Cocaine-induced planarian behavior and its modulation by sesquiterpene lactones

描述（由申请人提供）：发现能够在最小的生理影响下防止可卡因有害特性的化合物是一个有前途的研究领域。对可卡因滥用进行了深入研究；然而，目前还没有经过证实的药物治疗可卡因成瘾或过量。涡虫扁虫是研究可卡因行为影响的有希望的动物模型。从进化的角度来看，涡虫是第一个具有明确定义的大脑的生物，它与脊椎动物的神经系统在结构上有许多相似之处。涡虫可表现出与可卡因“戒断”一致的行为症状，并表现出与急性和慢性可卡因暴露直接相关的神经系统形态学变化。涡虫是药理学研究中典型的“未充分利用”的动物模型。与这种有机体一起工作有几个明显的优势。它们在市场上很容易买到，成本很低，而且很容易在实验室里保存。天然环倍半萜内酯（SL）、帕thenolide及其类似物可阻止急性可卡因给药对涡虫行为影响的表达。此外，parthenolide防止诱导戒断行为，以应对慢性可卡因暴露在同一生物体。本项目的主要目的是筛选额外的SL类似物，以对抗古柯碱对涡虫的影响。拟议的实验将提供指向药效团的信息（一种化合物必须具备的一组结构特征，以表现出某种活性），这种化合物能够逆转古柯碱在涡虫中引起的行为。这种药效团将有助于发现能够作为抗可卡因药物的新化合物。在涡虫中，任何关于parthenolides类化合物和可卡因相互作用的信息都将有助于在包括人类在内的各种生物体中寻找能够作为抗可卡因剂的化合物。我们研究的长期目标是发现和开发能够预防或减轻滥用药物对人类的影响的化合物。公共卫生相关性：可卡因滥用是一个重大的公共卫生问题。到目前为止，还没有化合物可以减轻可卡因的毒性或行为影响。从拟议的实验中获得的信息将为寻找可作为反可卡因剂的物质提供新的方向。

DESCRIPTION (provided by applicant): The discovery of compounds capable of preventing cocaine's harmful properties with minimal physiological effects is a promising area of research. Cocaine abuse is intensively studied; however, there are no proven pharmacological treatments for cocaine addiction or overdose. Planarian flatworms are a promising animal model to study the behavioral effects of cocaine. In evolutionary terms, planarians are the first example of organisms displaying a well-defined brain, which shares many structural similarities with the vertebrate nervous system. Planarians can exhibit behavioral symptoms consistent with cocaine "withdrawal" and show morphological changes in their nervous system directly associated with acute and chronic cocaine exposure. Planaria is a classically "underused" animal model in pharmacological research. Working with this organism has several distinct advantages. They are commercially available at very low cost and are very easily kept in the laboratory. The natural cyclic sesquiterpene lactone (SL), parthenolide and related analogs prevent the expression of behavioral effects induced by acute cocaine administration to the flatworm planaria. Additionally, parthenolide prevents the induction of withdrawal-like behaviors in response to chronic cocaine exposure in the same organism. The main purpose of this project is to screen additional SL analogs for their ability to antagonize cocaine effects in planarians. The proposed experiments will provide information pointing at a pharmacophore (the set of structural features that a compound must possess to exhibit a certain activity) for the parthenolide-like family of compounds ability to reverse the cocaine-induced behaviors in planarians. This pharmacophore will help to discover novel compounds capable to act as anti-cocaine agents. Any information about the interaction of parthenolide-like compounds and cocaine in planaria will be useful in the search for compounds capable of acting as anti-cocaine agents in a variety of organisms, including humans. The long-term goal of our research is to discover and develop compounds capable to prevent or alleviate abused drugs effects in humans. PUBLIC HEALTH RELEVANCE: Cocaine abuse is a significant public health problem. To date, no compounds exist that can alleviate the toxic or behavioral effects of cocaine. The information that will be obtained from the proposed experiments will provide novel directions in the search for substances that may serve as anti-cocaine agents.