Fredriksson Anders, Archer Trevor
University of Uppsala, Department of Neuroscience and Psychiatry, Ulleråker, SE-750 17 Uppsala, Sweden.
Neurotox Res. 2003;5(7):549-64. doi: 10.1007/BF03033165.
Three experiments were performed to study the effects of neonatal administration of glutamate receptor antagonists, on either Day 11 (dizocilpine = MK-801, 3 x 0.5 mg/kg, s.c., injected at 0800, 1600 and 2400 h) or Day 10 (Ketamine, 1 x 50 mg/kg, s.c., or Ethanol-Low, 1 x 2.5 mg/kg, or, Ethanol-High, 2 x 2.5 mg/kg, s.c., with 2-h interval) to male mice pups, on spontaneous motor behavior, habituation to a novel situation and D-amphetamine-induced activity in the adult animals. Mice administered MK-801 showed initial hypoactivity followed by hyperactivity over the later (20-40 and 40-60 min) periods of testing. Mice administered Ketamine and Ethanol-High similarly displayed an initial hypoactivity followed by hyperactivity over the later time (20-60 min) of testing. Habituation to the novel activity test chambers was reduced drastically in the MK-801 mice compared with vehicle-treated mice. Similarly, mice administered Ketamine and Ethanol-High displayed too drastically reduced habituation behavior. The low dose of D-amphetamine (0.25 mg/kg) reduced the hyperactivity of neonatal MK-801-treated mice, particularly from 30-60 min onwards, and elevated the activity level of the vehicle-treated mice. Similarly, the low dose of D-amphetamine (0.25 mg/kg) reduced the hyperactivity of neonatally Ketamine-treated and Ethanol-High-treated mice, particularly from 30-60 min onwards, and elevated the activity level of the respective vehicle-treated mice. Fluoro-jade staining per mm(2) regional brain tissue of MK-801 mice pups expressed as percent of vehicle mice pups showed also that the extensiveness of staining was markedly greater in the parietal cortex, hippocampus, frontal cortex, and lesser so in the laterodorsal thalamus. Ketamine-treated mice showed cell degeneration mainly in the parietal cortex, whereas the Ethanol-High mice showed marked cell degeneration in both the parietal and laterodorsal cortex. The present findings that encompass a pattern of regional neuronal degeneration, disruptions of spontaneous motor activity, habituation deficits and reversal of hyperactivity by a low dose of D-amphetamine suggest a model of Attention Deficit Hyperactivity Disorder that underlines the intimate role of N-methyl-D-aspartate (NMDA) receptors in the developing brain.
进行了三项实验，以研究在出生后第11天（地佐环平=MK-801，3×0.5mg/kg，皮下注射，于08:00、16:00和24:00注射）或第10天（氯胺酮，1×50mg/kg，皮下注射；低剂量乙醇，1×2.5mg/kg；或高剂量乙醇，2×2.5mg/kg，皮下注射，间隔2小时）给雄性幼鼠注射谷氨酸受体拮抗剂，对成年动物的自发运动行为、对新环境的适应能力以及右旋苯丙胺诱导的活动的影响。注射MK-801的小鼠在测试后期（20 - 40分钟和40 - 60分钟）表现出最初的活动减少，随后活动增加。注射氯胺酮和高剂量乙醇的小鼠在测试后期（20 - 60分钟）同样表现出最初的活动减少，随后活动增加。与注射赋形剂的小鼠相比，MK-801小鼠对新活动测试室的适应能力大幅降低。同样，注射氯胺酮和高剂量乙醇的小鼠也表现出适应行为大幅减少。低剂量的右旋苯丙胺（0.25mg/kg）降低了新生期经MK-801处理的小鼠的活动亢进，特别是从30 - 60分钟起，并提高了注射赋形剂小鼠的活动水平。同样，低剂量的右旋苯丙胺（0.25mg/kg）降低了新生期经氯胺酮处理和高剂量乙醇处理的小鼠的活动亢进，特别是从30 - 60分钟起，并提高了各自注射赋形剂小鼠的活动水平。以注射赋形剂小鼠幼崽为对照，每平方毫米MK-801小鼠幼崽区域脑组织的氟玉染色显示，顶叶皮质、海马体、额叶皮质的染色范围明显更大，而背外侧丘脑的染色范围较小。氯胺酮处理的小鼠主要在顶叶皮质出现细胞变性，而高剂量乙醇处理的小鼠在顶叶皮质和背外侧皮质均出现明显的细胞变性。目前的研究结果包括区域神经元变性模式、自发运动活动的破坏、适应缺陷以及低剂量右旋苯丙胺对活动亢进的逆转，提示了一种注意力缺陷多动障碍模型，强调了N-甲基-D-天冬氨酸（NMDA）受体在发育中的大脑中的密切作用。
