Drosophila to elucidate serotonin's role in stimulant drug abuse

 描述（由申请人提供）：滥用可卡因和甲基苯丙胺等兴奋剂是美国的一个重大公共卫生问题。虽然对传统哺乳动物系统的研究已经提供了非常丰富的信息，但仍然没有FDA批准的治疗方法。迫切需要开发新的工具和模式来解决这些问题。将果蝇（Drosophila melanogaster）纳入研究药物滥用的模型库是该领域最近令人兴奋的发展。在哺乳动物中，多巴胺是果蝇中的一种关键神经递质，已发现其介导对CNS兴奋剂的保守行为，包括增加的运动活性和刻板性。尽管在果蝇中发现了与人类药物作用相关的发现，但兴奋剂如何在基本水平上引起果蝇的行为仍然不确定。除了多巴胺是一个关键成分，蘑菇体也参与其中之外，人们对可卡因和安非他明在果蝇中的作用背后的神经化学和回路知之甚少。在哺乳动物中，血清素已被证明可以调节这些兴奋剂的行为效应。然而，在与药物滥用相关的细胞和电路水平上，这种调制的潜在分子机制在很大程度上仍然未知。虽然果蝇大脑的整体电路和结构与人类大脑不同，但在基本和基础层面上，涉及单个神经元和较大结构和电路之间的输入和输出的过程以及它们如何机械地相互通信在果蝇和哺乳动物之间保持了很大程度。更好地理解这些回路如何相互作用，并使用神经递质如血清素和多巴胺相互交流，以产生急性和/或适应性变化，改变正常行为，以响应兴奋剂，将在基础水平上转化为更好地理解哺乳动物大脑中的神经元和回路如何利用相同的神经递质机械地响应相同的药物，以产生保守的行为。我们建议在这里阐明神经回路的甲基苯丙胺和可卡因的反应，并检查在这些反应中的作用，5-羟色胺和5-羟色胺受体。对于我们提出的工作，我们将结合联合收割机药理学，遗传学，行为学和药物遗传学DREADD受体的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，所有三个5-羟色胺受体家族在苍蝇（5-HT 1A，5-HT 2和5-HT 7）调解方面的反应，以刺激药物。最终，我们的工作可能会发现新的兴奋剂药物滥用的分子和/或遗传方面，并促进潜在的治疗策略的发展。

 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.