The Involvement of Tyramine in Cocaine Sensitization

在精神刺激剂滥用的脊椎动物模型和黑腹果蝇中，暴露于诸如可卡因之类的心理刺激剂会诱导刻板的、反射性的运动行为。反复服用可卡因会导致一种被称为行为敏化的现象，它被定义为药物反应性的长期增强，被认为是成瘾过程中相关的一部分。在果蝇中，微量的酪胺及其合成酶酪氨酸脱羧酶(TDC)在行为敏化的发展中起着重要的作用。可卡因暴露显着增加了大脑中TDC酶的活性，并与敏化的发展平行，呈时间依赖的方式。此外，在未能发展敏化并显著降低TDC水平的突变不活跃(IAV)中，敏化可以通过喂食酪胺来挽救。拟议的研究将寻求进一步确定TDC活性上调的机制，并表征这种上调如何参与果蝇可卡因敏化的发展。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间和空间分布。通过加强对果蝇TDC调控和表达的了解，我希望为可卡因在无脊椎动物和脊椎动物脑中敏化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.