Exposure of NMDA receptor antagonists during developmental stages leads to behavioral consequences like attention deficit hyperactivity disorder (ADHD). However, the underlying molecular mechanisms have remained poorly understood. Herein, we studied the phosphorylated Akt (pAkt) and caspase-3, the key regulators of neuronal cell survival/death, as the probable downstream targets of MK-801 often used to engender ADHD-like condition. Swiss albino mice at postnatal days (PND) 7, 14 or 21 were injected with a single dose of MK-801 and evaluated for hyperactivity (open field test) and memory deficit at adolescence (PND 30) and adult stages (PND 60). PND 7 or 14 treatment groups (but not PND 21) consistently showed hyperactivity at the adolescence stage. A significant increase in working and reference memory errors in radial arm maze was noted at the adolescence age. PND 7 group continued to display the symptoms even in adulthood. All the treatment groups showed a significant decrease in the percent alterations (Y-maze) and discrimination index (novel object recognition test) at adolescence age. A significant increase in caspase-3 expression was noted in the prefrontal cortex (PFC) and hippocampus, whereas increased pAkt was noticed only in the hippocampus, following a single injection of MK-801 at PND 7. Concurrently, PND 7 treatment group showed significantly decreased neuronal nuclei (NeuN) expression (a marker for mature neurons) in the dentate gyrus, cornu ammonis-3 and PFC, but not in cornu ammonis-1, at adolescence age. We suggest that the observed symptoms of ADHD at adolescence and adulthood stages may be linked to alteration in pAkt and caspase-3 followed MK-801 treatment at PND 7.

在发育阶段接触NMDA受体拮抗剂会导致行为后果，例如注意力不足过动症（ADHD）。但是，基本的分子机制仍然知之甚少。在这里，我们研究了磷酸化的Akt（pAkt）和caspase-3，它们是神经元细胞存活/死亡的关键调节因子，作为MK-801可能的下游靶标，经常用于引起ADHD样疾病。在出生后第7天，第14天或第21天给瑞士白化病小鼠注射单剂量的MK-801，并评估其过度活跃（开放视野测试）和青春期（PND 30）和成年阶段（PND 60）的记忆力减退。PND 7或14个治疗组（而非PND 21）在青春期始终表现出活动过度。在青春期，radial臂迷宫的工作和参考记忆错误显着增加。PND 7组甚至在成年期仍继续表现出症状。所有治疗组在青春期的变化百分率（Y迷宫）和辨别指数（新奇物体识别测试）均显着降低。在PND 7处单次注射MK-801后，前额叶皮层（PFC）和海马中caspase-3表达显着增加，而pAkt仅在海马中发现。同时，PND 7治疗组显示在青春期，齿状回，cornu ammonis-3和PFC中神经元核（NeuN）的表达降低（成熟神经元的标志物），而在cornu ammonis-1中则没有。