Periadolescent Methylphenidate exposure: Brain function

青春期哌甲酯暴露：脑功能

• 批准号: 6777976
• 负责人: DIANA L DOW-EDWARDS
• 金额: $ 17.21万
• 依托单位: SUNY DOWNSTATE MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6777976
• 关键词: attention deficit disorder; behavior test; behavioral /social science research tag; behavioral habituation /sensitization; biomarker; brain metabolism; deoxyglucose; dopamine; dosage; drug administration rate /duration; drug adverse effect; histochemistry /cytochemistry; immature animal; in situ hybridization; laboratory rat; learning; methylphenidate; neuropharmacology; neuropsychology; pediatric pharmacology; pharmacokinetics; psychopharmacology; space perception

DESCRIPTION (provided by applicant): Widespread administration of psychoactive drugs to children, often without documented pathology, occurs in most of the United States today. New trends toward prescribing medications for Attention Deficit Hyperactivity Disorder (ADHD) to children without parental/family physician approval will surely increase the exposure of our population to drugs containing methylphenidate. Adequate knowledge about the long-term effects of chronic exposure of healthy children does not exist. These studies will utilize a rat model to address the following: Specific Aim 1 will determine the behavioral consequences of repeated methylphenidate (MPD) administration during periadolescence. Methylphenidate will be administered orally throughout the periadolescent period. A. Behavioral activation: Behavioral responses to MPD will be determined in photobeam boxes initially and after every thirteen days of dosing. The goal will be to find doses that activate behavior without producing sensitization. B. Spatial Learning: Effects of methylphenidate on performance in the radial arm maze (RAM) will be used as a measure of spatial learning. Rats will be trained on the 8-arm RAM daily following MPD dosing to determine whether MPD at doses which activate behavior facilitates learning. It is expected that MPD will enhance acquisition of spatial learning in the radial arm maze task. Specific Aim 2 will determine the neurofunctional consequences of periadolescent methylphenidate exposure. Brain metabolism using the deoxyglucose method will be determined in rats trained on RAM (Aim 1B) after the last dose on day 60 and shifted to the 12-arm RAM. Brain sections will be analyzed for molecular markers of dopamine function using in situ hybridization histochemistry (ISHH). Correlations of brain function and behavior on the 12-arm RAM (assessed simultaneously) and between brain function within specific neuronal circuits will be determined. It is expected that repeated exposure to MPD will alter brain metabolism in two ways: increasing metabolism in components of the mesolimbic and nigrostriatal dopamine circuits and by increasing functional coupling (correlations) among components of the hippocampus. Specific Aim 3 will determine the long-term behavioral and neurofunctional consequences of periadolescent methylphenidate exposure. It is expected that basal levels of brain metabolic function will also be altered 1 month after periadolescent exposure to MPD. Correlations between spontaneous behavior and metabolism as well as among metabolic rates in structures within identified neuronal circuits will be determined. Animals generated in Aim 1A will be used. Specific Aim 4 will determine the plasma levels of methylphenidate which produce behavioral activation. Plasma drug levels will be determined at those doses which were found to produce behavioral alterations. This will facilitate comparison with human studies reporting therapeutic plasma drug levels. These studies will determine the immediate and long-term consequences of administration of methylphenidate in rats during childhood and adolescence. The overall hypothesis to be tested is that chronic administration of methylphenidate to periadolescent rats will alter learning as assessed in the radial arm maze, activate behavior, and produce immediate and long-term alterations in function of critical neural circuits. The functional relationships between components of the hippocampus and spatial cognition will be established and the effects of MPD on these relationships explored. Through these studies, a comprehensive pre-clinical evaluation of the effects of chronic methylphenidate on learning, behavior, brain function and molecular patterns will be completed.

描述（由申请人提供）：当今美国大部分地区都普遍对儿童服用精神活性药物，但往往没有病理记录。未经父母/家庭医生批准就给儿童开治疗注意力缺陷多动障碍 (ADHD) 药物的新趋势肯定会增加我们的人口接触含有哌醋甲酯的药物的机会。对于健康儿童长期接触该物质的长期影响尚不存在足够的了解。这些研究将利用大鼠模型来解决以下问题： 具体目标 1 将确定青春期期间重复施用哌醋甲酯 (MPD) 的行为后果。哌甲酯将在整个青春期期间口服给药。 A. 行为激活：对 MPD 的行为反应将在给药最初和每十三天后在光束箱中确定。我们的目标是找到能够激活行为而不产生致敏作用的剂量。 B. 空间学习：哌甲酯对径向臂迷宫（RAM）表现的影响将被用作空间学习的衡量标准。 MPD 给药后，每天对大鼠进行 8 臂 RAM 训练，以确定激活行为的剂量的 MPD 是否有利于学习。预计 MPD 将增强径向臂迷宫任务中空间学习的获取。 具体目标 2 将确定青春期哌甲酯暴露的神经功能后果。使用脱氧葡萄糖方法在第 60 天最后一次给药后接受 RAM 训练（目标 1B）并转移到 12 臂 RAM 的大鼠中测定脑代谢。将使用原位杂交组织化学 (ISHH) 分析脑切片的多巴胺功能分子标记。将确定 12 臂 RAM 上的大脑功能和行为（同时评估）以及特定神经元回路内的大脑功能之间的相关性。预计反复接触 MPD 会以两种方式改变大脑代谢：增加中脑边缘和黑质纹状体多巴胺回路成分的代谢，以及增加海马成分之间的功能耦合（相关性）。具体目标 3 将确定青春期暴露于哌醋甲酯的长期行为和神经功能后果。预计在青春期接触 MPD 后 1 个月，大脑代谢功能的基础水平也会发生改变。将确定自发行为和代谢之间的相关性以及已识别的神经元回路内结构的代谢率之间的相关性。将使用目标 1A 中生成的动物。具体目标 4 将确定产生行为激活的哌醋甲酯血浆水平。血浆药物水平将按照被发现会产生行为改变的剂量来确定。这将有助于与报告治疗血浆药物水平的人体研究进行比较。 这些研究将确定在儿童期和青春期的大鼠中给予哌醋甲酯的直接和长期后果。待测试的总体假设是，对青春期大鼠长期给予哌醋甲酯会改变在径向臂迷宫中评估的学习能力，激活行为，并对关键神经回路的功能产生即时和长期的改变。将建立海马体各部分与空间认知之间的功能关系，并探讨 MPD 对这些关系的影响。通过这些研究，将完成对长期服用哌醋甲酯对学习、行为、大脑功能和分子模式影响的全面临床前评估。