetamine (0.25 mg/kg). All three treatments, MK-801, Ketamine and Ethanol-High, induced a deficit in acquisitive performance in the radial arm maze test of instrumental learning. The deficit induced by postnatal MK-801 was abolished by acute treatment with the low dose of D-amphetamine. All three treatments, MK-801, Ketamine and Ethanol-High, resulted in normal acquisitive performance during the first three test days in the circular swim with the submerged platform maintained in a constant position, but on the fourth test day, with the platform position shifted to a different "quadrant", induced marked deficits. Fluoro-jade staining analyses indicated a devastating cell degeneration in several brain regions of mice administered NMDA antagonists postnatally, including the hippocampus, frontal cortex, parietal cortex, and cerebellum. Severe cell degeneration in the laterodorsal thalamus due to Ethanol or diazepam (5 mg/kg) appeared not to affect the different aspects of function. The pattern of dysfunctional outcome and apoptotic cell loss following postnatal NMDA antagonist treatment offers a plausible similarity to the major aspects of 'syndromatic continuity' in ADHD, hyperactivity, inattention and impulsivity, thereby providing an interesting animal model of the disorder.