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

项目概要 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。针对在这些功能中发挥作用的神经调节信号通路的小分子 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，我们开发了使用行为的方法- 基于筛选来询问天然产物的新来源对神经调节信号传导的影响 微观动物的神经系统 - 线虫秀丽隐杆线虫。我们将筛选的天然产品 是逃避检测的微生物代谢物，因为它们在基础条件下不表达 但只能由环境触发因素引起。这种微生物的“暗代谢组”含有小分子 具有多种生物活性。尚未分析这些化合物对 动物神经系统，它们构成了新型精神药理学丰富且未开发的资源。 通过旨在展示概念验证的屏幕，我们已经确定了以下化合物： 强烈且特异性地作用于使用神经肽和血清素产生行为的电路。我们有 还为多巴胺信号传导的新型调节剂设计了基于行为的屏幕。除了提供 进行基于行为的高通量筛选的机会，线虫模型的强大遗传学 允许将神经活性化合物分配给特定的神经调节信号通路。成功 该项目目标的完成将产生增强和扩大的新型天然产物库 以前从未分析过对神经系统的影响，确定神经的新型小分子调节剂 电路，并将这些化合物与特定的神经调节信号系统相匹配，这些神经调节信号系统是病理学不可或缺的一部分 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.