Locus Coeruleus Function and Methylphenidate Action

描述(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应用哌醋甲酯(MPH)-利他林R之间的相互作用。20多年来，这种苯丙胺类精神刺激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身上作为认知增强剂的标签外使用而臭名昭著。尽管有很长的处方使用历史和最近的非法上诉，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阻止大脑中突触释放的去甲肾上腺素(NE)和多巴胺的重新摄取，但这些生化作用并不能为该药物在正常人或ADHD患者中的疗效提供明确的生理解释。在这一背景下，我们对去甲肾上腺素和多巴胺在脑靶神经元上的细胞/膜作用的了解已经取得了重大进展，但我们仍然不完全理解全身用药如何与去甲肾上腺素和多巴胺能系统相互作用，从而改变完整动物的神经元功能、信号传递和行为。以前资助的和目前的工作重点是内生NE系统。主题是在低剂量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。该项目采用了各种实验方法，包括：1)全身给药后血浆中药物浓度的测量；2)去甲肾上腺素能在不同脑区的分布和密度的体视学分析；3)微透析和高效液相色谱-电化学检测(HPLC-EC)法检测给药前后感觉和认知脑区NE的释放；4)在清醒或麻醉大鼠的躯体感觉通路上，多通道、多神经元记录；以及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。这些方案将主要在成年动物身上进行，但也会在青春期前、幼年和老年大鼠身上进行。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的作用和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去甲肾上腺素系统功能和精神刺激药物作用的了解，还将为ADHD的病理机制以及在健康受试者中非标签使用这类药物以促进觉醒和增强认知提供洞察力。 与公共健康相关：拟议项目的目标是调查大脑中内源性去甲肾上腺素递质系统与全身注射的哌醋甲酯(利他林)之间的相互作用。利他林是一种苯丙胺样精神刺激剂，是治疗ADHD的首选药物，因其促进觉醒和增强认知的作用而在其他年龄段的健康人群中越来越受欢迎。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，但其治疗和认知增强作用的基本生理机制尚不清楚。我们将通过一系列的解剖学、神经化学和电生理学实验，在幼年、成年和老年大鼠的感觉和认知脑回路中，建立哌醋甲酯的作用与内源性去甲肾上腺素递质系统的运作之间的联系。

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.