National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, United States of America.
3D Imaging, LLC, Little Rock, AR 72113 and University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States of America.
Neurotoxicol Teratol. 2023 May-Jun;97:107173. doi: 10.1016/j.ntt.2023.107173. Epub 2023 Mar 8.
Attention-deficit hyperactivity disorder (ADHD) is a common human neurobehavioral disorder that usually begins in early childhood. Methylphenidate (MPH) has been used extensively as a first-line medicine for the treatment of ADHD. Since ADHD is often diagnosed in early childhood and can persist for the entire lifespan, individuals may take MPH for many years. Given that in the course of one's lifetime a person may stop taking MPH for periods of time, or may implement lifestyle changes that may reduce the need for MPH entirely, it is important to understand how cessation of MPH affects the adult brain following long-term use of MPH. The blockage of the dopamine transporter (DAT) and the norepinephrine transporter (NET) by MPH may help with ADHD symptoms by boosting monoamine levels in the synapse. In the present study, microPET/CT was used to investigate possible neurochemical alterations in the cerebral dopamine system after cessation of long-term MPH administration in nonhuman primates. MicroPET/CT images were collected from adult male rhesus monkeys 6 months after they stopped receiving vehicle or MPH following 12 years of chronic treatment. The neurochemical status of brain dopaminergic systems was evaluated using the vesicular monoamine transporter 2 (VMAT2) ligand [F]-AV-133 and a tracer for imaging dopamine subtype 2 (D) and serotonin subfamily 2 (5HT) receptors, [F]-FESP. Each tracer was injected intravenously and ten minutes later microPET/CT images were obtained over 120 min. The binding potential (BP) of each tracer in the striatum was obtained using the Logan reference tissue model with the cerebellar cortex time activity curve (TAC) as an input function. Brain metabolism was also evaluated using microPET/CT images of [F]-FDG. [F]-FDG was injected intravenously, and ten minutes later, microPET/CT images were obtained over 120 min. Radiolabeled tracer accumulation in regions of interest (ROIs) in the prefrontal cortex, temporal cortex, striatum, and cerebellum were converted into standard uptake values (SUVs). Compared to the vehicle control group, the BPs of [F] AV-133 and [F]-FESP in the striatum were not significantly altered in MPH treated groups. Additionally, no significant differences were detected in the SUVs of [F]-FDG in the MPH treated group compared with control. This study demonstrates that 6 months after cessation of long-term, chronic MPH treatment, there are no significant neurochemical or neural metabolic changes in the central nervous system (CNS) of non-human primates (NHPs) and suggests that microPET imaging is helpful in assessing the status of biomarkers of neurochemical processes linked to chronic CNS drug exposure. (Supported by NCTR).
注意缺陷多动障碍（ADHD）是一种常见的人类神经行为障碍，通常始于儿童早期。哌醋甲酯（MPH）已被广泛用作治疗 ADHD 的一线药物。由于 ADHD 通常在儿童早期被诊断出来，并且可能持续一生，因此个体可能会服用 MPH 多年。鉴于一个人可能会在一生中停止服用 MPH 一段时间，或者可能会实施生活方式的改变，这些改变可能会完全减少对 MPH 的需求，因此了解停止服用 MPH 对长期使用 MPH 后成人大脑的影响非常重要。MPH 对多巴胺转运体（DAT）和去甲肾上腺素转运体（NET）的阻断可能通过提高突触中单胺类物质的水平来帮助缓解 ADHD 症状。在本研究中，使用 microPET/CT 研究了在非人类灵长类动物停止长期 MPH 给药后，多巴胺系统的神经化学变化。在接受了 12 年的慢性治疗后，6 个月后，microPET/CT 图像从停止接受载体或 MPH 的成年雄性恒河猴中收集。使用囊泡单胺转运体 2（VMAT2）配体 [F]-AV-133 和用于成像多巴胺 2 型（D）和 5-羟色胺亚家族 2（5HT）受体的示踪剂 [F]-FESP 评估大脑多巴胺能系统的神经化学状态。将每种示踪剂静脉内注射，十分钟后，使用小脑皮质时间活动曲线（TAC）作为输入功能，通过 Logan 参考组织模型获得纹状体中每个示踪剂的结合潜力（BP）。使用 microPET/CT 图像还评估了脑代谢[F]-FDG。将 [F]-FDG 静脉内注射，十分钟后，在 120 分钟内获得 microPET/CT 图像。将前额叶皮层、颞叶皮层、纹状体和小脑等感兴趣区域（ROI）中的放射性示踪剂积聚转化为标准摄取值（SUV）。与载体对照组相比，MPH 治疗组纹状体中 [F] AV-133 和 [F]-FESP 的 BPs 没有明显改变。与对照组相比，MPH 治疗组中 [F]-FDG 的 SUV 也没有差异。本研究表明，在停止长期慢性 MPH 治疗 6 个月后，非人类灵长类动物（NHPs）的中枢神经系统（CNS）没有明显的神经化学或神经代谢变化，并表明 microPET 成像有助于评估与慢性 CNS 药物暴露相关的神经化学过程的生物标志物状态。（由 NCTR 支持）。
