Engineering Drosophila that self-administer cocaine

- 项目概要/摘要- 数以百万计的美国人滥用非法药物，包括兴奋剂可卡因。每年的经济负担 创造了数千亿美元。基因对这种疾病的发展有很大的影响 药物滥用障碍（SUD），但许多分子途径仍有待阐明。醋蝇， 黑腹果蝇（Drosophila melanogaster）作为遗传模式生物已有一百多年的历史。重大进展 在过去的10年里，研究了苍蝇对酒精的行为反应， 表征新的保守基因和途径，而且在开发新的检测方法， 更紧密地上瘾。这项计划的目标是设计果蝇自我服用可卡因。这 化合物通常作为一种令人厌恶的抗草食动物化学物质，我们假设这是因为 可卡因放大多巴胺能信号，这在苍蝇中主要是，但不完全是，令人厌恶的。一是 确定苍蝇是否会自行吸食可卡因。我们将建立剂量反应曲线，并测试 可卡因预暴露对可卡因偏好/厌恶的影响。我们还将测试多巴胺信号对 可卡因消费第二，我们将设计只含有可卡因敏感多巴胺转运蛋白的果蝇， 在这些多巴胺神经元的发展所需的自我管理。另一方面，厌恶 多巴胺神经元，这些工程苍蝇将含有可卡因不敏感的多巴胺转运蛋白。的 提出的实验将在具有以下特征的模式生物中产生新的可卡因自我施用测定： 历史上证明了巨大的规模经济和成功阐明的分子机制， 许多基本的生理和行为过程。

–––– PROJECT SUMMARY / ABSTRACT ––––––––––––––––––––––––––––––––––––––––––––––––––––––– Millions of Americans abuse illicit drugs, including the stimulant cocaine. The annual economic burden this creates is in the hundreds of billions of dollars. There is a substantial genetic contribution to the development of substance abuse disorders (SUD), but many molecular pathways remain to be elucidated. The vinegar fly, Drosophila melanogaster, has been a genetic model organism for more than a hundred years. Major strides have been made in the last 10 years studying the behavioral responses to alcohol in flies, both in characterizing novel conserved genes and pathways, but also in the development of new assays that resemble addiction more closely. The goal of this proposal is to engineer Drosophila flies to self-administer cocaine. This compound normally acts as an aversive antiherbivore chemical, and we hypothesize that this is because cocaine amplifies dopaminergic signaling, which in flies is mainly, but not exclusively, aversive. First, we will determine whether flies self-administer cocaine. We will establish dose response curves, and test the effects of cocaine pre-exposure on cocaine preference/aversion. We will also test the impact of dopamine signaling on cocaine consumption. Second, we will engineer flies that contain cocaine-sensitive dopamine transporters only in these dopamine neurons required for the development of self-administration. In the other, aversive dopamine neurons, these engineered flies will contain a cocaine-insensitive dopamine transporter. The proposed experiments will yield a novel cocaine self-administration assay in a model organism that has historically demonstrated great economy of scale and success in elucidating the molecular mechanisms of numerous basic physiological, and behavioral processes.