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MicroPET/CT assessment of neurochemical effects in the brain after long-term methylphenidate treatment in nonhuman primates
Neurotoxicology and Teratology ( IF 2.6 ) Pub Date : 2021-07-12 , DOI: 10.1016/j.ntt.2021.107017
X Zhang 1 , J Talpos 1 , M S Berridge 2 , S M Apana 2 , W Slikker 1 , C Wang 1 , M G Paule 1
Affiliation  

Methylphenidate (MPH) is a psychostimulant approved by the FDA to treatment Attention-Deficit Hyperactivity Disorder (ADHD). MPH is believed to exert its pharmacological effects via preferential blockade of the dopamine transporter (DAT) and the norepinephrine transporter (NET), resulting in increased monoamine levels in the synapse. We used a quantitative non-invasive PET imaging technique to study the effects of long-term methylphenidate use on the central nervous system (CNS). We conducted microPET/CT scans on young adult male rhesus monkeys to monitor changes in the dopaminergic system. We used [18F] AV-133, a ligand for the vesicular monoamine transporter 2 (VMAT2), and [18F]FESP a ligand for the D2 and 5HT2 receptors. In this study we evaluated the effects if chronic MPH treatment in the nonhuman primates (NHP). Two-year-old, male rhesus monkeys were orally administered MPH diluted in the electrolyte replenisher, Prang, twice a day, five days per week (M-F) over an 8-year period. The dose of MPH was gradually escalated from 0.15 mg/kg initially to 2.5 mg/kg/dose for the low dose group, and 1.5 mg/kg to 12.5 mg/kg/dose for the high dose group (Rodriguez et al., 2010). Scans were performed on Mondays, about 60 h after their last treatment, to avoid the acute effects of MPH. Tracers were injected intravenously ten minutes before microPET/CT scanning. Sessions lasted about 120 min. The Logan reference tissue model was used to determine the Binding Potential (BP) of each tracer in the striatum with the cerebellar cortex time activity curve as an input function. Both MP treatment groups had a lower [18F] AV-133 BP, although this failed to reach statistical significance. MPH treatment did not have a significant effect on The BP of [18F] FESP in the striatum. Long-term administration of MPH did not significant change any of the marker of monoamine function used here. These data suggest that, despite lingering concerns, long-term use of methylphenidate does not negatively impact monoamine function. This study also demonstrates that microPET imaging can distinguish differences in binding potentials of a variety of radiotracers in the CNS of NHPs. This approach may provide minimally-invasive biomarkers of neurochemical processes associated with chronic exposure to CNS medications. (Supported by NCTR).



中文翻译:

MicroPET/CT 评估非人灵长类动物长期哌醋甲酯治疗后大脑中的神经化学作用

哌醋甲酯 (MPH) 是一种经 FDA 批准用于治疗注意力缺陷多动障碍 (ADHD) 的精神兴奋剂。MPH 被认为通过优先阻断多巴胺转运蛋白 (DAT) 和去甲肾上腺素转运蛋白 (NET) 发挥其药理作用,导致突触中单胺水平升高。我们使用定量无创 PET 成像技术来研究长期使用哌醋甲酯对中枢神经系统 (CNS) 的影响。我们对年轻的成年雄性恒河猴进行了 microPET/CT 扫描,以监测多巴胺能系统的变化。我们使用 [ 18 F] AV-133,一种用于囊泡单胺转运蛋白 2 (VMAT2) 的配体,以及 [ 18 F]FESP 一种用于 D 2和 5HT 2的配体受体。在这项研究中,我们评估了慢性 MPH 治疗对非人类灵长类动物 (NHP) 的影响。在 8 年的时间里,每天两次,每周 5 天 (MF) 口服给予 2 岁雄性恒河猴在电解质补充剂 Prang 中稀释的 MPH。MPH 的剂量从最初的 0.15 mg/kg 逐渐增加到低剂量组的 2.5 mg/kg/dose,高剂量组从 1.5 mg/kg 增加到 12.5 mg/kg/dose (Rodriguez et al., 2010 )。在最后一次治疗后约 60 小时的星期一进行扫描,以避免 MPH 的急性影响。在 microPET/CT 扫描前十分钟静脉注射示踪剂。会议持续了大约 120 分钟。Logan 参考组织模型用于确定纹状体中每个示踪剂的结合电位 (BP),其中小脑皮层时间活动曲线作为输入函数。两个 MP 治疗组的 [18 F] AV-133 BP,尽管这未能达到统计学意义。MPH处理对纹状体中[ 18 F] FESP的BP没有显着影响。长期服用 MPH 并没有显着改变这里使用的任何单胺功能标志物。这些数据表明,尽管存在挥之不去的担忧,但长期使用哌醋甲酯不会对单胺功能产生负面影响。该研究还表明,microPET 成像可以区分 NHP 的 CNS 中各种放射性示踪剂的结合电位差异。这种方法可以提供与慢性接触 CNS 药物相关的神经化学过程的微创生物标志物。(由 NCTR 支持)。

更新日期:2021-07-19
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