Endotoxin-induced inflammation affects striatal dopamine: A raclopride PET study

内毒素诱导的炎症影响纹状体多巴胺：雷氯必利 PET 研究

基本信息

批准号：
8726269
负责人：
Evan D Morris
金额：
$ 24.98万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8726269
关键词：
Address Affect Autoimmune Diseases Binding Brain Brain imaging Clinical Corpus striatum structure Cytokine Signaling Data Analyses Development Disease Dopamine Double-Blind Method Drug Targeting Endotoxins Exploratory/Developmental Grant Fatigue Genetic Crossing Over Height Human Image Infection Inflammation Inflammatory Interferon-alpha Lead Malignant Neoplasms Measures Medical Mental disorders Metabolism Methods Methylphenidate Minor Modeling Nerve Degeneration Neurobiology Neurosciences Neurotransmitters Occupational Outcome Measure Pathogenesis Pathway interactions Patients Peripheral Personal Satisfaction Placebos Play Positron-Emission Tomography Raclopride Randomized Resistance Role Sample Size Scanning Serum Signal Transduction Stimulus Study Section Symptoms System Time Tumor Necrosis Factor-alpha common treatment cytokine design dopamine system extracellular follow-up glucose metabolism improved in vivo innovation novel novel therapeutic intervention public health relevance putamen radiotracer social

项目摘要

DESCRIPTION (provided by applicant): Fatigue is a debilitating and often treatment-resistant symptom that occurs in many medical and psychiatric disorders. The neurobiology of fatigue is not clearly delineated; however, at the brain level dopamine (DA) signaling in the striatum appears to play an important role. Peripherally, inflammatory cytokines such as tumor necrosis factor have been implicated. Little is known about how inflammatory cytokines interact with brain dopamine systems to produce fatigue. We have developed a human model of fatigue, by using endotoxin administration to induce systemic inflammation, which results in transient fatigue. This model is unique in that it mimics the same pathogenic pathway that appears to cause fatigue in a variety of medical disorders, e.g. cancer and autoimmune disorders. Because of its pathogenic relevance to medical and psychiatric disorders, our human fatigue model can be used to study this cytokine-dopamine interface in vivo in humans. We recently found that endotoxin-induced systemic inflammation reduces glucose metabolism in the striatum; this fits well with the known role of dopamine in fatigue. In this exploratory/developmental study we propose to extend these results by investigating whether inflammatory cytokines produce fatigue by altering dopaminergic activity. In a cross-over, random-order, double-blind study, we will use positron emission tomography (PET) and [C-11]raclopride to measure methylphenidate-induced release of dopamine in the striatum in 10 healthy subjects. Each subject will have two baseline PET scans on two different days. After each baseline scan, they will receive endotoxin on one day and placebo on the other. They will receive MP on both days. We expect that on the placebo day, MP will cause increased dopamine levels, which will displace [C-11]raclopride, resulting in lower binding potential (a well-established phenomenon). On one day they receive endotoxin, we expect this effect to be reduced because systemic inflammation will inhibit dopamine release. This study will allow us to estimate the effect of endotoxin-induced systemic inflammation on striatal dopamine function. These estimates will be used to design larger studies to definitively determine the effect of systemic inflammation on striatal dopamine. The proposed study and the follow-up studies will bridge the current gap between our understanding of peripheral mechanisms of fatigue (inflammation) and central mechanisms of fatigue (dopamine). A better understanding of these pathways can lead to the development of new treatments for this common and disabling symptom; such treatments could ultimately improve the wellbeing of millions of patients.

描述（由申请人提供）：疲劳是许多医学和精神疾病中发生的令人衰弱且经常抗治疗的症状。疲劳的神经生物学尚未清楚地描述。但是，纹状体中的大脑水平（DA）信号传导似乎起着重要作用。在外围，已经涉及炎症细胞因子，例如肿瘤坏死因子。关于炎性细胞因子如何与脑多巴胺系统相互作用以产生疲劳的知之甚少。我们通过使用内毒素给药诱导全身性炎症开发了人类疲劳模型，从而导致瞬时疲劳。该模型的独特之处在于它模拟了同样的致病途径，该通路似乎在多种医学疾病中引起疲劳，例如癌症和自身免疫性疾病。由于它与医学和精神疾病的致病性相关，因此我们的人类疲劳模型可用于研究人类体内的细胞因子 - 多巴胺界面。我们最近发现，内毒素诱导的全身性炎症会减少纹状体中的葡萄糖代谢。这非常符合多巴胺在疲劳中的已知作用。在这项探索性/发育研究中，我们建议通过研究炎症性细胞因子是否通过改变多巴胺能活性而产生疲劳来扩展这些结果。在一项跨越，随机，双盲的研究中，我们将使用正电子发射断层扫描（PET）和[C-11] raclopride测量甲基苯甲酸甲酯诱导的10位健康受试者中纹状体中多巴胺的释放。每个受试者将在两个不同的日期进行两次基线PET扫描。每次基线扫描后，他们将有一天会收到内毒素，而安慰剂将在另一天收到。他们将在这两天都将获得国会议员。我们预计，在安慰剂日，MP会导致多巴胺水平增加，这将置换[C-11] raclopride，从而导致较低的结合电位（一种已建立的现象）。有一天，他们收到内毒素，我们希望这种作用会降低，因为全身性炎症会抑制多巴胺的释放。这项研究将使我们能够估计内毒素诱导的全身性炎症对纹状体多巴胺功能的影响。这些估计将用于设计较大的研究，以确定确定全身性炎症对纹状体多巴胺的影响。拟议的研究和后续研究将弥合我们对疲劳（炎症）周围机制的理解与疲劳（多巴胺）的中心机制之间的差距。更好地了解这些途径可以导致这种常见和残疾症状的新疗法发展；这种治疗最终可以改善数百万患者的福祉。