In Vivo Discovery of Psychotropic Drugs by High-Throughput Behavioral Phenotyping

通过高通量行为表型分析在体内发现精神药物尽管它们普遍存在并具有影响力，但中枢神经系统（CNS）疾病仍然是治疗最差的医疗条件之一。需要新的CNS药物，但神经系统的复杂性在很大程度上使CNS药物发现难以还原和体外方法。因此，大多数现有的中枢神经系统药物都是通过对活体动物行为效应的偶然观察发现的，而不是通过合理设计或体外筛选发现的。发现新的中枢神经系统药物受到体外模拟复杂脑功能的困难和用现有哺乳动物行为测定法在体内筛选新药的不切实际的限制。我们的方法，我们建议使用高通量行为分析作为一种手段，筛选新的神经活性药物。我们正在开发能够以高通量96孔格式跟踪和量化斑马鱼行为的全自动系统。使用这些检测方法之一，我们已经测试了700精神药物从几个功能类，并确定了强烈的相关性之间的特定功能类和斑马鱼的行为概况，他们诱导。我们现在建议扩大自动化行为测定的小组，并对大量小分子文库进行筛选，以鉴定具有体内神经活性的新型化合物。我们正在开发的自动化斑马鱼检测小组的潜在影响是第一个能够评估脊椎动物中小分子行为影响的高通量筛选。由于斑马鱼的行为整合了来自几个主要神经递质系统的输入，因此该测定可用于鉴定通过不同机制作用于CNS的化合物。该项目的成功完成将为发现神经活性化合物创造一个强大而灵活的系统。它还将直接导致发现通过不同作用机制改变CNS功能的新型化合物。这些化合物将是研究神经系统的有力工具，在某些情况下，可能会进一步开发用于治疗神经系统疾病。神经系统疾病，如精神分裂症和阿尔茨海默氏病是广泛的，往往是毁灭性的，但他们仍然没有得到很好的治疗，因为传统的药物发现方法是装备不良，以处理大脑的复杂性。该项目提出了一种大胆的神经系统药物发现新方法，该方法基于对数千种潜在新药的机器人测试，以改变显微镜下斑马鱼的大脑功能。

In vivo discovery of psychotropic drugs by high-throughput behavioral phenotyping the challenge despite their ubiquity and impact, diseases of the central nervous system (CNS) remain among the most poorly treated medical conditions. New CNS drugs are needed, but the complexity of the nervous system has largely made CNS drug discovery refractory to reductionist and in vitro approaches. For this reason, most existing CNS drugs were discovered by serendipitous observation of behavioral effects in living animals, not by rational design or in vitro screening. Discovering new CNS drugs is limited by the difficulty of modeling complex brain function in vitro and the impracticality of screening for new drugs in vivo with existing mammalian behavioral assays. Our approach we propose to use high-throughput behavioral assays as a means of screening for novel neuroactive drugs. We are developing fully-automated systems capable of tracking and quantifying zebrafish behaviors in high- throughput, 96-well format. Using one of these assays, we have tested 700 psychotropic drugs from several functional classes and identified strong correlations between specific functional classes and the zebrafish behavioral profiles they induce. We now propose to expand the panel of automated behavioral assays and conduct screens of vast small molecule libraries to identify novel compounds with in vivo neurological activity. The potential impact the automated panel of zebrafish assays we are developing is the first high-throughput screen capable of assessing behavioral effects of small molecules in a vertebrate. Because the zebrafish behaviors integrate inputs from several major neurotransmitter systems, the assays can be used to identify compounds that act on the CNS through diverse mechanisms. Successful completion of this project will create a robust and flexible system for discovering neuroactive compounds. It will also lead directly to discovery of novel compounds that alter CNS function through diverse mechanisms of action. These compounds will be powerful tools for studying the nervous system and in some cases may be developed further for treating nervous system disorders. Nervous system disorders like schizophrenia and Alzheimer's disease are widespread and frequently devastating, but they remain poorly treated because conventional drug discovery methods are poorly equipped to deal with the complexity of the brain. This project proposes a bold new approach to nervous system drug discovery based on robotic testing of thousands of potential new drugs for their ability to alter brain function in microscopic zebrafish.