Effects of early methylphenidate exposure on opioid receptor functioning

项目摘要 据估计，美国7%-8%的学龄儿童符合诊断标准 注意缺陷多动障碍(ADHD)的标准，这些儿童中的大多数是 用哌醋甲酯(利他林)治疗。接受治疗的学龄儿童的百分比 在过去的十年里，哌醋甲酯稳步增加，近年来，有一种 服用这种化合物的学龄前儿童数量急剧增加。尽管有大量的 儿童正在接受哌醋甲酯治疗，令人惊讶的是，人们对长期疗效知之甚少 这种药物的后果。特别令人感兴趣的问题是早期的哌甲酯 治疗改变了后来对奖励或情绪刺激的反应。数据收集在我们的 实验室表明，在断奶前阶段(PD 11-PD 20)暴露于哌甲酯 增强对吗啡和蔗糖的后期反应性，提示阿片类药物可能发生变化 系统运行正常。因此，本项目的目标是通过以下方式更好地了解这些机制 哪个早期使用哌醋甲酯可以加强吗啡诱导的作用。为此，我们将 确定在断奶前阶段暴露哌醋甲酯是否会增加对 特异性阿片受体以及这些敏感性的变化是否对 阿片类药物介导的行为和生理反应的多样性。我们还将评估是否及早 暴露于哌醋甲酯改变了特定阿片受体的密度，以及是否有 阿片受体/G蛋白偶联的伴随变化。最后，我们将研究长期的 早期接触哌醋甲酯对焦虑和抑郁样行为的影响 确定药物治疗时的年龄是否会改变这些行为。

Project Summary It is estimated that 7-8% of all school-age children in the United States meet the diagnostic criteria for attention deficit hyperactivity disorder (ADHD) and the majority of these children are treated with methylphenidate (Ritalin). The percentage of school-age children treated with methylphenidate has increased steadily over the last decade and, in recent years, there has been a sharp increase in the number of preschool children given this compound. Despite the large number of children being treated with methylphenidate, surprisingly little is known about the long-term consequences of this drug. Of particular interest is the question of whether early methylphenidate treatment alters later responsiveness to rewarding or emotional stimuli. Data gathered in our laboratory indicates that methylphenidate exposure during the preweanling period (PD 11-PD 20) enhances later responsiveness to both morphine and sucrose indicating a possible change in opioid system functioning. Thus the goal of the present project is to better understand the mechanisms by which early methylphenidate treatment potentiates morphine-induced effects. To this end, we will determine whether methylphenidate exposure during the preweanling period enhances sensitivity of specific opioid receptors and whether these changes in sensitivity have a consistent effect on a variety of opioid-mediated behaviors and physiological responses. We will also assess whether early methylphenidate exposure changes the density of specific opioid receptors and whether there are concomitant changes in opioid receptor/G-protein coupling. Lastly, we will examine the long-term consequences of early methylphenidate exposure on anxiety- and depressive-like behaviors and determine whether age at drug treatment modifies these behaviors.