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

描述（由申请人提供）：疲劳是一种使人衰弱且经常难以治疗的症状，发生在许多医学和精神疾病中。疲劳的神经生物学还没有被清楚地描述；然而，在大脑水平上，纹状体中的多巴胺（DA）信号似乎起着重要作用。外周，炎性细胞因子如肿瘤坏死因子也有牵连。关于炎症细胞因子如何与大脑多巴胺系统相互作用产生疲劳，我们知之甚少。我们开发了一种人体疲劳模型，通过使用内毒素引起全身炎症，从而导致短暂的疲劳。该模型的独特之处在于，它模拟了在各种医学疾病（如癌症和自身免疫性疾病）中似乎导致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，我们的人体疲劳模型可用于研究人体体内的这种细胞因子-多巴胺界面。我们最近发现内毒素引起的全身性炎症会降低纹状体的葡萄糖代谢；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]raclopride来测量10名健康受试者的苯甲酸甲酯诱导的纹状体多巴胺释放。每个受试者将在不同的两天进行两次基线PET扫描。在每次基线扫描后，他们将在一天内接受内毒素治疗，另一天接受安慰剂治疗。他们将在这两天接受MP。我们预计，在安慰剂日，MP会导致多巴胺水平升高，从而取代[C-11]raclopride，导致结合电位降低（一个公认的现象）。有一天，他们接受内毒素，我们希望这种效果会减少，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。这些估计将用于设计更大规模的研究，以确定全身性炎症对纹状体多巴胺的影响。本研究和后续研究将弥合目前我们对疲劳外围机制（炎症）和疲劳中枢机制（多巴胺）的理解之间的差距。更好地了解这些途径可以为这种常见的致残症状开发新的治疗方法；这种治疗方法最终可以改善数百万患者的健康状况。

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.