Extracellular vesicles, meth relapse and sex differences

滥用强效精神刺激剂甲基苯丙胺(冰毒)继续构成重大威胁 不仅在美国，而且在全球也是如此。与慢性冰毒引起的脑功能障碍有关的一个重要因素是 炎症包括星形胶质细胞和小胶质细胞等胶质细胞的激活，这些细胞在 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串扰是由 细胞外小泡(EVS)正在成为调节大脑功能的关键因素。慢性冰毒 依赖的人，包括那些禁欲然后复发的人，表现出显著的行为(情绪) 精神错乱等改变。知识上的一个重大差距是了解冰毒是如何引起炎症的 扰乱谷氨酸能生理学，从而损害EV动力学并加剧复发。添加 另一个重要层面是正在出现的研究，表明性别差异在女性进步中所起的作用 更快地定期使用冰毒，以及更大的依赖性和更高的复发率。考虑到缺乏 研究阐明了EVS在男女之间的冰毒复发中的作用，我们提议的研究是很有准备的 以解决这一重要的知识鸿沟。因此，这项提案的首要目标是审查 EVS在毒品引发的性行为恢复(复发)冰毒损害效应中的作用 大鼠静脉注射冰毒后自行熄灭。基于我们最近对女性的初步研究 表现出更高的炎症，增强的谷氨酸变化，以及显著更高的药物触发 恢复(即寻找冰毒)，我们假设EV的生物发生、释放和相关货物 女性比男性更容易受到影响。使用一系列互补的行为、分子和生化 在“黄金标准”临床前模型或恢复的方法我们将：确定如何抗炎 药物异丁司特改变肠道病毒的释放、生物发生和相关的两性间货物的动态(Aim1)； 两性EVS在突触树突触树突触损伤中的作用(目标2和试验方法) EV相关表面蛋白在性别之间的变化(目标3)。这些研究将开辟新的天地， 重要的是，提供了新的概念研究证据，这将进一步作为未来基础研究的前奏 关于开发EVS作为针对性别的治疗冰毒成瘾的药物开发。 。!

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. .!