Behavior-based chemical screening for GABAergic and startle modifying drugs

描述（由申请人提供）：神经活性化合物是神经科学研究中最强大的工具之一。识别具有新活性的新化合物可能有助于神经科学研究。然而，这些神经活性药物很难识别。在这里，我们提出了一种新的方法来确定神经活性化合物，影响惊跳和焦虑相关的行为在生活斑马鱼的行为。这些研究旨在加快神经活性药物发现的步伐，并为理解脊椎动物行为提供小分子工具。焦虑症，如广泛性焦虑症，恐慌症和创伤后应激障碍是广泛和毁灭性的疾病。尽管需要改进精神药物，但精神疾病和其他神经系统疾病的药物发现成功率低于其他治疗领域。为了满足对新型神经活性药物的巨大未满足的需求，开发新的神经活性药物发现方法至关重要。但是，由于缺乏对导致精神疾病的生化机制的详细了解，如何发现新的神经活性药物？遗传学和药理学是理解神经系统中分子信号通路的两种主要方法。然而，传统的药物遗传学方法严重偏向于系统生物学的基因组方面。全基因组应用于研究单一药物的作用正变得越来越普遍。相比之下，对化学物质如何影响特定基因型和表型的大规模分析的发展要慢得多。一个原因是基于表型的化学筛选对于大多数模式生物来说并不实用或成本效益不高。考虑到通过低通量和非系统方法发现的小分子的影响，系统的基于行为的化学筛选可能会提供很多东西。基于斑马鱼表型的化学筛选是一种非传统的方法，用于识别新的生物活性化合物。具有有价值的神经活性的未表征的化合物很可能已经存在于现代化学图书馆的威尔斯井中。然而，体外测定过于简单，并且哺乳动物中的表型测定的通量太低，无法有效地鉴定这些有价值的分子。与较大的脊椎动物不同，斑马鱼足够小，可以很容易地排列在96孔板的各个威尔斯中沿着从化学库中获得化学物质。因此，基于行为的斑马鱼化学筛选提供了系统评估化学物质如何影响完整脊椎动物神经系统的机会。

DESCRIPTION (provided by applicant): Neuroactive compounds are among the most powerful tools available for neuroscience research. Identifying novel compounds with new activities would likely aid neuroscience research. However, these neuroactive drugs are difficult to identify. Here, we propose a new approach to identify neuroactive compounds that affect startle and anxiety-related behaviors behaviors in living zebrafish. These studies aim to accelerate the pace of neuroactive drug discovery and provide small-molecule tools for understanding vertebrate behavior. Anxiety disorders such as generalized anxiety disorder, panic disorder and post-traumatic stress disorder are widespread and devastating illnesses. Despite the need for improved psychiatric medicines, drug discovery success rates for psychiatric illnesses and other disorders of the nervous system are lower than for other therapeutic areas. To meet the vast unmet need for novel neuroactive drugs, it will be essential to develop new approaches to neuroactive drug discovery. But, lacking a detailed understanding of the biochemical mechanisms that cause psychiatric disease, how can novel neuroactive drugs be discovered? Genetics and pharmacology are the two dominant approaches for understanding molecular signaling pathways in the nervous system. However, traditional pharmacogenetic approaches are heavily biased towards the genome side of systems biology. Genome-wide applications for investigating the effects of single drugs are becoming more common. By contrast, large-scale analyses of how chemicals affect specific genotypes and phenotypes have been much slower to develop. One reason is that phenotype based chemical screens have not been practical or cost-effective using most model organisms. Given the impact of small molecules that were discovered via low throughput and non-systematic approaches, it is likely that systematic behavior-based chemical screening has much to offer. Phenotype based chemical screens in the zebrafish are a non-conventional approach for identifying novel bioactive compounds. It is likely that uncharacterized compounds with valuable neuroactive activity already exist in the wells of modern chemical libraries. However, in vitro assays are too simplistic and phenotypic assays in mammals too low throughput, to efficiently identify these valuable molecules. Unlike larger vertebrates, zebrafish are small enough to be easily arrayed in the individual wells of a 96-well plate along with chemicals from a chemical library. As a result, behavior-based chemical screens in the zebrafish provide the opportunity to systematically assess how chemicals affect the intact vertebrate nervous system.