Extracellular vesicles, meth relapse and sex differences

细胞外囊泡、冰毒复发和性别差异

• 批准号: 10432055
• 负责人: Rick A Bevins
• 金额: $ 47.33万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10432055
• 关键词: Actins; Address; Affect; Animal Model; Anti-Inflammatory Agents; Archives; Astrocytes; Attenuated; Basic Science; Behavioral; Biochemical; Biogenesis; Biological Assay; Brain; Cells; Chronic; Complement; Complex; Data; Dendritic Spines; Dependence; Development; Drug usage; Extinction (Psychology); Female; Foundations; Functional disorder; Future; Gene Targeting; Glutamates; Goals; Gold; Impairment; In Vitro; Individual; Inflammation; Injury; Intravenous; Knowledge; Measures; Mediating; Membrane Proteins; Methamphetamine; Methamphetamine dependence; Methamphetamine relapse; Methodology; MicroRNAs; Microglia; Modeling; Molecular; Mood Disorders; Neuroglia; Neurons; Outcome; Pathway interactions; Pharmaceutical Preparations; Physiology; Plasma; Play; Pre-Clinical Model; Psychoses; Publishing; Rattus; Recording of previous events; Relapse; Research; Research Personnel; Role; Sampling; Self Administration; Sex Differences; Solid; Sorting - Cell Movement; Synapses; Technology; Testing; Western Blotting; Work; affective disturbance; base; brain dysfunction; confocal imaging; efficacy testing; excitotoxicity; exosome; extracellular vesicles; glial activation; male; methamphetamine effect; methamphetamine use; nanoplasmonic; neurotransmission; novel; potential biomarker; pre-clinical; protein biomarkers; psychostimulant; sex; transcriptome sequencing; vesicular release

The abuse of the potent psychostimulant methamphetamine (meth) continues to pose a significant threat not just in the US but also globally. A significant attribute associated with chronic meth induced brain dysfunction is inflammation includes activation of glial cells such as astrocytes and microglia that play a crucial role in modulating inflammation including glutamate excitotoxicity at the synapse. Mounting evidence suggests that inflammation and alterations in glutamate neurotransmission are two novel pathways associated with the pathophysiology in mood disorders. Notably, this cross talk between neurons and glial cells is mediated by extracellular vesicles (EVs) which are emerging as key players in regulating brain function. Chronic meth dependent individuals, including those abstinent and then relapse, display significant behavioral (mood) alterations such as psychosis. A significant gap in knowledge is understanding how meth-induced inflammation perturbs glutamatergic physiology which subsequently impair EV dynamics and exacerbates relapse. Adding another layer of importance is emerging studies showing a role for sex differences with females progressing more quickly to regular use of meth as well as greater dependence and higher relapse rates. Given the lack of studies elucidating the role of EVs with meth relapse between the sexes, our proposed studies are well poised to address this important knowledge gap. Accordingly, the overarching goal of this proposal is to examine the role of EVs in the damaging effects of meth between the sexes using drug-triggered reinstatement (relapse) of extinguished intravenous meth self-administration in rats. Based on our recent preliminary studies with females showing higher inflammation, enhanced glutamatergic alterations, and significantly higher drug-triggered reinstatement (i.e., meth seeking), we hypothesize that EV biogenesis, release, and associated cargo are more impacted in females than males. Using an array of complementing behavioral, molecular, and biochemical approaches in a “gold standard” preclinical model or reinstatement we will : determine how the anti-inflammatory drug ibudilast alters dynamics of EV release, biogenesis, and associated cargo between the sexes (Aim1); Characterize role of EVs isolated from the sexes on synaptodendritic damage (Aim 2 and) test meth induced changes in EV-associated surface proteins between the sexes (Aim 3). These studies will break new ground and importantly provide novel proof of concept studies which will further serve as a prelude to future basic research on developing EVs as sex-specific medication development for treating meth addiction. .!

强效精神兴奋剂甲基苯丙胺（甲基苯丙胺）的滥用继续构成重大威胁， 不仅在美国，而且在全球范围内，与慢性冰毒引起的脑功能障碍相关的一个重要特征是。 炎症包括星形胶质细胞和小胶质细胞等神经胶质细胞的激活，这些细胞在炎症反应中发挥着至关重要的作用。 调节炎症，包括突触处的谷氨酸兴奋性毒性。 炎症和谷氨酸神经传递的改变是与 情绪障碍的病理生理学值得注意的是，神经元和神经胶质细胞之间的这种交流是由介导的。 细胞外囊泡（EV）正在成为调节大脑功能的关键角色。 依赖个体，包括那些戒酒然后复发的人，表现出明显的行为（情绪） 认知上的一个重大差距是了解甲基苯丙胺如何引起炎症。 扰乱谷氨酸生理机能，从而损害 EV 动力学并加重病情复发。 另一层重要性是新兴研究表明性别差异对女性进步的影响 由于缺乏冰毒，人们会更快地定期使用冰毒，并产生更大的依赖性和更高的复发率。 研究阐明了 EV 在两性之间冰毒复发中的作用，我们提出的研究已经做好准备 为了解决这一重要的知识差距，本提案的首要目标是审查 使用药物触发的恢复（复发）研究 EV 在两性之间冰毒的破坏性影响中的作用 根据我们最近对雌性大鼠的初步研究，消除了大鼠的静脉注射冰毒。 显示出更高的炎症、增强的谷氨酸能改变以及显着更高的药物触发 恢复（即寻求冰毒），我们发现 EV 的生物发生、释放和相关货物更多 使用一系列补充行为、分子和生化方法对女性的影响大于男性。 在“黄金标准”临床前模型或恢复中的方法，我们将：确定如何抗炎 药物异丁司特改变两性之间 EV 释放、生物发生和相关货物的动态（Aim1）； 表征从性别中分离出的 EV 对突触树突损伤（目标 2 和）测试甲基诱导的作用 两性之间 EV 相关表面蛋白的变化（目标 3）。 重要的是提供新颖的概念验证研究，这将进一步作为未来基础研究的前奏 开发 EV 作为治疗冰毒成瘾的性别特异性药物开发。 .!