Locus Coeruleus Function and Methylphenidate Action

蓝斑功能和哌甲酯作用

• 批准号: 7050226
• 负责人: BARRY Dale WATERHOUSE
• 金额: $ 29.3万
• 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 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7050226
• 关键词: amphetamines; biological signal transduction; dosage; electrostimulus; high performance liquid chromatography; laboratory rat; locus coeruleus; methylphenidate; microdialysis; neurons; neuropharmacology; neurotransmitter transport; norepinephrine; somesthetic sensory cortex; synapses; trigeminal nerve

DESCRIPTION (provided by applicant): Amphetamine (AMPH)-Iike psychostimulants, such as methylphenidate, are notorious for their abuse potential but also have considerable therapeutic value in treatment of attention deficit, hyperactive disorder (ADHD). These agents have prominent effects on monoaminergic neurotransmission yet little is known regarding the specific physiological mechanism(s) through which they exert their therapeutic action in ADHD. Instead, almost all of our information concerning AMPH-like stimulants derives from drug abuse studies that employ doses far in excess of those used clinically. Identification of the mechanisms underlying AMPH-Iike stimulant action are critical for future development of compounds that have greater efficacy, less toxicity, and lower abuse liability. Recent evidence links the therapeutic actions of methylphenidate to the locus cocruleus (LC) - norepinephrine (NE) system in the brain, yet there are still many unanswered questions regarding the basic output functions of this major monoaminergic pathway. For example, much is known about the effects of exogenous NE on postsynaptic cellular targets, but there have been few comprehensive studies of the impact of LC-mediated NE-release on the operation of cells, circuits and neural networks that receive LC efferent projections. With these considerations in mind the present proposal establishes three major goals. The first is to show that activation of the LC efferent pathway can exert NE-like modulatory actions on signal processing functions of individual thalamic and cortical sensory neurons. The second is to determine how extracellular levels of NE fluctuate within sensory networks as a function of LC output. The third is to determine how low dose methylphenidate affects LC-mediated modulation of thalamic and cortical sensory neuron responses to synaptic input. These studies will use the rat trigeminal somatosensory system as a model and will employ microdialysis and HPLC-EC detection methods for NE, multi-channel, multi-neuron recording procedures in awake and anesthetized rats, tactile and electrical stimulation of the trigeminal somatosensory pathway, and electrical and chemical activation of the LC efferent path. By characterizing the effect of LC output on sensory neuron response properties and by clarifying the relationship between LC discharge and NE release in sensory pathways, it will be possible to begin predicting how signal processing through sensory networks are altered under conditions, such as arousal and sustained attention, where output from the LC efferent system is increased. This work will not only fill a large gap between the results of direct NE application studies and predictions of LC efferent actions but will also provide a solid framework for evaluating the effects of AMPH-Iike stimulants in sensory circuit operations and ADHD treatment.

描述（由申请人提供）：苯丙胺（AMPH）类精神兴奋剂，例如哌醋甲酯，因其滥用潜力而臭名昭著，但在治疗注意力缺陷、多动症（ADHD）方面也具有相当大的治疗价值。这些药物对单胺能神经传递具有显着的作用，但人们对它们在 ADHD 中发挥治疗作用的具体生理机制知之甚少。相反，我们几乎所有有关 AMPH 类兴奋剂的信息都来自药物滥用研究，这些研究使用的剂量远远超过临床使用的剂量。鉴定 AMPH 类兴奋剂作用的潜在机制对于未来开发具有更高功效、更低毒性和更低滥用可能性的化合物至关重要。最近的证据将哌醋甲酯的治疗作用与大脑中的蓝斑 (LC) - 去甲肾上腺素 (NE) 系统联系起来，但关于这一主要单胺能途径的基本输出功能，仍有许多未解答的问题。例如，人们对外源性 NE 对突触后细胞靶标的影响了解很多，但很少有关于 LC 介导的 NE 释放对接收 LC 传出投射的细胞、回路和神经网络的影响的全面研究。考虑到这些因素，本提案确立了三个主要目标。首先是证明 LC 传出通路的激活可以对单个丘脑和皮质感觉神经元的信号处理功能发挥类似 NE 的调节作用。第二个是确定感觉网络内 NE 的细胞外水平如何作为 LC 输出的函数波动。第三个是确定低剂量哌醋甲酯如何影响 LC 介导的丘脑和皮质感觉神经元对突触输入反应的调节。这些研究将使用大鼠三叉神经体感系统作为模型，并采用微透析和 HPLC-EC 检测方法进行 NE、清醒和麻醉大鼠的多通道、多神经元记录程序、三叉神经体感通路的触觉和电刺激以及 LC 传出通路的电和化学激活。通过表征 LC 输出对感觉神经元反应特性的影响，并阐明感觉通路中 LC 放电和 NE 释放之间的关系，将有可能开始预测在唤醒和持续注意力等条件下，LC 传出系统的输出增加时，通过感觉网络的信号处理如何改变。这项工作不仅将填补直接 NE 应用研究结果与 LC 传出作用预测之间的巨大差距，而且还将为评估 AMPH 类兴奋剂在感觉回路操作和 ADHD 治疗中的效果提供坚实的框架。