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）：拟议项目的目的是研究中央甲肾上腺素能系统与少年，成人和老年大鼠的中央甲肾上腺素能和系统给药的相互作用。这种类似苯丙胺的精神刺激剂一直是注意力不足多动障碍（ADHD）的核心症状（不注意，分散性，冲动性，多动症）的首选药物，已有20多年的历史了，现在正臭名昭著，因为其在健康受试者中的认知增强剂而臭名昭著。尽管处方使用的历史悠久，并且最近的非法吸引力，但尚未阐明负责哌醋甲酯对感觉信号处理和认知影响的神经回路机制。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，但是这些生化作用并不能为正常人或ADHD患者的药物有效性提供明确的生理解释。在这种情况下，我们对NE和多巴胺对大脑靶神经元的细胞/膜作用的理解取得了重大进展，但是我们仍然没有完全理解系统施用的剂如何与甲肾上腺素能和多巴胺能系统相互作用，以引起神经元功能，信号传递以及完整动物的行为的变化。先前资助和当前的工作着重于内源性NE系统。主题是在低剂量的精神刺激药物作用的背景下更好地理解中枢去甲肾上腺素能功能的特定维度。该项目采用了多种实验方法，包括：1）全身MPH给药后血浆中的药物水平测量，2）对各种大脑区域的去甲肾上腺素能特征的分布和密度的立体分析，3）微压和高压液体色物学伴随电力学释放（HPLC-ECL）在感觉型脑部和CONTING中的高压液体色谱，并在有意义的脑中，并在有意义在药物前后，在唤醒或麻醉大鼠中沿体感途径的继电器部位记录多神经元，以及5）在醒来或麻醉动物中激活基因座二氧化核酸杆菌 - 甲状腺 - 甲状腺素能传递途径。方案将主要在成年动物中进行，但也将在青春期前和老年大鼠中进行。总体目标是建立低剂量MPH的作用与内源性中央甲肾上腺素能发射器系统在少年，成人和老年大鼠的感觉和认知脑回路内的操作之间的联系。这项工作的完成不仅将进一步了解LC Nor腺能系统功能和心理刺激药物作用，而且还将提供有关ADHD病理学的见解，以及非标签使用此类药物的动机，以促进觉醒并增强健康受试者的认知。 公共卫生相关性：拟议项目的目的是调查大脑中内源性去甲肾上腺素发射机系统与全身给药的甲苯甲酸酯（Ritalin），这是一种类似苯丙胺的心理刺激剂，是对ADHD的首选药物，用于治疗ADHD，并在其其他健康的个体中促进了eaking spectrum spectivation spectivation spectivation spectivation spectivation seplanting seppadivation seplivation spectivation。哌醋甲酯升高了大脑认知和感觉区域中的去甲肾上腺素和多巴胺发射机水平，但是它带来的基本生理机制却尚不清楚其治疗和认知增强作用。一系列解剖学，神经化学和电生理实验将用于在幼年，成人和年龄大鼠的感觉和认知脑电路中内源性去甲肾上腺素发射机系统之间建立联系。