Voltammetric determination of neuronal serotonin and histamine co-regulation

项目摘要 神经精神疾病严重缺乏有效的治疗方法，因为神经化学 这些疾病的潜在原因还不清楚。预计神经精神疾病的患病率 增加，给患者个人及其照顾者和家庭带来更大的压力。集体 生产力的损失造成了沉重的经济负担。因此，更好地理解神经化学 精神障碍的治疗是设计有效治疗所需的相关和基本任务。长期 这项研究的目的是确定调节细胞外5-羟色胺的机制， 组胺在精神疾病中改变。实现这一目标的第一步，如《千年宣言》的目标所概述， 该建议是能够精确、同时地在体内化学测量血清素， 组胺，并建立数学模型来描述这两种信使在生理上是如何 在细胞外空间调节。这里的核心假设是血清素和组胺迅速 调节彼此的化学反应这一中心假设源于我们的初步数据， 组胺通过H3受体快速反向调节乳头体前核中的5-羟色胺， 5-羟色胺转运蛋白再摄取组胺（组胺的转运蛋白尚未确定）。的 基本原理是，了解调节细胞外体内5-羟色胺的生理机制， 组胺将使这两种神经递质的作用，在不同的系统探索。 神经精神病理生理学，开放和推进新的治疗策略。引导初步 数据，跨学科的方法将通过两个具体目标来测试中心假设：1。实时执行， 体内血清素和组胺的同时测量和2.确定共同作用的潜在机制 调节细胞外5-羟色胺和组胺。在aim 1中，将开发尖端的电分析技术， 开发提供第一个实时同步测量血清素和组胺在体内。在 具体目标2，化学家和数学家之间强大的跨学科合作将解开 5-羟色胺和组胺的体内共同调节机制。这种方法是创新的，因为它带来了 先进的分析技术和数学一起解决重要的分析和神经科学 挑战本文的研究具有重要的意义，因为它为我们系统研究奠定了基础 血清素和组胺在不同的神经精神疾病中是如何变化的，丰富了 药物开发人员可以利用这些信息来创造更有效的疗法。这将使个人受益， 社会和经济。这项研究还将对更广泛的研究议程产生影响。的 同时实时测量血清素和组胺的分析方法和模型， 描述这两种信使在体内是如何调节的，对于希望了解 研究过多的与血清素和组胺有关的疾病。

PROJECT SUMMARY There is a critical lack of effective therapies for neuropsychiatric diseases because the neurochemistry underlying these illnesses is not well-understood. The prevalence of neuropsychiatric diseases is predicted to increase, placing augmented stress on individual sufferers and their caregivers and families. The collective loss of productivity here creates heavy economic burdens. Therefore better understanding the neurochemistry of mental disorders is a pertinent and fundamental task required to design effective treatments. The long-term goal of the proposed research is to establish how mechanisms that regulate extracellular serotonin and histamine in vivo alter during mental illness. The first steps towards this goal, as outlined in the objectives of the proposal are to are to enable precise, simultaneous in vivo chemical measurements of serotonin and histamine and to create models that mathematically describe how these two messengers are physiologically regulated in the extracellular space. The central hypothesis here is that serotonin and histamine rapidly modulate each other's chemistry. This central hypothesis stems from our preliminary data showing that histamine rapidly, inversely modulates serotonin in the premammillary nucleus via H3 receptors and that serotonin transporters reuptake histamine (a transporter for histamine has not yet been identified). The rationale is that understanding the physiological mechanisms that regulate extracellular in vivo serotonin and histamine will enable a systematic exploration of the roles of these two neurotransmitters in different neuropsychiatric pathophysiologies, opening and advancing novel treatment strategies. Guided by preliminary data, an interdisciplinary approach will test the central hypothesis via two specific aims: 1. Perform real-time, simultaneous measurements of serotonin and histamine in vivo and 2. Determine mechanisms underlying co- regulation of extracellular serotonin and histamine. In aim 1, a cutting edge electroanalytical technique will be developed to provide the first real-time simultaneous measurements of serotonin and histamine in vivo. In specific aim 2, a powerful interdisciplinary collaboration between chemists and mathematicians will unravel serotonin and histamine co-regulatory mechanisms in vivo. The approach is innovative because it brings advanced analytical techniques and mathematics together to tackle important analytical and neuroscience challenges. The proposed research is significant because it can set the stage for us to systematically study how serotonin and histamine alter during different neuropsychiatric diseases, enriching the chemical scope of information that drug developers have available to create more effective therapies. This will benefit individuals, society and the economy. The research will also have impact on a much broader research agenda. The analytical methodology that simultaneously measures serotonin and histamine in real-time and models that describe how these two messengers are regulated in vivo are extremely valuable to researchers wishing to study the plethora of disorders in which serotonin and histamine are co-implicated.