Thorase Regulation of the Actions of Cocaine

可卡因作用中的激动素酶调节 对可卡因等滥用药物的上瘾是一个世界性的健康危机。在美国有一种 据估计，目前有150万可卡因使用者，这一数字一直相对稳定。广泛的研究已经 研究表明，可卡因会导致大脑中的可塑性变化，这些变化是行为变化的基础，包括 AMPA受体表达的变化及雷帕霉素作用靶点的激活 复合体1(MTORC1)在可卡因成瘾发生和维持中的作用。我们发现了Thorase，AAA级的 用于促进AMPA受体分解的ATPase，最近还发现了它 反汇编mTORC1。我们的假设是，Thorase准备在 通过调控AMPA受体和mTORC1对可卡因的行为和细胞反应 活性，因此是多巴胺能神经可塑性的重要变化的基础，我们将在 遵循目标。 目的1：为了全面了解可卡因对Thorase和mTOR信号转导功能的作用 以及Thorase与mTOR和mTORC1组分的生化相互作用。 已定义。 目的2：研究Thorase活性在可卡因增强特性中的作用。自我管理和 将监测野生型、Thorase KO和Thorase TG小鼠恢复寻找可卡因的行为。 目的3：当雷帕霉素阻断可卡因诱导的啮齿动物行为时，可以合理地预测可卡因是 过度激活mTORC1.因为nNOS的抑制或基因缺失，从而NO，对 可卡因的行为类似于雷帕霉素，而S-亚硝化抑制Thorase活性，我们假设可卡因是 S亚硝化抑制胸腺苷酶导致mTORC1超激活并改变mTORC1mRNA的表达 AMPA受体。 目标4：将解决mTORC1和Thorase是否在很大程度上负责蛋白质组和 暴露于可卡因后的翻译变化。转录组、翻译组和 将探索对可卡因暴露作出反应的蛋白质组。 这个项目的首要目标是确定Thorase在神经可塑性调节中的作用 对可卡因上瘾行为的反应。

Thorase Regulation of the Actions of Cocaine Addiction to drugs of abuse such as cocaine is a world-wide health crisis. In the USA there are an estimated 1.5 million current cocaine users, a number that has been relatively stable. Extensive studies have revealed that cocaine, induces plastic changes in the brain that underlie the behavioral changes including changes in expression of AMPA receptors as well as activation of the mechanistic target of rapamycin complex 1 (mTORC1) in the onset and maintenance of cocaine addiction. We discovered Thorase, an AAA+ ATPases that serves to facilitate the disassembly AMPA receptors and recently discovered it also disassembles mTORC1. Our hypothesis is that Thorase is poised to play a pivotal and critical role in the behavioral and cellular responses to cocaine by directing both AMPA receptor expression and mTORC1 activity and thus underlies important changes in dopaminergic neuroplasticity which we will explore in the following Aims. Aim 1: In order to fully comprehend the actions of cocaine on Thorase and mTOR signaling the functional and biochemical interactions of Thorase with mTOR and components of mTORC1 will be explored and defined. Aim 2: The role of Thorase activity on cocaine’s reinforcing properties will be studied. Self-administration and reinstatement to cocaine seeking behavior will be monitored in wild type, Thorase KO and Thorase TG mice. Aim 3: As Rapamycin blocks cocaine induced behaviors in rodents, it is reasonable to predict that cocaine is hyperactivating mTORC1. Since inhibition or genetic deletion of nNOS, and thus NO, has similar effects on cocaine behaviors as rapamycin, and S-nitrosylation inhibits Thorase activity, we hypothesize that cocaine is inhibiting Thorase through S-nitrosylation resulting in hyperactivation of mTORC1 and altering expression of AMPA receptors. Aim 4: Will address whether mTORC1 and Thorase are largely responsible for the proteomic and translational changes following exposure to cocaine. Changes to the transcriptome, translatome and proteome in response to cocaine exposure will be explored. The overarching goal of this project is to define the role of Thorase in the regulation of neuroplastic responses that underlie the addictive behaviors to cocaine.