Locus Coeruleus Function and Methylphenidate Action

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与全身给药哌甲酯(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，现在因其在健康受试者中作为认知增强剂的标签外使用而臭名昭著。尽管哌醋甲酯的处方使用历史悠久，最近也有非法使用，但哌醋甲酯对感觉信号处理和认知的影响的神经回路机制尚未阐明。例如，众所周知，MPH阻断了大脑中突触释放的去甲肾上腺素（NE）和多巴胺的再摄取，但这些生化作用并不能为该药物对正常人或ADHD患者的疗效提供明确的生理学解释。在此背景下，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系统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，从而在完整动物中带来神经元功能、信号传递和行为的变化。以前资助和目前的工作主要集中在内源性NE系统。主题是更好地了解在低剂量精神兴奋剂作用下中枢去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给药后血浆药物水平的测定，2)脑各区域去甲肾上腺素能谱分布和密度的立体学分析，3)微透析和高压液相色谱电化学检测（HPLC-EC）给药前后大脑感觉和认知区NE的释放，4)多通道，清醒或麻醉大鼠用药前后体感觉通路中继站的多神经元记录；清醒或麻醉大鼠蓝斑-去甲肾上腺素能输出通路的激活。方案将主要在成年动物中进行，但也在青春期前的幼年和老年大鼠中进行。总体目标是在幼鼠、成年鼠和老年鼠的感觉和认知脑回路中，建立低剂量MPH与内源性中枢去甲肾上腺素能递质系统运行之间的联系。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剂药物作用的理解，而且还将为ADHD的病理和这类药物的超说明书使用动机提供见解，以促进清醒和增强健康受试者的认知。

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.