March5 and Associated Mitochondrial Dynamics in Incubation of Oxycodone Craving

March5 和相关线粒体动力学在羟考酮渴望孵化中的作用

基本信息

批准号：
10724668
负责人：
Xuan Anna Li
金额：
$ 22.47万
依托单位：
UNIV OF MARYLAND, COLLEGE PARK
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10724668
关键词：
Abstinence Anatomy Behavior Biochemical Cell physiology Clinical Cues Data Drug Addiction Drug usage Dynamin Exploratory/Developmental Grant Exposure to Extinction Frequencies Incubated Intervention Label Lead Length Link Literature Mediating Mediator Mitochondria Modeling Molecular Molecular Target Morphine Morphology Mus Neurons Nucleus Accumbens Opiate Addiction Opioid Oxycodone Pharmaceutical Preparations Play Proteins Publishing Rattus Regulation Relapse Research Rewards Role Saline Self Administration System Testing Time Ubiquitin Ubiquitination Viral Viral Vector Work activity marker addiction cocaine relapse cocaine seeking craving drug abstinence drug craving genetic manipulation innovation mRNA Expression male mitochondrial dysfunction multicatalytic endopeptidase complex neuromechanism opioid epidemic pharmacologic prescription opioid abuse prolonged abstinence protein degradation protein expression psychostimulant relapse prevention therapeutic target ubiquitin-protein ligase

Abstinence Anatomy Behavior Biochemical Cell physiology Clinical Cues Data Drug Addiction Drug usage Dynamin Exploratory/Developmental Grant Exposure to Extinction Frequencies Incubated Intervention Label Lead Length Link Literature Mediating Mediator Mitochondria Modeling Molecular Molecular Target Morphine Morphology Mus Neurons Nucleus Accumbens Opiate Addiction Opioid Oxycodone Pharmaceutical Preparations Play Proteins Publishing Rattus Regulation Relapse Research Rewards Role Saline Self Administration System Testing Time Ubiquitin Ubiquitination Viral Viral Vector Work activity marker addiction cocaine relapse cocaine seeking craving drug abstinence drug craving genetic manipulation innovation mRNA Expression male mitochondrial dysfunction multicatalytic endopeptidase complex neuromechanism opioid epidemic pharmacologic prescription opioid abuse prolonged abstinence protein degradation protein expression psychostimulant relapse prevention therapeutic target ubiquitin-protein ligase

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项目摘要

Project summary/abstract Reducing rates of relapse after abstinence is a key challenge for curbing the ongoing opioid epidemic. One of the common factors for triggering relapse is re-exposure to drug-associated cues. In rats, cue-induced oxycodone seeking progressively intensifies (incubates) over the first weeks of abstinence from extended access oxycodone self-administration, and remains high for at least a month of abstinence. Our recently published work demonstrated a critical role of orbitofrontal cortex (OFC) in this incubation. However, molecular mechanisms in OFC underlying this incubation are largely unknown. Specifically, our observation of a progressive increase of neuronal activation in OFC associated with oxycodone seeking could be the result of time-dependent molecular adaptations in OFC during abstinence. Emerging evidence has implicated both the ubiquitin proteasome system (UPS) and mitochondrial regulation in addiction-related plasticity. Linking these two lines of work, we found that mRNA expression of March5, a mitochondrial E3 ubiquitin ligase, was significantly decreased in OFC on abstinence day 15 compared with saline control. A key role of March5 is to suppress mitochondrial fission, by degrading mitochondrial fission mediators such as dynamin-related protein 1(Drp1). Based on this preliminary work, here we propose to examine the role of March5 and associated mitochondria dynamics in incubation of oxycodone craving. In Aim 1, we will use biochemical approaches to examine protein expression of March5 and its downstream target Drp1 in the OFC, and use viral-mediated gene manipulation to determine if March5 in the OFC plays a causal role in the incubation of oxycodone craving. In Aim 2, we will use viral vectors to label mitochondria in OFC neurons and examine the morphology of mitochondria in OFC neurons during incubation of oxycodone craving. Overall, this proposal will initiate a new line of research focusing on the mitochondrial E3 ubiquitin ligase in OFC in relapse to drug seeking. From a clinical perspective, this work will provide targets for developing pharmacological interventions to decrease drug craving and promote abstinence.

项目摘要/摘要减少禁欲后复发率是遏制正在进行的阿片类药物流行病的关键挑战。一触发复发的常见因素是重新暴露与药物相关线索。在大鼠中，提示引起羟考酮寻求逐步加强（孵化）在戒酒的最初几周。羟考酮自我给药，至少戒酒至少一个月。我们最近发表的作品在此孵育中表现出轨道额皮层（OFC）的关键作用。但是，分子机制此孵育的基础cc基本上未知。具体而言，我们对逐步增加的观察与寻求羟考酮有关的OFC中的神经元激活可能是时间依赖性分子的结果禁欲期间OFC的适应。新兴证据牵涉到泛素蛋白酶体系统（UPS）和与成瘾相关的可塑性中的线粒体调节。将这两条工作联系起来，我们发现 March5（线粒体E3泛素连接酶）的mRNA表达在OFC上显着降低与盐水对照相比，禁欲第15天。 March5的关键作用是抑制线粒体裂变，线粒体裂变介质（如动力蛋白相关蛋白1（DRP1））的降解。基于这个初步工作，我们建议在这里研究March5和相关线粒体动态在孵育中的作用羟考酮的渴望。在AIM 1中，我们将使用生化方法检查March5的蛋白质表达和它的下游目标DRP1在OFC中，并使用病毒介导的基因操纵来确定March5是否在 OFC在羟基渴望的孵育中起因果作用。在AIM 2中，我们将使用病毒向量标记 OFC神经元中的线粒体并检查孵育过程中OFC神经元中线粒体的形态羟考酮的渴望。总体而言，该提案将启动一系列新的研究，重点是线粒体E3 OFC中的泛素连接酶复发。从临床角度来看，这项工作将为制定药理干预措施，以减少药物渴望并促进戒酒。