Investigating Parkin-mediated Neuronal Energy Maintenance in Methamphetamine Use Disorder

研究甲基苯丙胺使用障碍中 Parkin 介导的神经元能量维持

基本信息

批准号：
10736697
负责人：
Anna Moszczynska
金额：
$ 31.78万
依托单位：
WAYNE STATE UNIVERSITY
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：
2023-09-30 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10736697
关键词：
Abstinence Addictive Behavior Adenosine Triphosphate Alzheimer&apos s Disease Antioxidants Area Behavior Therapy Biogenesis Brain Cessation of life Chronic Citric Acid Cycle Clinical Trials Communities Consumption Country Data Development Disease Dose Down-Regulation Drug Targeting Drug usage Energy Metabolism Enzymes FDA approved Generations Glutathione Goals Health Height Impairment Individual Knock-out Knowledge Laboratories Maintenance Mediating Metabolic Pathway Methamphetamine Methamphetamine overdose Methamphetamine relapse Methamphetamine use disorder Mitochondria Mitochondrial Proteins Modeling Molecular Motivation Neurologic Neurons Nucleus Accumbens Overdose Oxidative Stress Oxidative Stress Induction Parkin Parkinson Disease Participant Pathway interactions Patients Persons Pharmaceutical Preparations Pharmacotherapy Phase Play Production Property Proteins Proteomics Public Health Rattus Relapse Reporting Research Rewards Role Self Administration System Testing Therapeutic Toxic effect Transferase Ubiquitin United States Up-Regulation Work alcohol use disorder attenuation community based participatory research craving high risk innovation insight loss of function methamphetamine exposure methamphetamine use mitochondrial dysfunction multicatalytic endopeptidase complex neurochemistry neuroprotection neurotoxicity new therapeutic target novel opioid epidemic opioid use disorder overexpression oxidative damage relapse prevention response translational impact ubiquitin-protein ligase

项目摘要

PROJECT SUMMARY / ABSTRACT In the height of the opioid crisis in our country, deaths from methamphetamine (METH) overdose are on the rise, and there is no FDA-approved medication for METH use disorder (MUD). New drug targets are needed, particularly for people who heavily use the drug because they have the most difficulty quitting METH use, suffer from a variety of serious neurological problems, and are at high risk to overdose on the drug. Our work with a rat model of heavy compulsive METH consumption (severe MUD) provided evidence that overexpression of neuroprotective protein parkin in the nucleus accumbens (NAc), a key reward-mediating brain area, plays a role in severe MUD. Parkin is a protein-ubiquitin ligase known to play a critical role in maintaining mitochondrial health and, therefore, in maintaining generation of cellular energy - adenosine triphosphate (ATP). Our preliminary proteomic data shows that upregulation of parkin in the NAc leads to upregulation of several Krebs cycle enzymes whereas parkin knockout leads to their downregulation. Dysfunctional mitochondria are the known consequence of METH use. This proposal investigates the novel hypothesis that parkin decreases METH cravings and addictive behaviors by the Krebs cycle function in the NAc from METH neurotoxicity. This helps to maintain ATP generation in METH-exposed NAc neurons, which otherwise would be impaired by METH- induced oxidative stress. In other words, we will test whether dysfunctional mitochondria are a cause of MUD. We will test the hypothesis by three independent specific aims. The specific aim 1 will establish whether and how parkin protects Krebs cycle function in rat NAc from neurotoxicity of self-administered METH. The specific aim 2 will determine whether parkin overexpression in the NAc of rats with developed severe MUD will decrease METH addictive behaviors. The specific aim 3 will determine whether overexpression of oxidative stress- sensitive Krebs cycle enzyme DLST (dihydrolipoamide S-succinyl-transferase) in the NAc of rats with developed severe MUD will decrease METH addictive behaviors. Given that parkin may serve a dual function of decreasing METH neurotoxicity and METH cravings, these studies will determine whether targeting parkin has a significant therapeutic potential in severe MUD. Given the limited indirect data suggesting that METH neurotoxicity in NAc mitochondria contributes to development of MUD, these studies will provide clarity about the role of METH- induced oxidative stress in mediating METH use and in development of motivation to seek METH during abstinence. Furthermore, the results will benefit opioid and alcohol use disorder research as these disorders induce mitochondrial dysfunction. Lastly, since chronic use of METH, particularly at high doses, predisposes to development of Parkinson’s disease and potentially also to Alzheimer’s disease, the results from this research will add information to these research areas.

项目摘要 /摘要在我国阿片类药物危机的高峰期，甲基苯丙胺（甲基苯丙胺）过量的死亡是上升，并且没有FDA批准的甲基甲基苯丙胺使用障碍药物（泥）。需要新的药物目标特别是对于那些大量使用该药物的人，因为他们使用最困难的甲基苯丙胺使用，来自各种严重的神经系统问题，并且对药物过量的高风险。我们与老鼠的工作重型甲基甲基甲基苯丙胺消耗（严重的泥浆）的模型提供了证据表明过表达的神经保护蛋白帕克蛋白伏伏核（NAC）是一种关键的奖励奖励脑区域，起着作用在严重的泥浆中。 Parkin是一种蛋白质 - 泛素连接酶，已知在维持线粒体健康中起关键作用因此，在维持细胞能的产生时 - 三磷酸腺苷（ATP）。我们的初步蛋白质组学数据表明，NAC中帕金的上调导致几个克雷布斯周期的上调酶，而帕金淘汰赛则导致其下调。功能失调的线粒体是已知的甲基苯丙胺的后果。该提案调查了帕金拒绝甲基苯丙胺的新颖假设 NAC中KREBS循环功能的渴望和加性行为来自甲基NAC的神经毒性。这有助于维持ATP在暴露于METH暴露的NAC神经元中的生成，否则该神经元会受到甲基甲基元的损害诱导氧化应激。换句话说，我们将测试功能失调的线粒体是否是导致泥浆的原因。我们将通过三个独立的特定目标检验假设。具体目标1将确定是否及 Park如何保护大鼠NAC中的Krebs循环功能免受自我管理甲基甲基甲基苯丙胺神经毒性的影响。具体 AIM 2将确定帕金过表达的大鼠NAC是否会减少泥浆的发达大鼠甲基上瘾的行为。具体目标3将确定是否过表达氧化应激 - 敏感的克雷布斯循环酶DLST（二氢丙酰胺S-核酸转移酶）在大鼠的NAC中，发育严重的泥浆会降低甲基甲基苯丙胺的额外行为。鉴于Parkin可能具有减少的双重功能甲基毒性神经毒性和渴望，这些研究将确定靶向帕金是否具有显着严重泥浆中的治疗潜力。考虑到有限的间接数据表明NAC中的甲基毒性神经毒性线粒体有助于泥浆的发展，这些研究将为甲基甲基作用提供明确的作用。在介导甲基甲基苯丙胺的使用和开发动机时诱导氧化应激节制。此外，由于这些疾病，结果将使阿片类药物和酒精使用障碍研究受益诱导线粒体功能障碍。最后，由于长期使用甲基甲基苯丙胺，尤其是在高剂量下，因此倾向于这项研究的结果将为这些研究领域添加信息。