Developmental Affects of Ritalin on Brain

描述（由申请人提供）：利他林（哌甲酯; MPH）是一种 注意力缺陷儿童最常用的处方药 多动症（ADHD）。在过去的十年里，利他林的使用 在美国增加，这样的儿童诊断为多动症往往是 在整个儿童晚期和青春期维持药物。之甚少 然而，关于治疗剂量的MPH的长期后果， 对大脑发育的影响发育中的MPH暴露可能会深刻影响 突触发生、髓鞘形成和胶质细胞生成。的 特别值得注意的是突触发生的过程，它发生在出生后， 大脑中与学习和记忆有关的几个区域 (e.g.,海马和大脑皮层）。因此，本建议旨在 生成数据以帮助评估MPH治疗维持的安全性 在儿童和青少年中。为实现这一目标，提出了两个目标：（1） 开发一种动物模型，反映MPH的临床维持， 儿童和（2）评估长期发育暴露的影响， 治疗剂量的MPH在该模型中对成人脑的作用。原本这 模型将利用MPH的最大治疗剂量和持续时间， 用于治疗儿童多动症长期暴露于治疗剂量的MPH 然后在两个时间点在年轻成年大鼠的前脑中进行评估 使用灵敏的定量免疫细胞化学方法。重点将放在： (a)多巴胺能系统;（B）上行去甲肾上腺素能系统;和（c）上行 神经能系统（尤其是大脑皮层的神经支配， 海马），因为目前的实验证据表明，这些 单胺直接或间接地受到MPH的影响 局此外，基底前脑胆碱能和皮质 将分析单胺能系统，因为两者都是单胺能靶向的。 传入系统在注意力中起着重要作用，并经历突触发生 出生后单胺能和胆碱能神经元及其传出过程 将使用其合成酶的抗体或 转运体（即，标记在摄取中重要的亚群， 释放），而皮层神经元能突触将通过 NMDA受体的抗体。如果免疫细胞化学的任何变化 在这个模型中使用这些参数看到标记，未来的实验将 关注：（1）剂量（例如，来确定最大剂量 这些变化）;（2）持续时间（例如，以确定变化是否随着 更短的暴露时间或确定可能 对药物作用唯一敏感）;和（3）评估的年龄（例如， 以确定这些变化是否随着大脑年龄的增长而持续）。确定如何 治疗剂量方案对这些递质系统的影响至关重要， 了解MPH长期治疗剂量的安全性， 患有ADHD和其他相关疾病的儿童和青少年

DESCRIPTION (provided by applicant): Ritalin (methylphenidate; MPH) is one of the most commonly prescribed drugs for children with attention deficit hyperactivity disorder (ADHD). Over the past decade, ritalin usage has increased in the United States such that children diagnosed with ADHD often are maintained on the drug throughout late childhood and adolescence. Little is known however, regarding the long term consequences of therapeutic doses of MPH on brain development. Developmental MPH exposure may profoundly affect synaptogenesis, myelination and gliogenesis in several brain regions. Of particular note is the process of synaptogenesis, which occurs postnatally in several regions of the brain that are associated with learning and memory (e.g., hippocampus and cerebral cortex). Thus, the present proposal seeks to generate data to aid in evaluating the safety of therapeutic maintenance of MPH in children and adolescents. To achieve this goal, two aims are proposed: (1 ) to develop an animal model that reflects the clinical maintenance of MPH in children and (2) to assess the effects of long-term developmental exposure to therapeutic doses of MPH in this model on the adult brain. Initially, this model will utilize the maximum therapeutic dosage and duration of MPH that is used to treat ADHD in children. Long-term exposure to therapeutic doses of MPH then will be assessed in the forebrain of young adult rats at two time-points using sensitive, quantitative immunocytochemical methods. Focus will be on the: (a) dopaminergic system; (b) ascending noradrenergic system; and (c) ascending serotonergic system (especially their innervation of the cerebral cortex and hippocampus), since current experimental evidence indicates that these monoamines are either directly or indirectly affected following MPH administration. Additionally, the basal forebrain cholinergic and cortical glutamatergic systems will be analyzed since both are targeted by monoaminergic afferent systems, play a prominent role in attention and undergo synaptogenesis postnatally. Monoaminergic and cholinergic neurons and their efferent processes will be identified using antibodies to either their synthetic enzymes or transporters (i.e., to label subpopulations that are important in uptake and release), whereas cortical glutamatergic synapses will be identified by antibodies to NMDA receptors. If changes in any of the immunocytochemical markers are seen using these parameters in this model, future experiments would focus on: (1) dosage (e.g., to determine the maximum dose necessary to see these changes); (2) duration (e.g., to determine if the changes diminish with smaller periods of exposure or to identify developmental stages that may be uniquely sensitive to the drug effects); and (3) the age of assessment (e.g., to determine if the changes persist as the brain ages). Determining how therapeutic dosage regimens effect these transmitter systems is critical in understanding the safety of long-term therapeutic doses of MPH administered to children and adolescents with ADHD and other related disorders.