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.

项目概要/摘要在我国阿片类药物危机最严重的时期，因甲基苯丙胺 (METH) 过量服用而导致的死亡人数正在增加上升，并且没有 FDA 批准的治疗冰毒使用障碍 (MUD) 的药物，需要新的药物靶标。特别是对于那些大量使用该药物的人来说，因为他们最难戒掉冰毒，患有各种严重的神经系统问题，并且服用药物过量的风险很高。重度强迫性冰毒消耗（严重 MUD）模型提供的证据表明，伏隔核 (NAc) 中的神经保护蛋白 Parkin 是一个关键的奖励介导大脑区域，在其中发挥着重要作用 Parkin 是一种蛋白质泛素连接酶，在严重的 MUD 中发挥着重要作用。因此，维持细胞能量——三磷酸腺苷（ATP）的产生。蛋白质组数据显示 NAc 中 Parkin 的上调导致多个克雷布斯循环的上调众所周知，parkin 敲除会导致线粒体功能失调。该提案研究了帕金减少冰毒的新假设。渴望和成瘾行为是由 NAc 中的克雷布斯循环功能引起的 METH 神经毒性。有助于维持暴露于 METH 的 NAc 神经元中 ATP 的生成，否则该神经元会受到 METH 的损害换句话说，我们将测试功能失调的线粒体是否是 MUD 的一个原因。我们将通过三个独立的具体目标来检验该假设，具体目标 1 将确定是否和。 Parkin 如何保护大鼠 NAc 中的克雷布斯循环功能免受自我施用 METH 的神经毒性。目标 2 将确定患有严重 MUD 的大鼠 NAc 中的 Parkin 过度表达是否会减少冰毒成瘾行为的具体目标3将决定氧化应激是否过度表达。大鼠NAc中敏感的克雷布斯循环酶DLST（二氢硫辛酰胺S-琥珀酰转移酶）严重的 MUD 会减少冰毒成瘾行为，因为帕金可能具有减少冰毒成瘾的双重功能。 METH 神经毒性和 METH 渴望，这些研究将确定靶向 Parkin 是否具有显着效果鉴于有限的间接数据表明 METH 对 NAc 具有神经毒性。线粒体有助于 MUD 的发展，这些研究将阐明 METH-的作用诱导氧化应激介导 METH 使用和发展寻求 METH 的动机此外，该结果将有利于阿片类药物和酒精使用障碍的研究，因为这些疾病。最后，由于长期使用冰毒，特别是高剂量，容易导致线粒体功能障碍。这项研究的结果表明，帕金森病以及阿尔茨海默病也有可能发展将为这些研究领域添加信息。