Voltammetric determination of neuronal serotonin and histamine co-regulation

项目总结 目前严重缺乏治疗神经精神疾病的有效方法，因为神经化学 这些疾病背后的原因还没有被很好地理解。据预测，神经精神疾病的流行率 增加，给个别患者及其照顾者和家庭带来更大的压力。集体 这里的生产力损失造成了沉重的经济负担。因此，更好地理解神经化学 治疗精神障碍是设计有效治疗方法所必需的一项有针对性的基本任务。长期的 这项拟议的研究的目标是建立调节细胞外5-羟色胺和 精神疾病期间体内的组胺会发生变化。实现这一目标的第一步，如以下目标所述 该提议是为了能够对5-羟色胺和5-羟色胺进行精确、同时的体内化学测量。 并建立数学模型来描述这两个信使是如何在生理上 在细胞外空间进行调节。这里的中心假设是5-羟色胺和组胺迅速 调节彼此的化学反应。这一中心假设源于我们的初步数据显示 组胺通过H3受体快速、反向地调节哺乳动物前核中的5-羟色胺 5-羟色胺转运体再摄取组胺(组胺转运体尚未确定)。这个 基本原理是了解体内调节细胞外5-羟色胺和 组胺将使系统地探索这两种神经递质在不同的 神经精神病学病理生理学，开拓和推进新的治疗策略。由预赛指导 数据，跨学科的方法将通过两个特定的目标来检验中心假设：1.执行实时、 体内5-羟色胺和组胺的同时测定及2.确定协同作用的机制 细胞外5-羟色胺和组胺的调节。在目标1中，尖端的电分析技术将是 开发的目的是提供体内5-羟色胺和组胺的实时同时测量。在……里面 特定目标2，化学家和数学家之间强大的跨学科合作将解体 5-羟色胺和组胺在体内的共同调节机制。这种方法是创新的，因为它带来了 高级分析技术和数学一起处理重要的分析和神经科学 挑战。提出的研究具有重要意义，因为它可以为我们系统地研究奠定基础。 5-羟色胺和组胺在不同神经精神疾病中的变化，丰富了 药物开发者可以用来创造更有效的治疗方法的信息。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。这个 实时同时测量5-羟色胺和组胺的分析方法和模型 描述这两个信使是如何在体内被调控的，这对希望 研究与5-羟色胺和组胺相关的过多的疾病。

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.