Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA.
Neurotoxicol Teratol. 2011 Nov-Dec;33(6):668-73. doi: 10.1016/j.ntt.2011.06.004. Epub 2011 Jul 7.
As more adults take the stimulant medication methylphenidate to treat attention deficit hyperactivity disorder (ADHD) residual type, the risk arises with regard to exposure during early development if people taking the medication become pregnant. We studied the neurobehavioral effects of methylphenidate in zebrafish. Zebrafish offer cellular reporter systems, continuous visual access and molecular interventions such as morpholinos to help determine critical mechanisms underlying neurobehavioral teratogenicity. Previously, we had seen that persisting neurobehavioral impairment in zebrafish with developmental chlorpyrifos exposure was associated with disturbed dopamine systems. Because methylphenidate is an indirect dopamine agonist, it was thought that it might also cause persistent behavioral impairment after developmental exposure. Zebrafish embryos were exposed to the ADHD stimulant medication methylphenidate 0-5 days post fertilization (12.5-50mg/l). They were tested for long-term behavioral effects as adults. Methylphenidate exposure (50mg/l) caused significant increases in dopamine, norepinepherine and serotonin on day 6 but not day 30 after fertilization. In the novel tank diving test of predatory avoidance developmental methylphenidate (50mg/l) caused a significant reduction in the normal diving response. In the three-chamber spatial learning task early developmental methylphenidate (50mg/l) caused a significant impairment in choice accuracy. These data show that early developmental exposure of zebrafish to methylphenidate causes a long-term impairment in neurobehavioral plasticity. The identification of these functional deficits in zebrafish enables further studies with this model to determine how molecular and cellular mechanisms are disturbed to arrive at this compromised state.
随着越来越多的成年人服用兴奋剂药物哌醋甲酯来治疗注意力缺陷多动障碍（ADHD）残留型，如果服用该药物的人怀孕，早期发育过程中暴露于药物的风险就会出现。我们研究了哌醋甲酯对斑马鱼的神经行为影响。斑马鱼提供了细胞报告系统、连续的视觉通道以及分子干预手段，如 morpholino，以帮助确定神经行为致畸性的关键机制。此前，我们曾发现，在接触持续神经行为损伤的斑马鱼中，发育性毒死蜱暴露与多巴胺系统紊乱有关。由于哌醋甲酯是一种间接的多巴胺激动剂，因此人们认为它在发育暴露后也可能导致持续的行为障碍。斑马鱼胚胎在受精后 0-5 天（12.5-50mg/l）暴露于 ADHD 兴奋剂药物哌醋甲酯中。作为成年人，他们接受了长期行为效应测试。哌醋甲酯暴露（50mg/l）在受精后第 6 天而非第 30 天导致多巴胺、去甲肾上腺素和血清素显著增加。在捕食回避的新鱼缸潜水测试中，发育性哌醋甲酯（50mg/l）显著降低了正常潜水反应。在早期发育的三箱空间学习任务中，早期发育的哌醋甲酯（50mg/l）显著损害了选择准确性。这些数据表明，斑马鱼早期发育暴露于哌醋甲酯会导致神经行为可塑性的长期损害。在斑马鱼中识别出这些功能缺陷，使我们能够进一步使用该模型进行研究，以确定分子和细胞机制是如何受到干扰而导致这种受损状态的。
