Locus Coeruleus Function and Methylphenidate Action

蓝斑功能和哌甲酯作用

• 批准号: 7935168
• 负责人: BARRY Dale WATERHOUSE
• 金额: $ 33.91万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7935168
• 关键词: Acute; Address; Adolescent; Adult; Age; Aging; Agreement; Amphetamines; Animals; Area; Attention; Attention deficit hyperactivity disorder; Behavior; Behavioral; Biochemical; Biological Assay; Brain; Brain region; Cellular Membrane; Child; Clinical; Cognition; Cognitive; Coupled; Data; Detection; Development; Dimensions; Disease model; Dopamine; Dopamine-beta-monooxygenase; Dose; Drug effect disorder; Efferent Pathways; Exhibits; Fiber; Funding; Goals; High Pressure Liquid Chromatography; Hyperactive behavior; Impulsivity; Individual; Label; Left; Life; Link; Measurement; Measures; Mediating; Methylphenidate; Microdialysis; Motivation; Neurons; Nootropic Agents; Norepinephrine; Outcome; Output; Pathology; Pathway interactions; Patients; Performance; Pharmaceutical Preparations; Phase; Physiological; Plasma; Property; Protocols documentation; Rattus; Receptor Activation; Recording of previous events; Regimen; Research; Ritalin; Sensory; Series; Signal Transduction; Site; Staging; Stimulus; Symptoms; Synapses; System; Techniques; Testing; Thalamic structure; Therapeutic; Trigeminal System; Varicosity; Vibrissae; Wakefulness; Work; age related; aged; base; computerized data processing; density; drug efficacy; extracellular; improved; inattention; insight; locus ceruleus structure; mature animal; neural circuit; neurochemistry; noradrenergic; norepinephrine system; operation; prepuberty; psychostimulant; public health relevance; research study; response; reuptake; somatosensory

DESCRIPTION (provided by applicant): The goal of the proposed project is to investigate interactions between the central noradrenergic system and systemically administered methylphenidate (MPH) - RitalinR in juvenile, adult and aged rats. This amphetamine-like psychostimulant has been the drug of choice for treating the core symptoms (inattention, distractibility, impulsivity, hyperactivity) of attention deficit hyperactivity disorder (ADHD) for more than 20 years and is now gaining notoriety for its off-label use as a cognitive enhancer in healthy subjects. Despite a long history of prescription use and more recent illicit appeal, the neural circuit mechanisms responsible for methylphenidate's effects on sensory signal processing and cognition have not been elucidated. For example, it is well known that MPH blocks reuptake of synaptically released norepinephrine (NE) and dopamine in the brain but these biochemical actions do not provide a clear physiological explanation for the drug's efficacy in either normal individuals or ADHD patients. In this context there have been major advances in our understanding of the cellular/membrane actions of NE and dopamine on target neurons in the brain, yet we still do not fully comprehend how systemically administered agents interact with noradrenergic and dopaminergic systems to bring about changes in neuronal function, signal transfer, and behavior in intact animals. Previously funded and current work focuses on the endogenous NE system. The theme is to better understand specific dimensions of central noradrenergic function in the context of low dose psychostimulant drug action. The project employs a variety of experimental approaches including: 1) measurement of drug levels in blood plasma following systemic MPH administration, 2) stereological analysis of the distribution and density of noradrenergic profiles across various brain regions, 3) microdialysis and high pressure liquid chromatography with electrochemical detection (HPLC-EC) of NE release in sensory and cognitive brain areas before and after drug administration, 4) multi-channel, multi-neuron recording at relay sites along the somatosensory pathway in waking or anesthetized rats before and after drug, and 5) activation of the locus coeruleus-noradrenergic efferent pathway in waking or anesthetized animals. Protocols will be carried out primarily in adult animals but also in prepubertal juvenile and aged rats. The overall goal is to establish a link between the actions of low dose MPH and operation of the endogenous central noradrenergic transmitter system within sensory and cognitive brain circuits of juvenile, adult, and aged rats. Completion of this work will not only further our understanding of LC noradrenergic system function and psychostimulant drug action but will also provide insight regarding the pathology of ADHD and the motivation for off-label use of this class of drugs to promote wakefulness and enhance cognition in healthy subjects. PUBLIC HEALTH RELEVANCE: The goal of the proposed project is to investigate interactions between the endogenous norepinephrine transmitter system in the brain and systemically administered methylphenidate (Ritalin), an amphetamine-like psychostimulant that is the drug of choice for treating ADHD and is gaining popularity among otherwise healthy individuals across the aging spectrum for its wake promoting and cognitive enhancing effects. Methylphenidate elevates norepinephrine and dopamine transmitter levels in cognitive and sensory regions of the brain, yet the basic physiological mechanisms through which it brings about its therapeutic and cognitive enhancing effects are unknown. A series of anatomical, neurochemical, and electrophysiological experiments will be used to establish a link between methylphenidate's actions and operation of the endogenous norepinephrine transmitter system within sensory and cognitive brain circuits of juvenile, adult, and aged rats.

