LIKEABILITY AND DOPAMINE TRANSPORTER OCCUPANCY OF ORAL METHYLPHENIDATE

口服哌醋甲酯的好感度和多巴胺转运蛋白的占有率

• 批准号: 7349589
• 负责人: Thomas J Spencer
• 金额: $ 3.5万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7349589
• 关键词: LIKEABILITY; DOPAMINE; TRANSPORTER; OCCUPANCY; ORAL

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The abuse potential of methylphenidate has been related to the drug's capacity to produce a rapid onset of blockade of the presynaptic dopamine transporter in the brain. An oral once-a-day osmotic controlled-release formulation of methylphenidate produces a more gradual rise in plasma methylphenidate concentration, compared with immediate-release methylphenidate. The authors hypothesized that osmotic-release methylphenidate would produce a slower onset of blockade of the presynaptic dopamine transporter and would be associated with a lower risk for detection and likeability, compared to immediate-release methylphenidate. Twelve healthy adults were randomly assigned to receive single doses of immediate-release methylphenidate or osmotic-release methylphenidate. Doses predicted to produce equivalent maximum concentration (C(max)) values were selected (40 mg of immediate-release methylphenidate and 90 mg of osmotic-release methylphenidate). Plasma d-methylphenidate levels and responses to detection/likeability questionnaire items were obtained for 10h after methylphenidate administration on two separate occasions. Dopamine transporter receptor occupancies were measured at hours 1, 3, 5, and 7 with a carbon-11-labeled imaging agent (Altropane) and positron emission tomography. Results: Despite similar C(max) values for both formulations, osmotic-release methylphenidate was associated with a longer time to maximum concentration, longer time to maximum CNS dopamine transporter occupancy, and no detection/likeability, compared with immediate-release methylphenidate. Discussion: The findings suggest that the abuse potential of oral methylphenidate is strongly influenced by the rate of delivery and not solely by the magnitude of plasma concentration or brain transporter occupancy. These results advance understanding of the underlying central effects of methylphenidate in humans and identify a potentially less abusable methylphenidate formulation.

该子项目是利用 NIH/NCRR 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中出现。列出的机构是中心的机构，不一定是研究者的机构。哌醋甲酯的滥用潜力与该药物快速阻断大脑突触前多巴胺转运蛋白的能力有关。与速释哌甲酯相比，每日一次口服哌甲酯渗透控释制剂可使血浆哌甲酯浓度逐渐升高。作者假设，与速释哌甲酯相比，渗透释放哌甲酯会对突触前多巴胺转运蛋白产生较慢的阻断作用，并且与较低的检测风险和喜爱度相关。十二名健康成年人被随机分配接受单剂量的立即释放哌甲酯或渗透释放哌甲酯。选择预计产生等效最大浓度 (C(max)) 值的剂量（40 mg 立即释放哌甲酯和 90 mg 渗透释放哌甲酯）。在两次单独施用哌醋甲酯后 10 小时内获得血浆 d-哌醋甲酯水平和对检测/喜爱度问卷项目的反应。在第 1、3、5 和 7 小时用碳 11 标记显像剂（Altropane）和正电子发射断层扫描测量多巴胺转运蛋白受体占用率。结果：尽管两种制剂的 C(max) 值相似，但与速释哌甲酯相比，渗透释放哌甲酯与达到最大浓度的时间较长、达到最大中枢神经系统多巴胺转运蛋白占用时间较长有关，并且没有检测/喜爱性。讨论：研究结果表明，口服哌醋甲酯的滥用可能性很大程度上受到输送速率的影响，而不仅仅是血浆浓度或脑转运蛋白占用率的大小。这些结果促进了对哌甲酯对人类潜在中心作用的理解，并确定了一种潜在不易滥用的哌甲酯制剂。