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，暴露于可卡因等精神兴奋剂会诱发刻板的反射性运动行为。重复剂量的可卡因会导致一种被称为行为致敏的现象，这种现象被定义为对药物反应的长期增强，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（tyrosine decarboxylase， TDC）在行为致敏的发展中起着重要作用。可卡因暴露显著增加大脑中TDC酶的活性，其时间依赖性与致敏性的发展相似。此外，在失活突变体（iav）中，不能产生致敏，TDC水平显著降低，可以通过喂食酪胺来恢复致敏。拟议的研究将寻求进一步确定TDC活性上调的机制，并描述这种上调如何参与果蝇可卡因致敏的发展。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。通过加强我们对果蝇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.