Cytokine Effects on Amphetamine-Induced Dopamine Release using PET Neuroimaging

使用 PET 神经影像研究细胞因子对安非他明诱导的多巴胺释放的影响

• 批准号: 8060824
• 负责人: Jennifer C Felger
• 金额: $ 5.55万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-21 至 2012-09-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8060824
• 关键词: Affect; Amphetamines; Anhedonia; Animal Model; Basal Ganglia; Behavior; Behavioral; Binding; Brain; Cerebrospinal Fluid; Chronic; Communicable Diseases; Complement; Consumption; Corpus striatum structure; Data; Development; Disease; Dopamine; Dopamine D2 Receptor; Education; Exhibits; Exploratory Behavior; Exposure to; Fatigue; Fostering; Goals; Human; Image; Immune; Immune system; Injection of therapeutic agent; Interferon-alpha; Interferons; International; Intravenous; Laboratories; Ligands; Macaca mulatta; Major Depressive Disorder; Malignant Neoplasms; Measurement; Measures; Mental Depression; Mentors; Metabolism; Microdialysis; Monkeys; Moods; Motivation; Motor Activity; National Research Service Awards; Parkinson Disease; Pathway interactions; Patients; Peripheral; Play; Positron-Emission Tomography; Procedures; Protocols documentation; Raclopride; Research; Research Training; Rest; Rewards; Role; Saline; Sampling; Scanning; Sucrose; Synapses; Techniques; Testing; Tracer; Training; Translating; attenuation; brain behavior; career development; caudate nucleus; cytokine; depressive symptoms; design; dopamine system; experience; extracellular; glucose metabolism; immune activation; in vivo; insight; interest; meetings; neuroimaging; neuropsychiatry; neurotransmitter metabolism; nonhuman primate; post-doctoral training; public health relevance; putamen; research study; response; training project; uptake

This proposal is designed to provide the applicant with supervised education and research training in translational neuroimaging to assess the impact of innate immune cytokines on basal ganglia dopamine (DA). Neuropsychiatric disorders including depression are common in medically ill patients, possibly as a result of chronic peripheral immune system activation and release of innate immune cytokines. Although innate immune cytokines have been shown to interact with virtually every pathophysiologic domain relevant to depression including neurotransmitter metabolism, the exact mechanisms by which these cytokines exert behavioral effects are unknown. Basal ganglia DA plays a pivotal role in regulating behaviors including mood, motor activity, motivation and reward, and mounting evidence indicates that the DA system may be targeted by innate immune cytokines. For example, administration of the innate immune cytokine, interferon (IFN)-alpha, is associated with behavioral changes consistent with DA depletion including depressive behavior, fatigue, and reduced locomotor activity. In addition, neuroimaging studies using positron emission tomography (PET) in patients undergoing IFN-alpha therapy have revealed increased basal ganglia glucose metabolism similar to that seen in Parkinson¿s disease. Increased uptake and decreased release of the DA precursor, [18F]fluorodopa, in the caudate and putamen of IFN-alpha-treated patients has also been observed. Preliminary findings from in vivo microdialysis indicate decreased basal ganglia DA under resting conditions and following amphetamine (AMPH) administration via reverse microdialysis. The goal of the proposed research is to use neuroimaging techniques to examine DA availability and release in basal ganglia during IFN-alpha-treatment. The primary hypothesis of the study is that reduced DA availability and/or release is a key mechanism of cytokine-induced behavioral change. To test the hypothesis, [11C]raclopride neuroimaging with intravenous AMPH challenge will be used to indirectly measure DA availability and release during IFN-alpha or saline administration. This PET protocol will be complemented by direct measurement of extracellular DA using in vivo microdialysis in the striatum under basal conditions and in response to AMPH administered via reverse microdialysis. In addition to providing important insight into the effects of cytokines on basal ganglia DA, these studies will help the applicant develop an independent line of research in neuro-immune interactions, while fostering her career development. To accomplish her goals, the applicant¿s training plan will include a combination of mentored research, coursework, seminars, and attendance at national and international meetings.

该提案旨在为申请人提供转化神经影像学方面的监督教育和研究培训，以评估先天免疫细胞因子对基底神经节多巴胺（DA）的影响。包括抑郁症在内的神经精神疾病在患病患者中很常见，可能是由于慢性外周免疫系统激活和先天免疫细胞因子释放所致。尽管先天免疫细胞因子已被证明与抑郁症相关的几乎所有病理生理领域（包括神经递质代谢）相互作用，但这些细胞因子发挥行为作用的确切机制尚不清楚。基底神经节 DA 在调节情绪、运动活动、动机和奖励等行为中发挥着关键作用，越来越多的证据表明 DA 系统可能是先天免疫细胞因子的目标。例如，先天免疫细胞因子干扰素 (IFN)-α 的施用与与 DA 消耗一致的行为变化相关，包括抑郁行为、疲劳和运动活动减少。此外，对接受 IFN-α 治疗的患者使用正电子发射断层扫描 (PET) 进行的神经影像学研究显示，基底神经节葡萄糖代谢增加，与帕金森病相似。还观察到接受 IFN-α 治疗的患者尾状核和壳核中 DA 前体 [18F]氟多巴的摄取增加和释放减少。体内微透析的初步结果表明，在静息条件下以及通过反向微透析给予安非他明 (AMPH) 后，基底神经节 DA 减少。拟议研究的目标是使用神经影像技术来检查 IFN-α 治疗期间基底神经节中 DA 的可用性和释放。该研究的主要假设是，DA 可用性和/或释放减少是细胞因子诱导行为改变的关键机制。为了检验这一假设，[11C]雷氯必利神经影像学静脉注射 AMPH 激发将用于间接测量 IFN-α 或盐水给药期间 DA 的可用性和释放。该 PET 方案将通过在基础条件下使用纹状体体内微透析直接测量细胞外 DA 来补充，并响应通过反向微透析施用的 A​​MPH。 除了提供关于细胞因子对基底神经节 DA 的影响的重要见解外，这些研究还将帮助申请人在神经免疫相互作用方面开展独立的研究，同时促进她的职业发展。为了实现她的目标，申请人的培训计划将包括指导研究、课程作业、研讨会以及参加国内和国际会议。