Abstract：
Executive function, including working memory, attention and inhibitory control, is crucial for decision making, thinking and planning. Lisdexamfetamine, the prodrug of d-amphetamine, has been approved for treating attention-deficit hyperactivity disorder and binge eating disorder, but whether it improves executive function under non-disease condition, as well as the underlying pharmacokinetic and neurochemical properties, remains unclear. Here, using trial unique non-matching to location task and five-choice serial reaction time task of rats, we found lisdexamfetamine (p.o) enhanced spatial working memory and sustained attention under various cognitive load conditions, while d-amphetamine (i.p) only improved these cognitive performances under certain high cognitive load condition. Additionally, lisdexamfetamine evoked less impulsivity than d-amphetamine, indicating lower adverse effect on inhibitory control. In vivo pharmacokinetics showed lisdexamfetamine produced a relative stable and lasting release of amphetamine base both in plasma and in brain tissue, whereas d-amphetamine injection elicited rapid increase and dramatical decrease in amphetamine base levels. Microdialysis revealed lisdexamfetamine caused lasting release of dopamine within the medial prefrontal cortex (mPFC), whereas d-amphetamine produced rapid increase followed by decline to dopamine level. Moreover, lisdexamfetamine elicited more obvious efflux of noradrenaline than that of d-amphetamine. The distinct neurochemical profiles may be partly attributed to the different action of two drugs to membranous catecholamine transporters level within mPFC, detecting by Western Blotting. Taken together, due to its certain pharmacokinetic and catecholamine releasing profiles, lisdexamfetamine produced better pharmacological action to improving executive function. Our finding provided valuable evidence on the ideal pharmacokinetic and neurochemical characteristics of amphetamine-type psychostimulants in cognition enhancement.
摘要：
执行功能，包括工作记忆，注意和抑制控制，对决策至关重要，思考和规划。Lisdexamfetamine,d-苯丙胺的前药，已被批准用于治疗注意力缺陷多动障碍和暴食症，但是它是否在非疾病状态下改善执行功能，以及潜在的药代动力学和神经化学性质，尚不清楚。这里,使用试验独特的非匹配定位任务和五选连续反应时间任务的大鼠，我们发现了lisdexamfetamine(p.o)在各种认知负荷条件下增强空间工作记忆和持续注意力，而d-苯丙胺(i.p)仅在某些高认知负荷条件下改善了这些认知表现。此外,lisdexamfetamine诱发的冲动比d-苯丙胺少，表明对抑制控制的不利影响较低。体内药代动力学显示，在血浆和脑组织中，右旋苯丙胺产生相对稳定和持久的苯丙胺碱释放，而d-苯丙胺注射引起苯丙胺碱水平的快速增加和急剧下降。微透析显示利德西非他明导致内侧前额叶皮质（mPFC）内多巴胺的持续释放，而d-苯丙胺产生快速增加，然后下降到多巴胺水平。此外，lisdexamfetamine引起的去甲肾上腺素外排比d-苯丙胺更明显。不同的神经化学谱可能部分归因于两种药物对mPFC内膜儿茶酚胺转运蛋白水平的不同作用。通过蛋白质印迹检测。一起来看,由于其某些药代动力学和儿茶酚胺释放谱，lisdexamfetamine产生更好的药理作用，以改善执行功能。我们的发现为苯丙胺型精神兴奋剂在认知增强中的理想药代动力学和神经化学特征提供了有价值的证据。
