Locus Coeruleus Function and Methylphenidate Action

描述（由申请人提供）：安非他明（AMPH）样精神兴奋剂，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障碍（ADHD）中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作用，但关于它们在ADHD中发挥治疗作用的具体生理机制却知之甚少。相反，我们几乎所有关于AMPH样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。确定潜在的AMPH样兴奋剂作用的机制是至关重要的未来发展的化合物，具有更大的功效，更小的毒性，和更低的滥用倾向。最近的证据表明哌甲酯的治疗作用与大脑中的核轨迹（LC）-去甲肾上腺素（NE）系统有关，但关于这一主要单胺能通路的基本输出功能仍有许多未回答的问题。例如，许多人知道外源性NE对突触后细胞靶点的影响，但LC介导的NE释放对接受LC传出投射的细胞、回路和神经网络的操作的影响的全面研究很少。考虑到这些因素，本提案确定了三个主要目标。第一个是表明LC传出通路的激活可以对单个丘脑和皮层感觉神经元的信号处理功能施加NE样调节作用。第二是确定细胞外NE水平如何在感觉网络内波动作为LC输出的函数。第三是确定低剂量哌甲酯如何影响LC介导的丘脑和皮层感觉神经元对突触输入的反应的调制。这些研究将使用大鼠三叉神经躯体感觉系统作为模型，并将采用微透析和HPLC-EC检测方法进行NE、清醒和麻醉大鼠中的多通道、多神经元记录程序、三叉神经躯体感觉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输出对感觉神经元响应特性的影响，并通过阐明LC输出对感觉神经元响应特性的影响，LC放电和NE释放之间的关系在感觉通路中，它将有可能开始预测如何通过感觉网络的信号处理被改变的条件下，如唤醒和持续的注意，其中输出从LC传出系统增加。这项工作将不仅填补了直接NE应用研究和预测LC传出动作的结果之间的巨大差距，但也将提供一个坚实的框架，用于评估AMPH样兴奋剂在感觉回路操作和ADHD治疗的影响。

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.