描述（由申请人提供）：拟议项目的目标是研究幼年、成年和老年大鼠中枢去甲肾上腺素能系统和全身给药哌甲酯（MPH）-利他林R之间的相互作用。 20 多年来，这种类似安非他明的精神兴奋剂一直是治疗注意力缺陷多动障碍 (ADHD) 核心症状（注意力不集中、注意力不集中、冲动、多动）的首选药物，现在因其标签外使用而声名狼藉。健康受试者的认知增强剂。尽管处方使用历史悠久且最近出现非法诉求，但哌甲酯对感觉信号处理和认知产生影响的神经回路机制尚未阐明。例如，众所周知，MPH 会阻止大脑中突触释放的去甲肾上腺素 (NE) 和多巴胺的再摄取，但这些生化作用并没有为该药物在正常个体或 ADHD 患者中的功效提供明确的生理学解释。在这种情况下，我们对 NE 和多巴胺对大脑目标神经元的细胞/膜作用的理解取得了重大进展，但我们仍然没有完全理解全身给药的药物如何与去甲肾上腺素能和多巴胺能系统相互作用，从而带来改变完整动物的神经元功能、信号传递和行为。先前资助的和当前的工作重点是内源性 NE 系统。主题是更好地了解低剂量精神兴奋药物作用背景下中枢去甲肾上腺素能功能的具体维度。该项目采用了多种实验方法，包括：1）全身 MPH 给药后血浆中药物水平的测量，2）不同脑区去甲肾上腺素能分布和密度的体视学分析，3）微透析和高压液相色谱法给药前后感觉和认知脑区 NE 释放的电化学检测 (HPLC-EC)，4) 清醒或清醒状态下沿体感通路中继位点的多通道、多神经元记录药物前后麻醉大鼠，以及 5) 清醒或麻醉动物中蓝斑-去甲肾上腺素能传出通路的激活。方案将主要在成年动物中进行，但也会在青春期前的幼年和老年大鼠中进行。总体目标是在幼年、成年和老年大鼠的感觉和认知脑回路中建立低剂量 MPH 的作用与内源性中枢去甲肾上腺素能递质系统的操作之间的联系。这项工作的完成不仅将进一步加深我们对 LC 去甲肾上腺素能系统功能和精神兴奋药物作用的理解，而且还将提供有关 ADHD 病理学的见解以及超说明书使用此类药物以促进清醒和增强健康人认知的动机。科目。 公共健康相关性：拟议项目的目标是研究大脑中内源性去甲肾上腺素递质系统与全身给药的哌醋甲酯（利他林）之间的相互作用，利他林是一种类似安非他明的精神兴奋剂，是治疗多动症的首选药物，在儿童中越来越受欢迎。由于其促进觉醒和增强认知的作用，对整个老龄化范围内的其他健康个体都有影响。哌醋甲酯可提高大脑认知和感觉区域的去甲肾上腺素和多巴胺递质水平，但其产生治疗和认知增强作用的基本生理机制尚不清楚。将使用一系列解剖学、神经化学和电生理学实验来建立哌醋甲酯的作用与幼年、成年和老年大鼠感觉和认知脑回路中内源性去甲肾上腺素递质系统的操作之间的联系。