Preweanling Methylphenidate Exposure and Reward Behavior

据估计，美国所有学龄儿童中有3-9%符合注意力缺陷多动障碍（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增加后来对药物滥用的脆弱性，因为最近的研究表明，早期哌甲酯暴露会改变可卡因强化行为。因此，拟议的研究的目标是确定早期暴露于哌醋甲酯对年轻成年大鼠奖励机制的影响。计划进行五组实验。在前两组实验中，我们将在断奶前阶段（大致类似于人类幼儿期的时间）将大鼠暴露于哌甲酯，并评估吗啡诱导的位置偏好，可卡因自我管理，以及成年后新奇和可卡因诱导的运动活动。在第三组实验中，我们将检查断奶前多巴胺D2受体数量和功能的变化 哌甲酯暴露D2受体功能将通过测量腺苷酸 环化酶活性，G蛋白亚基水平（即，Gi-α和Go-α），以及NPA刺激的纹状体和丘脑核中的GTP γ S结合。在第四组实验中，我们将确定给药途径（口服vs. ip）或每天注射次数是否会改变断奶前哌甲酯暴露对吗啡诱导的位置偏爱的影响。最后，在第五组实验中，我们将确定药物暴露的年龄是否会改变早期哌甲酯暴露对吗啡诱导的位置偏好和可卡因自我管理的影响。

It is estimated that 3-9% 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 increases later vulnerability to drugs of abuse, because recent research has indicated that early methylphenidate exposure alters cocaine reinforced behavior. Thus, the goal of the proposed research is to determine the effects of early exposure to methylphenidate on reward mechanisms in young adult rats. Five sets of experiments are planned. In the first two sets of experiments, we will expose rats during the preweanling period (a time roughly analogous to early childhood in humans) to methylphenidate and assess morphine-induced place preference, cocaine self-administration, and novelty- and cocaine-induced locomotor activity in adulthood. In the third set of experiments, we will examine changes in the number and functioning of dopamine D2 receptors after preweanling methylphenidate exposure. D2 receptor functioning will be assessed by measuring adenylyl cyclase activity, G-protein subunits levels (i.e., Gi-alpha and Go-alpha), and NPA-stimulated GTPgammaS binding in the striatum and nucleus accumbens. In the fourth set of experiments, we will determine if route of administration (oral vs. ip) or number of injections per day alters the effects of preweanling methylphenidate exposure on morphine-induced place preference. Finally, in a fifth set of experiments, we will determine if age at drug exposure alters the effects of early methylphenidate exposure on morphine-induced place preference and cocaine-self administration.