DAT-Psychostimulant mediated dopamine release increases macrophage IL-1beta production through NF-kB activation and inflammasome priming

DAT 18 -01。滥用可卡因和甲基苯丙胺等兴奋剂会导致各种 严重的健康状况，吸毒者的健康结果比不吸毒者差， 相似的人口。在中枢神经系统中，使用兴奋剂会导致 神经炎症通过更大的炎症因子释放和募集额外的 白细胞这使药物滥用者更容易患上神经精神病， 脑血管和运动障碍，也可以加剧神经病变的影响， 感染HIV、HCV和一些细菌病原体。这些精确的路径 兴奋剂介导这些效应尚不清楚，但许多这些效应可能是由 与药物相关的特异性炎症触发因子如NF-κ B的激活。然而，直接链接 兴奋剂和这些神经炎症机制之间的关系还没有被描述。的 该提议的前提是多巴胺作为一种常见机制， 刺激物激活骨髓细胞NF-κ B，从而引发或加剧 神经炎症所有兴奋剂的使用都会急剧增加中枢神经系统多巴胺水平， 多巴胺含量异常高的大脑区域。在这些细胞中， 细胞群是髓样细胞，如血管周围巨噬细胞和小胶质细胞，它们是神经细胞的主要来源。 中枢神经系统中的初级免疫细胞。我们发表的研究表明，急性接触高浓度的 多巴胺增加炎性细胞因子如IL-1b、IL-6、CXCL 8的髓样产生 CXCL10我们的初步数据表明，多巴胺通过激活NF-κ B通路起作用， 引发NLRP 3炎性小体，一种调节IL-1b释放的复合物， 炎症调节因子。介导这种效应的具体途径尚不清楚，因此 这些研究将产生关于特定多巴胺受体、基因和 介导多巴胺激活的蛋白质靶点 NF-kB 和NLRP 3。 确定参与多巴胺诱导的特异性信号传导机制和基因 NF-kB活性的增加将表明可以靶向改善 使用兴奋剂的神经炎症效应，显著改善长期健康结果 兴奋剂使用者。本提案中开发的数据将作为未来项目的基础 检查作为治疗策略的髓样多巴胺能系统的调节， 限制与药物相关的神经系统疾病和炎症的发病率增加 虐待这些项目将研究新的效应器和现有的 多巴胺能治疗剂以改善兴奋剂滥用人群中的炎症。

DAT18-01. Abuse of stimulants, such as cocaine and methamphetamine, results in a variety of serious health conditions, and drug abusers have poorer health outcomes than non-drug using, demographically similar populations. In the central nervous system, the use of stimulants induces neuroinflammation through a greater release of inflammatory factors and recruitment of additional leukocytes. This predisposes drug abusers to a higher incidence of neuropsychiatric, cerebrovascular and motor disorders, and can also exacerbate the neuropathogenic impact of infection with HIV, HCV and a number of bacterial pathogens. The precise pathways by which stimulants mediate these effects are not clear, but many of these effects could be induced by drug-associated activation of specific inflammatory triggers such as NF- kB. However, direct links between stimulants and these neuroinflammatory mechanisms have not been described. The premise of this proposal is that dopamine acts as a common mechanism by which stimulants activate myeloid cell NF-kB and thereby initiate or exacerbate neuroinflammation. Use of all stimulants acutely increases CNS dopamine levels, exposing cells in dopamine-rich brain regions to aberrantly high dopamine concentrations. Among these cell populations are myeloid cells, such as perivascular macrophages and microglia, which are the primary immune cells in the CNS. Our published research shows that acute exposure to elevated dopamine increases myeloid production of inflammatory cytokines, such as IL-1b, IL-6, CXCL8 and CXCL10. Our preliminary data suggest that dopamine acts by activating the NF- kB pathway and priming the NLRP3 inflammasome, a complex that regulates the release of IL-1b, a master regulator of inflammation. The specific pathways mediating this effect are not clear, and therefore these studies will generate detailed information about specific dopamine receptors, gene and protein targets mediating dopamine activation of NF-kB and NLRP3 in human macrophages. Determining the specific signaling mechanisms and genes involved in dopamine induced increases in NF-kB activity will indicate pathways that could be targeted to ameliorate the neuroinflammatory effects of stimulant use, significantly improving the long-term health outcomes of stimulant users. The data developed in this proposal will serve as a basis for future projects examining the modulation of the myeloid dopaminergic system as a therapeutic strategy for limiting the increased incidence of neurologic disease and inflammation associated with drug abuse. These projects will examine both novel effectors and the repurposing of existing dopaminergic therapeutics to ameliorate inflammation in the stimulant abusing population.