Engineering Drosophila that self-administer cocaine

-项目摘要/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。这一年的经济负担 创造的价值高达数千亿美元。在发育过程中有很大的遗传因素 药物滥用障碍(SUD)，但许多分子途径仍有待阐明。醋飞， 一百多年来，黑腹果蝇一直是一种遗传模式生物。重大进步 在过去的10年里已经在研究苍蝇对酒精的行为反应方面取得了进展，这两项研究都是在 表征新的保守基因和途径，但也在开发类似于 更接近于上瘾。这项提议的目标是让果蝇自行注射可卡因。这 化合物通常作为一种令人厌恶的抗食草动物化学物质，我们假设这是因为 可卡因放大了多巴胺能信号，在果蝇中，这主要是但不是唯一的厌恶信号。首先，我们将 确定果蝇是否自我注射可卡因。我们将建立剂量反应曲线，并测试 可卡因暴露前对可卡因偏好/厌恶的影响。我们还将测试多巴胺信号对 吸食可卡因。其次，我们将改造只含有可卡因敏感的多巴胺转运体的苍蝇 在这些多巴胺神经元中发育所需的自我给药。另一种则是厌恶 这些基因改造的果蝇将包含一种可卡因不敏感的多巴胺转运体。这个 拟议中的实验将在一种模型生物中产生一种新的可卡因自我给药测试，该模型生物具有 历史证明了巨大的规模经济和在阐明分子机制方面的成功 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.