Extracellular vesicles, meth relapse and sex differences

滥用强效精神兴奋剂甲基苯丙胺（冰毒）继续构成重大威胁， 不仅在美国，而且在全球。与慢性冰毒诱导的脑功能障碍相关的一个重要特征是 炎症包括神经胶质细胞如星形胶质细胞和小神经胶质细胞的活化， 调节炎症，包括突触处的谷氨酸兴奋性毒性。越来越多的证据表明， 炎症和谷氨酸神经传递的改变是两种与神经递质相关的新途径。 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串扰是由 细胞外囊泡（EV）正在成为调节大脑功能的关键角色。慢性冰毒 依赖者，包括那些戒断然后复发的人，表现出显著的行为（情绪） 改变，如精神病。一个重大的知识缺口是理解甲基诱导的炎症是如何发生的。 扰乱了神经元能生理学，其随后损害EV动力学并加剧复发。添加 另一层重要的是，新的研究表明，随着女性的进步， 更快地定期使用冰毒以及更大的依赖性和更高的复发率。由于缺乏 研究阐明电动汽车与甲基复吸之间的作用，我们提出的研究是很好的准备 来弥补这一重要的知识缺口。因此，本提案的总体目标是审查 使用药物触发的恢复（复发）， 在大鼠中消除静脉内甲氨蝶呤自我给药。根据我们最近对女性的初步研究 显示出更高的炎症，增强的神经元能改变，以及显著更高的药物触发的 恢复（即，寻找冰毒），我们假设EV生物发生，释放和相关货物更多 女性比男性更受影响。使用一系列互补的行为，分子，和生化 方法在“金标准”临床前模型或恢复，我们将：确定如何抗炎 异丁司特药物改变了EV释放、生物发生和性别之间相关货物的动力学（Aim 1）; 表征从性别中分离的EV对突触树突状细胞损伤的作用（目的2和）试验方法诱导 不同性别之间EV相关表面蛋白的变化（目的3）。这些研究将开辟新的领域， 重要是，它提供了新的概念验证研究，这将进一步作为未来基础研究的前奏 开发电动汽车作为治疗冰毒成瘾的性别特异性药物开发。 .!

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. .!