Cytokine Effects on Amphetamine-Induced Dopamine Release using PET Neuroimaging

本提案旨在为申请人提供翻译神经影像学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疾病患者中很常见，可能是慢性外周免疫系统激活和先天免疫细胞因子释放的结果。虽然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相互作用，包括神经递质代谢，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(IFN)- α，与DA耗竭引起的行为改变有关，包括抑郁行为、疲劳和运动活动减少。此外，在接受ifn - α治疗的患者中使用正电子发射断层扫描（PET）进行的神经影像学研究显示，基底节区葡萄糖代谢增加，与帕金森病相似。还观察到，经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，释放减少。体内微透析的初步结果表明，在静息条件下和安非他明（AMPH）给药后，通过反向微透析，基底神经节DA减少。本研究的目的是利用神经成像技术检测干扰素α治疗期间基底神经节DA的可用性和释放。该研究的主要假设是，减少DA的可用性和/或释放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]将使用静脉AMPH刺激下的raclopride神经成像来间接测量ifn - α或生理盐水给药期间DA的可用性和释放。该PET方案将通过直接测量细胞外DA来补充，在基础条件下使用纹状体体内微透析，并通过反向微透析来响应AMPH。除了为细胞因子对基底神经节DA的影响提供重要见解外，这些研究将帮助申请人在神经免疫相互作用方面发展独立的研究方向，同时促进其职业发展。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、研讨会和参加国内和国际会议的组合。

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.