Dopaminergic Mechanisms of Cytokine-Induced Behavioral Change

描述(由申请人提供)：数据表明，先天免疫细胞因子可能是导致内科疾病患者行为并发症发生率高的原因。然而，所涉及的机制尚未建立。一种可能性包括细胞因子对基底节中的多巴胺(DA)代谢的影响。基底节DA在调节情绪、动机/奖赏、运动、睡眠和认知等多种行为中起着关键作用。为了探索细胞因子对DA和基底节的影响，我们研究了接受天然免疫细胞因子干扰素-α治疗的患者。干扰素-α与DA功能下降的显著行为改变有关，包括抑郁、快感丧失、疲劳、运动减慢、睡眠受损和认知功能障碍。与DA和基底节在这些效应中的作用相关，在接受干扰素-α治疗的患者中，使用正电子发射断层扫描(PET)的神经成像研究显示，基底节葡萄糖代谢增加，尾状核和壳核对DA前体[18F]Folodopa(FDOPA)的摄取增加。为了进一步表征这些干扰素-α对DA通路的影响，我们最近建立了一个干扰素-α诱导的行为改变的动物模型。该动物模型的初步数据表明，干扰素-α可能部分通过耗尽多巴胺而影响行为。然而，干扰素-α对DA细胞外利用度的直接影响及其机制尚不清楚。这项拟议的研究将检验这一假设，即干扰素-α通过耗尽相关基底节核团中DA的可获得性来调节其对行为的影响。还将探讨DA耗竭是继发于DA转运体(DAT)合成和释放减少和/或表达增加的假说。为了验证这些假说，将在用干扰素-α或生理盐水处理的动物中进行细胞外DA的体内微透析以及DAT结合和FDOPA摄取的PET神经成像。在血液和脑脊液中诱导细胞因子及其信号通路，包括丝裂原活化蛋白激酶(MAPK)，将与DA代谢和行为的变化相关。值得注意的是，MAPK的激活可以上调单胺转运体，细胞因子诱导的犬尿酸的激活可以减少DA的释放。最后，将检查使用DAT阻滞剂RTI-336治疗的动物的DA代谢和行为。这些翻译研究将确定干扰素-α对DA代谢的影响，以及它与行为和先天免疫反应激活的关系。此外，DAT阻滞剂在治疗细胞因子诱导的行为改变方面的效用将得到确定。公共卫生相关性：抑郁、疲劳、认知功能障碍和其他行为改变困扰着患有各种医学障碍的患者，并与治疗依从性降低和不良健康结果相关，包括增加发病率和死亡率。越来越多的数据表明，在内科疾病和/或慢性应激期间，炎症反应的激活和先天免疫细胞因子的释放可能会导致行为变化，这可能是内科疾病患者行为并存的高比率的原因。该项目旨在确定先天免疫细胞因子影响大脑和行为的神经系统途径，特别强调细胞因子对基底节多巴胺代谢的影响，该基底节调节包括情绪、动机/奖励、运动活动、睡眠/清醒周期和认知在内的多种行为。

DESCRIPTION (provided by applicant): Data indicate that innate immune cytokines may contribute to the high rate of behavioral co-morbidities found in medically ill patients. Nevertheless, the mechanisms involved have yet to be established. One possibility includes cytokine effects on dopamine (DA) metabolism in the basal ganglia. Basal ganglia DA plays a pivotal role in regulating multiple behaviors including mood, motivation/reward, motor activity, sleep and cognition. To explore effects of cytokines on DA and the basal ganglia, we have studied patients receiving treatment with the innate immune cytokine, interferon (IFN)-alpha. IFN-alpha is associated with marked behavioral changes consistent with decreased DA function including depression, anhedonia, fatigue, motor slowing, impaired sleep and cognitive dysfunction. Relevant to the role of DA and the basal ganglia in these effects, neuroimaging studies using positron emission tomography (PET) in patients undergoing IFN-alpha therapy have revealed increased basal ganglia glucose metabolism and increased uptake of the DA precursor, [18F]fluorodopa (FDOPA), in caudate and putamen. To further characterize these IFN-alpha effects on DA pathways, we have recently developed an animal model of IFN-alpha-induced behavioral change. Preliminary data in this animal model indicate that IFN-alpha may influence behavior in part through depletion of DA. However, the direct impact of IFN-alpha on the extracellular availability of DA and the mechanisms involved has yet to be determined. The proposed research will test the hypothesis that IFN-alpha mediates its effects on behavior by depleting the availability of DA in relevant basal ganglia nuclei. Hypotheses that DA depletion is secondary to decreased synthesis and release and/or increased expression of the DA transporter (DAT) will also be explored. To test these hypotheses, in vivo microdialysis of extracellular DA as well as PET neuroimaging of DAT binding and FDOPA uptake will be conducted in animals treated with IFN- alpha or saline. Induction of cytokines and their signaling pathways including mitogen activated protein kinases (MAPK) in blood and CSF will be correlated with changes in DA metabolism and behavior. Of note, activation of MAPK has been shown to upregulate monoamine transporters, and cytokine-induced activation of kynurenic acid has been shown to decrease DA release. Finally, DA metabolism and behavior will be examined in animals treated with the DAT blocker, RTI-336. These translational studies will establish the impact of IFN-alpha on DA metabolism and its relationship with behavior and activation of innate immune responses. Moreover, the utility of DAT blockers in treating cytokine-induced behavioral change will be determined. PUBLIC HEALTH RELEVANCE: Depression, fatigue, cognitive dysfunction and other behavioral alterations plague patients with a variety of medical disorders and are associated with reduced treatment adherence and poor health outcome including increased morbidity and mortality. Increasing data indicate that activation of the inflammatory response and the release of innate immune cytokines as may occur during medical illnesses and/or chronic stress can lead to behavioral changes and may account for the high rate of behavioral co-morbidities in medically ill patients. This project seeks to determine the nervous system pathways by which innate immune cytokines influence the brain and behavior, with a special emphasis on the effects of cytokines on dopamine metabolism in the basal ganglia, which regulates multiple behaviors including mood, motivation/reward, motor activity, sleep/wake cycles and cognition.