LIKEABILITY AND DOPAMINE TRANSPORTER OCCUPANCY OF ORAL METHYLPHENIDATE

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。哌醋甲酯的滥用潜力与该药物能够迅速阻断大脑突触前多巴胺转运体有关。与即刻释放的哌甲酯相比，每日口服一次的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，渗透释放的哌醋甲酯对突触前多巴胺转运体的阻断作用较慢，与立即释放的哌醋甲酯相比，被发现和受欢迎的风险较低。12名健康成人被随机分配接受单剂量立即释放的哌醋甲酯或渗透释放的哌醋甲酯。选择可产生等效最大浓度（C(max)）值的剂量（速释哌醋甲酯40mg和渗透释哌醋甲酯90mg）。在两次给药后10小时内血浆d-哌甲酯水平和对检测/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体受体占用。结果：尽管两种剂型的C（max）值相似，但与立即释放的哌醋甲酯相比，渗透释放的哌醋甲酯达到最大浓度所需时间更长，到达最大中枢神经系统多巴胺转运体占用时间更长，且无检测/亲和性。讨论：研究结果表明，口服哌甲酯的滥用潜力受到给药速度的强烈影响，而不仅仅受血浆浓度或脑转运体占用的大小的影响。这些结果促进了对哌醋甲酯对人类潜在中心效应的理解，并确定了一种可能较少被滥用的哌醋甲酯制剂。

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.