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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）：疲劳是一种使人衰弱且通常难以治疗的症状，发生在许多医学和精神疾病中。疲劳的神经生物学还没有明确的描述;然而，在大脑水平，纹状体中的多巴胺（DA）信号似乎起着重要的作用。在外周，炎症细胞因子如肿瘤坏死因子已被牵连。关于炎性细胞因子如何与大脑多巴胺系统相互作用产生疲劳，人们知之甚少。我们已经开发了一种疲劳的人类模型，通过使用内毒素给药诱导全身炎症，这导致短暂的疲劳。该模型的独特之处在于它模拟了在各种医学疾病（例如癌症和自身免疫性疾病）中似乎引起疲劳的相同致病途径。由于其与医学和精神疾病的致病相关性，我们的人类疲劳模型可用于研究人类体内的多巴胺-多巴胺界面。我们最近发现内毒素诱导的全身性炎症减少了纹状体中的葡萄糖代谢;这与多巴胺在疲劳中的已知作用非常吻合。在这项探索性/发展性研究中，我们建议通过研究炎症细胞因子是否通过改变多巴胺能活性产生疲劳来扩展这些结果。在一项交叉、随机顺序、双盲研究中，我们将使用正电子发射断层扫描（PET）和[C-11]雷氯必利测量10名健康受试者中哌甲酯诱导的纹状体多巴胺释放。每例受试者将在两个不同日期接受两次基线PET扫描。每次基线扫描后，他们将在一天接受内毒素治疗，另一天接受安慰剂治疗。他们将在这两天收到MP。我们预计在安慰剂日，MP将导致多巴胺水平升高，这将取代[C-11]雷氯必利，导致结合潜力降低（一种公认的现象）。当有一天他们接受内毒素时，我们预计这种影响会减少，因为全身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炎症对纹状体多巴胺功能的影响。这些估计值将用于设计更大规模的研究，以明确确定全身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的外周机制（炎症）和疲劳的中枢机制（多巴胺）之间的现有差距。更好地了解这些途径可以导致针对这种常见和致残症状的新治疗方法的开发;这些治疗方法最终可以改善数百万患者的健康。