Psychostimulant Response Pathways

描述(由申请人提供)： 该方案以果蝇--黑腹果蝇为模型进行研究 可卡因对游离碱基“裂解”反应的调控途径。 生物体与脊椎动物模型在以下两种类型中都显示出保守性 可卡因诱导的行为及其在生化和信号通路中的作用 在这些行为的基础上，它也显示出对反复使用的可卡因的敏感化。 暴露，这一过程很可能代表了上瘾的一种成分 在人类的过程中。目前的提案集中在神经适应和 导致敏化的信号通路。 前两个目标是为了理解所需的两条新途径 在之前的资助中确定的对果蝇的敏化作用 期间： 在第一个目标中，痕量胺酪胺和基因 将确定可卡因致敏所需的非活性物质。 在第二个目标中，昼夜节律基因产物的作用机制 可卡因中的致敏作用将被确定。 第三个目标将集中在生物胺途径和直接靶标上。 可卡因，多巴胺和5-羟色胺的转运体。 对于上述目标的每一个，都提出了潜在的基因筛查，可以 检测与给定途径相互作用的新基因。 在第四个目标中，脑基因表达的全球变化作为 将对可卡因暴露和致敏进行检查，以确定新的 参与调节可卡因反应的通路的候选基因。

DESCRIPTION (provided by applicant): This proposal uses the fruit fly, Drosophila melanogaster, as a model to study the pathways regulating responses to free base "crack about cocaine. This model organism shows conservation with vertebrate animal models both in the types of cocaine induced behaviors and in the biochemical and signaling pathways underlying these behaviors, it also shows sensitization to repeated cocaine exposures, a process that is likely to represent a component of the addictive process in humans. The current proposal focusses on the neural adaptations and signaling pathways leading to sensitization. The first two aims are directed at understanding two novel pathways required for sensitization in Drosophila that were identified in the previous funding period: In the first aim, the mechanisms by which the trace amine tyramine and the gene inactive are required for cocaine sensitization will be determined. In the second aim, the mechanisms by which the circadian gene products function in cocaine sensitization will be determined. The third aim will focus on the biogenic amine pathways and the direct targets of cocaine, the dopamine and serotonin transporters. For each of the above aims, potential genetic screens are proposed that could detect novel genes interacting with the given pathways. In the fourth aim, global changes in brain gene expression as a function of cocaine exposure and sensitization will be examined in order to identify new genes candidates involved in pathways modulating cocaine responses.