Cocaine-induced planarian behavior and its modulation by sesquiterpene lactones

描述(由申请人提供)：发现能够以最小的生理影响防止可卡因的有害特性的化合物是一个很有前途的研究领域。人们对可卡因滥用进行了深入的研究；然而，对于可卡因成瘾或过量，还没有得到证实的药物治疗方法。扁虫是研究可卡因行为影响的很有前途的动物模型。从进化论的角度来看，行星动物是第一个显示出大脑定义明确的有机体，大脑在结构上与脊椎动物神经系统有许多相似之处。浮游生物可以表现出与可卡因“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的形态变化。在药理学研究中，盘藻是一种经典的“未充分利用”的动物模型。与这种有机体合作有几个明显的优势。它们可以以非常低的成本在商业上获得，并且很容易在实验室中保存。天然环状倍半萜内酯(SL)、小白菊内酯及其类似物可阻止急性注射可卡因对扁平线虫的行为影响。此外，Parthenolide防止在同一生物体中诱导因长期接触可卡因而产生的戒断行为。该项目的主要目的是筛选更多的SL类似物，以了解它们对抗可卡因对浮游生物的影响的能力。拟议的实验将提供指向巴特内酯类化合物家族的药效团(一种化合物必须具有的一组结构特征)的信息，该家族有能力逆转可卡因诱导的浮游动物的行为。这种药效团将有助于发现能够作为抗可卡因制剂的新化合物。在包括人类在内的各种生物体中寻找能够作为抗可卡因制剂的化合物时，任何有关巴特内酯类化合物与浮萍体内可卡因相互作用的信息都将是有用的。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影响的化合物。公共卫生相关性：可卡因滥用是一个严重的公共卫生问题。到目前为止，还没有任何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能用作抗可卡因制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.