Behavior-based discovery of small-molecule modulators of neurochemical signaling pathways that underlie addiction

项目摘要 成瘾是一种复杂的神经回路病理学，其功能包括奖励处理、冲动控制和 目标导向的行为小分子靶向神经调质信号通路，在这些 电路是治疗成瘾的重要疗法。迫切需要改进 用于治疗成瘾的药理学。为了满足这一需求，我们开发了一些方法， 基于筛选，以询问天然产物的新来源对神经调节剂信号传导的影响， 神经系统的微观动物-线虫C。优雅我们将筛选的天然产品 是微生物代谢物，由于它们在基础条件下不表达， 但只能由环境因素引发这种微生物的“暗代谢组”含有小分子 具有广泛的生物活性。这些化合物尚未被测定对 动物神经系统，它们构成了一个丰富的和未开发的资源，为新的精神药理学。 通过旨在证明概念验证的筛选，我们已经确定了 强烈而特异地作用于使用神经肽和血清素产生行为的回路。我们有 还设计了基于行为的筛选多巴胺信号的新型调节剂。除了提供 有机会进行高通量的基于行为的筛选，C. elegans模型 允许将神经活性化合物分配给特定的神经调节剂信号传导途径。成功 该项目目标的完成将产生增强和扩大的新天然产品库 以前从未检测过对神经系统的影响，确定了新的神经系统小分子调节剂， 电路，并将这些化合物与特定的神经调节剂信号系统相匹配，这些信号系统是疾病病理学的组成部分。 成瘾

PROJECT SUMMARY Addiction is a complex pathology of neural circuits that function in reward-processing, impulse control, and goal-directed behaviors. Small molecules targeting neuromodulator signaling pathways that function in these circuits are important therapeutics for the treatment of addiction. There is an urgent need to improve the pharmacology used to treat addiction. To address this need, we have developed methods that uses behavior- based screens to interrogate a novel source of natural products for effects on neuromodulator signaling in the nervous system of a microscopic animal - the nematode C. elegans. The natural products that we will screen are microbial metabolites that have eluded detection because they are not expressed under basal conditions but can only be elicited by environmental triggers. This microbial 'dark metabolome' contains small molecules with a wide variety of biological activities. These compounds have not yet been assayed for effects on the animal nervous system, and they constitute a rich and untapped resource for novel psychopharmacology. Through screens designed to demonstrate proof-of-concept, we have already identified compounds that strongly and specifically act on a circuit that uses neuropeptides and serotonin to generate behavior. We have also designed behavior-based screens for novel modulators of dopamine signaling. In addition to providing the opportunity to perform high-throughput behavior-based screens, the powerful genetics of the C. elegans model allows assignment of neuroactive compounds to specific neuromodulator signaling pathways. Successful completion of the aims of this project will generate enhanced and expanded libraries of novel natural products never before assayed for effects on the nervous system, identify novel small-molecule regulators of neural circuits, and match those compounds to specific neuromodulator signaling systems integral to the pathology of addiction.