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

通过高通量行为表型在体内发现精神药物尽管这些疾病无处不在，影响巨大，但中枢神经系统(CNS)疾病仍然是治疗最差的疾病之一。需要新的中枢神经系统药物，但神经系统的复杂性在很大程度上使还原和体外方法难以发现中枢神经系统药物。因此，大多数现有的中枢神经系统药物是通过对活体动物行为影响的偶然观察而发现的，而不是通过合理的设计或体外筛选。新的中枢神经系统药物的发现受到复杂脑功能体外模拟的困难以及利用现有的哺乳动物行为分析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筛选新的神经活性药物的手段。我们正在开发能够以高吞吐量、96孔格式跟踪和量化斑马鱼行为的全自动化系统。使用这些测试之一，我们测试了来自几个功能类别的700种精神药物，并确定了特定功能类别与它们诱导的斑马鱼行为特征之间的强烈相关性。我们现在建议扩大自动化行为分析的小组，并对巨大的小分子文库进行筛选，以确定具有体内神经活性的新化合物。我们正在开发的斑马鱼自动分析小组的潜在影响是第一个能够评估脊椎动物小分子行为影响的高通量屏幕。由于斑马鱼的行为整合了几个主要神经递质系统的输入，这些分析可以用来识别通过不同机制作用于中枢神经系统的化合物。该项目的成功完成将创建一个强大而灵活的系统来发现神经活性化合物。它还将直接导致发现新的化合物，通过不同的作用机制改变中枢神经系统的功能。这些化合物将成为研究神经系统的强大工具，在某些情况下，可能会进一步开发用于治疗神经系统疾病。精神分裂症和阿尔茨海默病等神经系统疾病很普遍，而且往往具有破坏性，但它们的治疗仍然很差，因为传统的药物发现方法不足以应对大脑的复杂性。该项目提出了一种大胆的神经系统药物发现的新方法，该方法基于机器人对数千种潜在的新药进行测试，以确定它们是否具有改变微观斑马鱼大脑功能的能力。

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.