Neurochemistry and Neurophysiology of Methylphenidate

哌甲酯的神经化学和神经生理学

• 批准号: 6620780
• 负责人: BARRY Dale WATERHOUSE
• 金额: $ 15.34万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-10 至 2004-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6620780
• 关键词: attention deficit disorder; bioassay; catecholamines; cerebral cortex; dopamine; dosage; drug administration routes; drug adverse effect; electroencephalography; electromyography; gas chromatography; laboratory rat; locus coeruleus; mental disorder chemotherapy; methylphenidate; microdialysis; neural transmission; neurochemistry; neuropharmacology; neurophysiology; norepinephrine; pharmacokinetics; sensory signal detection; technology /technique development; thalamus

DESCRIPTION (provided by applicant): Attention deficit, hyperactive disorder (ADHD) is a childhood cognitive disorder characterized by inattentiveness and/or hyperactivity and impulsiveness. The most effective treatment for ADHD is chronic low dose administration of amphetamine (AMPH)-like stimulants such as methylphenidate. All of these agents have prominent effects on monoaminergic neurotransmission yet little is known regarding the specific mechanism(s) through which they exert their therapeutic action in ADHD. Almost all of our information concerning AMPH-like stimulants derives from drug abuse studies which employ doses far in excess of those used clinically. Furthermore, there are profound dose and drug-specific differences in AMPH-like stimulant actions on monoaminergic neurotransmission. The central tenet of the proposal is that it is inappropriate to postulate therapeutic mechanisms of action for AMPH-like stimulants on the basis of animal studies of drug abuse. Moreover, a better understanding of the therapeutic actions of these drugs is needed in order to develop pharmacological treatments that do not possess the negative properties of AMPH-like stimulants (e.g. unwanted behavioral side effects, long term toxicities, abuse potential). The goal of the proposed study is to develop methodologies for evaluating the effects of therapeutically-relevant doses of methylphenidate on: 1) catecholaminergic neurotrasmission, 2) the impact of acute and chronic low dose stimulants on sensory processing, sensory detection and attention, 3) the receptor mechanism involved in stimulant-induced alterations in sensory processing, sensory detection and attention, and 4) the long-term consequences of low dose stimulants on a variety of physiological and behavioral processes in developing animals. The major techniques to be employed here include gas chromotography for determining plasma levels of methylphenidate, microdialysis for determining plasma levels of methylphenidate, microdialysis for determining catecholamine levels in specified brain regions, EEG and EMG for identifying behavioral states of arousal, multi-channel many neuron recording in cerebral cortex, thalamus and locus coeruleus for characterizing patterns of neural discharge in awake behaving rats, and computer based analysis of many neuron spike train data. These studies will fill a significant gap in our understanding of therapeutic actions of AMPH-like stimulants in ADHD.

描述（由申请人提供）：注意力缺陷，多动障碍 （ADHD）是一种童年的认知障碍，其特征是不集中的 和/或多动症和冲动。多动症最有效的治疗方法 是慢性低剂量的苯丙胺（AMPH）类似刺激物 作为哌醋甲酯。所有这些药物对单胺能有显着影响 关于特定机制，神经传递尚不清楚 他们通过ADHD采取治疗作用。我们几乎全部 有关Amph样兴奋剂的信息来自药物滥用研究 使用的剂量远远超过临床上使用的剂量。此外，那里 是明显的剂量和药物特异性差异 关于单胺能神经传递。提案的中心宗旨是 假设类似Amph的治疗机制是不合适的 基于动物滥用的动物研究。而且，更好 需要了解这些药物的治疗作用 开发不具有负性特性的药理治疗 Amph样刺激剂（例如，不必要的行为副作用，长期 毒性，滥用潜力）。拟议的研究的目的是发展 评估治疗剂量的影响的方法论 哌醋甲酯on：1）儿茶酚胺能神经术，2） 感觉处理上的急性和慢性低剂量兴奋剂，感觉检测 3）参与刺激诱导的受体机制 感觉处理，感觉检测和注意力的改变，以及4） 低剂量兴奋剂对各种生理和 发展动物的行为过程。采用的主要技术 这里包括用于确定血浆水平的气体彩色造影 哌醋甲酯，微透析用于确定血浆水平的水平 哌醋甲酯，微透析用于确定儿茶酚胺水平 指定的大脑区域，脑电图和EMG，用于识别 唤醒，多通道在脑皮质，丘脑和 用于表征神经放电模式的基因座 行为大鼠，以及基于计算机的许多神经位峰列车数据的分析。 这些研究将填补我们对治疗的理解的显着空白 ADHD中的Amph样兴奋剂的作用。