The Involvement of Tyramine in Cocaine Sensitization

在精神兴奋剂滥用的脊椎动物模型和黑腹果蝇中，暴露于精神兴奋剂（如可卡因）会诱导刻板的、反射性的运动行为。重复服用可卡因会导致一种称为行为敏化的现象，其定义为药物反应性的长期增强，并被认为是成瘾过程的相关部分。在果蝇中，微量胺酪胺及其合成酶酪氨酸脱羧酶（TDC）在行为敏化的形成中起重要作用。暴露于可卡因会以时间依赖性方式显著增加大脑中的TDC酶活性，这与致敏作用的发展平行。此外，在突变失活（iav），这不能发展致敏和TDC水平显着降低，敏化可以通过喂养酪胺拯救拟议的研究将寻求进一步确定TDC活性的上调的机制，并表征这种上调是如何参与发展可卡因致敏在果蝇。为了实现这一目标，我将开发工具来表征果蝇TDC的调节，并确定其在神经系统中的时空分布。通过加深我们对果蝇中TDC调控和表达的理解，我希望为无脊椎动物和脊椎动物大脑中可卡因致敏的基本机制提供线索。

Exposure to psychostimulants such as cocaine induces stereotypic, reflexive motor behaviors in vertebrate animal models of psychostimulant abuse, and in Drosophila melanogaster. Repeated doses of cocaine result in a phenomenon known as behavioral sensitization, which is defined as a long-lasting augmentation of drug responsiveness and is believed to be a correlative part of the addictive process. In Drosophila, the trace amine tyramine and its synthesizing enzyme, tyrosine decarboxylase (TDC), play important roles in the development of behavioral sensitization. Cocaine exposure significantly increases TDC enzyme activity in the brain in a time-dependent manner that parallels the development of sensitization. Additionally, in the mutant inactive (iav), which fails to develop sensitization and has significantly reduced levels of TDC, sensitization can be rescued by feeding tyramine The proposed research will seek to further identify the mechanisms underlying the up-regulation of TDC activity and to characterize how this up-regulation is involved in the development of cocaine sensitization in Drosophila. In order to attain this goal, I will develop tools to characterize the regulation of the Drosophila TDC and to identify its temporal and spatial distribution in the nervous system. By enhancing our understanding of TDC regulation and expression in Drosophila, I hope to provide clues regarding the basic mechanisms of cocaine sensitization in both the invertebrate and vertebrate brain.