Drosophila to elucidate serotonin's role in stimulant drug abuse

果蝇阐明血清素在兴奋剂药物滥用中的作用

基本信息

批准号：
9312276
负责人：
CHARLES D NICHOLS
金额：
$ 18.25万
依托单位：
LSU HEALTH SCIENCES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-15 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9312276
关键词：
Acute Address Amphetamines Animals Arousal Back Behavior Behavioral Behavioral Genetics Biological Models Biology Brain Central Nervous System Stimulants Cocaine Complex Data Dependence Development Dopamine Drosophila genus Drosophila melanogaster Drug abuse Drug effect disorder FDA approved Family Future Genetic Genetic Models Genetic Techniques Glutamates Goals Health Human Individual Knowledge Mammals Maps Mediating Methamphetamine Modeling Molecular Molecular Genetics Motor Activity Motor output Mushroom Bodies Neurons Neuropharmacology Neuropil Neurotransmitters Output Pharmaceutical Preparations Pharmacogenetics Pharmacology Play Process Productivity Public Health Role Sensory Serotonin Structure Study models Sympathomimetics Synapses System Technology Therapeutic Tissues Translating Treatment Efficacy United States Work addiction behavioral pharmacology behavioral response cost drug of abuse experimental study fly gamma-Aminobutyric Acid neural circuit neurochemistry neurotransmission novel strategies novel therapeutic intervention public health relevance receptor receptor function relating to nervous system response serotonin receptor stereotypy stimulant abuse tool treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Abuse of stimulants like cocaine and meth amphetamines is a significant public health problem in the United States. Although the study of traditional mammalian systems has been very informative, there are still no FDA approved therapies for their abuse. The development of new tools and models is urgently needed to address these problems. Incorporation of the fruit fly, Drosophila melanogaster, into the repertoire of models to study drug abuse has been a recent and exciting development for the field. As in mammals, dopamine is a key neurotransmitter in flies that has been found to mediate conserved behaviors to CNS stimulants that include increased locomotor activity and stereotypy. Despite the discoveries made in the fly relevant to human drug action, how stimulants elicit their behaviors in the fly at a fundamental level remain undefined. Little is knon of the neurochemistry and circuitry underlying the effects of cocaine and amphetamines in the fly aside from the fact that dopamine is a key component, and that the mushroom body is involved. In mammals, serotonin has been shown to modulate the behavioral effects of these stimulants. The underlying molecular mechanisms of this modulation at the cellular and circuitry level related to drug abuse, however, remain largely unknown. Although the overall circuitry and structure of the fly brain is different from the human brain, at a basic and fundamental level, processes involving inputs and outputs between individual neurons and larger structures and circuits and how they mechanistically communicate with each other are conserved to a significant degree between fly and mammal. A greater understanding of how these circuitries interact and communicate with each other using neurotransmitters like serotonin and dopamine to produce acute and/or adaptive changes that alter normal behavior in response to stimulants will at a fundamental level translate to a better understanding of how neurons and circuits in mammalian brain that utilize the same neurotransmitters mechanistically respond to the same drugs to produce conserved behaviors. We propose here to elucidate the neural circuitry underlying the response to methamphetamine and cocaine, and to examine the role of serotonin and serotonin receptors in these responses. For our proposed work we will combine pharmacological, genetic, behavioral, and pharmacogenetic DREADD receptor approaches to manipulate circuitry and receptor function. Significantly, our preliminary data indicate that all three serotonin receptor families in the fly (5-HT1A, 5-HT2, and 5-HT7) mediate aspects of the response to stimulant drugs. Ultimately our work may uncover new molecular and/or genetic aspects of stimulant drug abuse and facilitate the development of potential therapeutic strategies.

描述（由适用提供）：在美国，滥用可卡因和甲基苯丙胺等兴奋剂是一个重大的公共卫生问题。尽管对传统哺乳动物系统的研究非常有用，但仍然没有FDA批准的滥用疗法。迫切需要开发新工具和模型来解决这些问题。将果蝇果蝇果蝇（Drosophila Melanogaster）纳入模型的曲目，研究滥用药物滥用的曲目一直是该领域的最新发展。与在哺乳动物中一样，多巴胺是果蝇中的关键神经递质，它被发现介导了CNS兴奋剂，其中包括增加运动活性和刻板印象。尽管与人类药物作用有关的飞行中发现了发现，但兴奋剂如何在基本层面上飞行的行为仍然不确定。除了多巴胺是关键成分，并且涉及肌肉体，可卡因和苯丙胺在飞行中的作用的神经化学和电路几乎没有。在哺乳动物中，已证明5-羟色胺可以调节这些兴奋剂的行为效应。然而，该调节在与药物滥用有关的细胞和电路水平上的基本分子机制仍然在很大程度上未知。尽管在基本和基本水平上，蝇脑的整体电路和结构与人脑不同，但涉及单个神经元与较大结构和电路之间的输入和输出的过程以及它们如何彼此机械通信在苍蝇和哺乳动物之间在很大程度上保持了一定程度。更了解这些电路如何使用神经递质（如5-羟色胺和多巴胺）产生急性和/或自适应变化的神经递质相互交流和交流，这些变化会改变对刺激剂的响应正常行为，这将转化为对同一神经培训的哺乳动物脑中的神经元和电路师如何使用同一神经培训响应的哺乳动物，从而可以更好地理解。我们在这里提出，旨在阐明对甲基苯丙胺和可卡因反应的基础神经记录，并检查5-羟色胺和5-羟色胺受体在这些反应中的作用。对于我们提出的工作，我们将结合药理学，遗传，行为和药物遗传学的Dreadd受体方法来操纵电路和受体功能。值得注意的是，我们的初步数据表明，所有三种血清素受体家族（5-HT1A，5-HT2和5-HT7）介导了对兴奋剂药物反应的方面。最终，我们的工作可能会发现刺激药物滥用的新分子和/或遗传方面，并支持潜在的治疗策略的发展。