Cytokine Effects on Amphetamine-Induced Dopamine Release using PET Neuroimaging

这项建议旨在为申请者提供翻译神经成像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节多巴胺(DA)的影响。包括抑郁在内的神经精神障碍在内科疾病患者中很常见，可能是由于慢性外周免疫系统激活和天然免疫细胞因子的释放造成的。尽管先天免疫细胞因子已被证明与几乎所有与抑郁相关的病理生理领域相互作用，包括神经递质代谢，但这些细胞因子发挥行为效应的确切机制尚不清楚。基底节DA在调节情绪、运动、动机和奖赏等行为中起着关键作用，越来越多的证据表明DA系统可能是先天免疫细胞因子的靶点。例如，给予先天免疫细胞因子干扰素(干扰素)-α与与DA耗竭一致的行为变化有关，包括抑郁行为、疲劳和运动活动减少。此外，在接受干扰素-α治疗的患者中，使用正电子发射断层扫描进行的神经成像研究显示，基底节葡萄糖代谢增加，与帕金森病患者的情况类似。在接受干扰素-α治疗的患者的尾核和壳核中，也观察到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，静息状态下和安非他明(AMPH)通过反向微透析给药后，基底节DA减少。这项拟议的研究的目标是使用神经成像技术来检查干扰素-α治疗期间基底神经节中DA的可用性和释放。这项研究的主要假设是，DA的可获得性和/或释放减少是细胞因子诱导的行为改变的关键机制。为了验证这一假设，[11C]雷氯必利的神经成像和静脉注射AMPH将被用来间接测量干扰素-α或生理盐水注射期间DA的利用度和释放。这一PET方案将通过在基础条件下在纹状体中使用体内微透析直接测量细胞外DA来补充，并通过反向微透析对AMPH进行响应。除了对细胞因子对基底节DA的影响提供重要的见解外，这些研究还将帮助申请者在神经免疫相互作用方面发展一条独立的研究路线，同时促进她的职业发展。为了实现她的目标，申请者S的培训计划将包括辅导性研究、课程作业、研讨会和参加国内和国际会议。

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.