Developmental Affects of Ritalin on Brain

描述(申请人提供)：利他林(哌甲酯；mph)是以下药物之一 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，因此被诊断为ADHD的儿童通常是 在儿童后期和青春期一直服用该药。小才是 然而，关于治疗性剂量的MPH的长期后果 关于大脑发育的研究。发育中的公共卫生小时数暴露可能会深刻影响 几个脑区的突触发生、髓鞘形成和胶质形成。的 特别要注意的是突触发生的过程，它发生在出生后的 大脑中与学习和记忆有关的几个区域 (例如，海马体和大脑皮层)。因此，本提案力求 生成数据以帮助评估MPH治疗性维持的安全性 在儿童和青少年中。为了实现这一目标，提出了两个目标：(1) 建立一种反映MPH临床维持的动物模型 以及(2)评估长期暴露在儿童发育中的影响。 在这个模型中，治疗剂量的mph对成年人的大脑。最初，这是 模型将利用最大治疗剂量和持续时间的公共卫生，即 用于治疗儿童多动症。长期接触治疗性剂量的公共卫生 然后在两个时间点对幼年成年大鼠的前脑进行评估 使用敏感、定量的免疫细胞化学方法。重点将放在以下方面： (A)多巴胺能系统；(B)上行去甲肾上腺素系统；及(C)上行 5-羟色胺能系统(尤其是它们对大脑皮层和 海马体)，因为目前的实验证据表明，这些 单胺类物质会直接或间接地受mph影响。 行政管理。此外，基底前脑的胆碱能和皮质 谷氨酸能系统将被分析，因为这两个系统都是单胺能 传入系统在注意中起重要作用，并经历突触发生 出生后。单胺能和胆碱能神经元及其传出突起 将使用其合成酶或抗体进行鉴定 转运体(即标记在摄取和 释放)，而皮质谷氨酸能突触将通过 抗NMDA受体抗体。如果任何一种免疫细胞化学的变化 在这个模型中可以看到使用这些参数的标记，未来的实验将 重点放在：(1)剂量(例如，确定所需的最大剂量 这些变化)；(2)持续时间(例如，确定变化是否随着 较短的暴露时间或确定可能是 对药物效果唯一敏感)；以及(3)评估年龄(例如， 以确定这些变化是否会随着大脑的老化而持续)。确定如何 影响这些递质系统的治疗剂量方案在 了解长期治疗剂量的公共卫生系统的安全性 患有多动症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.