Effects of early methylphenidate exposure on opioid receptor functioning

描述（由申请人提供）：据估计，美国所有学龄儿童中有7-8%符合注意缺陷多动障碍（ADHD）的诊断标准，这些儿童中的大多数接受哌醋甲酯（利他林）治疗。在过去十年中，接受哌醋甲酯治疗的学龄儿童比例稳步上升，近年来，接受这种化合物治疗的学龄前儿童人数急剧增加。尽管有大量儿童接受哌甲酯治疗，但令人惊讶的是，人们对这种药物的长期后果知之甚少。特别令人感兴趣的是早期哌甲酯治疗是否会改变后来对奖励或情绪刺激的反应。我们实验室收集的数据表明，在断奶前阶段（PD 11-PD 20）哌甲酯暴露增强了以后对吗啡和蔗糖的反应性，表明阿片系统功能可能发生变化。因此，本项目的目标是更好地了解早期哌甲酯治疗增强吗啡诱导效应的机制。为此，我们将确定在断奶前暴露哌甲酯是否会增强特定阿片受体的敏感性，以及这些敏感性的变化是否对各种阿片介导的行为和生理反应产生一致的影响。我们还将评估早期哌甲酯暴露是否会改变特定阿片受体的密度，以及阿片受体/G蛋白偶联是否伴随变化。最后，我们将研究早期哌醋甲酯暴露对焦虑和抑郁样行为的长期影响，并确定药物治疗的年龄是否会改变这些行为。 公共卫生相关性：在美国，每年都有数百万的幼儿接受哌醋甲酯（利他林）治疗注意力缺陷/多动障碍（ADHD）。这项拨款提案的目的是确定早期暴露于哌醋甲酯是否会改变后来对滥用药物的反应和情感障碍的易感性。

DESCRIPTION (provided by applicant): 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 pre-weanling 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 pre-weanling 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. Public Health Relevance: Each year millions of young children in the United States are treated with methylphenidate (Ritalin) for attention deficit/hyperactivity disorder (ADHD). The purpose of this grant proposal is to determine if early exposure to methylphenidate alters later responsiveness to drugs of abuse and predisposition to affective disorders.