Locus Coeruleus Function and Methylphenidate Action

描述（由申请方提供）：拟定项目的目的是研究中枢去甲肾上腺素能系统与全身给予幼龄、成年和老年大鼠哌甲酯（MPH）- RitalinR之间的相互作用。这种苯丙胺类精神兴奋剂已经成为治疗注意缺陷多动障碍（ADHD）核心症状（注意力不集中，注意力分散，冲动，多动）的首选药物超过20年，现在因其作为健康受试者的认知增强剂的标签外使用而声名狼借。尽管有很长的处方使用历史和最近的非法上诉，负责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，但这些生物化学作用并不能为药物在正常个体或ADHD患者中的疗效提供明确的生理学解释。在这种情况下，我们对NE和多巴胺对脑中靶神经元的细胞/膜作用的理解已经取得了重大进展，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，以引起完整动物神经元功能，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药物作用的背景下，中枢去甲肾上腺素能功能的具体方面。该项目采用了各种实验方法，包括：1）在全身性MPH给药后测量血浆中的药物水平，2）在不同脑区域中去甲肾上腺素能分布的分布和密度的体视学分析，3）在给药前后感觉和认知脑区域中NE释放的微透析和高压液相色谱电化学检测（HPLC-EC），4）清醒或麻醉大鼠给药前和给药后在沿躯体感觉通路的中继部位沿着的多通道、多神经元记录;和5）在清醒或麻醉动物中激活蓝斑-去甲肾上腺素能传出通路。方案将主要在成年动物中进行，但也在青春期前幼龄和老龄大鼠中进行。总体目标是建立低剂量MPH的行动和操作的内源性中枢去甲肾上腺素能递质系统内的感觉和认知脑回路的少年，成年和老年大鼠之间的联系。这项工作的完成不仅将进一步了解LC去甲肾上腺素能系统的功能和精神兴奋剂药物的作用，但也将提供有关ADHD的病理学和这类药物的标签外使用的动机，以促进清醒和增强健康受试者的认知的见解。 公共卫生相关性：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哌醋甲酯（利他林）之间的相互作用，哌醋甲酯是一种安非他明类精神兴奋剂，是治疗ADHD的首选药物，并且由于其唤醒促进和认知增强作用而在整个衰老范围内的其他健康个体中越来越受欢迎。哌醋甲酯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。一系列的解剖学，神经化学和电生理学实验将被用来建立哌甲酯的行动和操作的内源性去甲肾上腺素递质系统内的感觉和认知的幼年，成年和老年大鼠的脑回路之间的联系。

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.