Dopaminergic Mechanisms of Cytokine-Induced Behavioral Change

描述（由申请方提供）：数据表明，先天免疫细胞因子可能导致医学疾病患者中发现的行为共病的高发生率。然而，有关机制尚未建立。一种可能性包括细胞因子对基底神经节中多巴胺（DA）代谢的影响。基底神经节DA在调节包括情绪、动机/奖励、运动活动、睡眠和认知在内的多种行为中起着关键作用。为了探索细胞因子对DA和基底神经节的影响，我们研究了接受先天免疫细胞因子干扰素（IFN）-α治疗的患者。IFN-α与与DA功能降低一致的显著行为变化相关，包括抑郁、快感缺乏、疲劳、运动减慢、睡眠受损和认知功能障碍。与DA和基底神经节在这些效应中的作用相关，在接受IFN-α治疗的患者中使用正电子发射断层扫描（PET）的神经影像学研究显示，尾状核和壳核中基底神经节葡萄糖代谢增加，DA前体[18 F]氟多巴（FDOPA）的摄取增加。为了进一步描述这些IFN-α对DA通路的影响，我们最近开发了IFN-α诱导的行为变化的动物模型。在这个动物模型中的初步数据表明，IFN-α可能会影响行为的一部分，通过消耗DA。然而，IFN-α对DA的细胞外的可用性和所涉及的机制的直接影响尚未确定。拟议的研究将测试IFN-α通过消耗相关基底神经节核团中DA的可用性来介导其对行为的影响的假设。还将探讨DA耗竭继发于DA转运蛋白（DAT）合成和释放减少和/或表达增加的假设。为了检验这些假设，将在用IFN-α或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。细胞因子及其信号通路包括丝裂原活化蛋白激酶（MAPK）在血液和CSF中的诱导将与DA代谢和行为的变化相关。值得注意的是，MAPK的激活已显示上调单胺转运蛋白，并且马槟榔碱诱导的犬尿烯酸的激活已显示减少DA释放。最后，将在用DAT阻断剂RTI-336处理的动物中检查DA代谢和行为。这些转化研究将确定IFN-alpha对DA代谢的影响及其与先天免疫反应的行为和激活的关系。此外，将确定DAT阻断剂在治疗尼古丁诱导的行为变化中的效用。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疾病的患者，并与治疗依从性降低和健康状况不良（包括发病率和死亡率增加）相关。越来越多的数据表明，在医学疾病和/或慢性应激期间可能发生的炎症反应的激活和先天免疫细胞因子的释放可导致行为变化，并可能导致医学疾病患者中行为共病的高发生率。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神经节多巴胺代谢的影响，该代谢调节多种行为，包括情绪，动机/奖励，运动活动，睡眠/觉醒周期和认知。

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.