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. 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.

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赖右苯丙胺对大鼠执行功能的评估：转化认知研究

执行功能，包括工作记忆、注意力和抑制控制，对于决策、思考和规划至关重要。赖右苯丙胺是 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，但其是否能改善非疾病条件下的执行功能以及潜在的药代动力学和神经化学特性仍不清楚。在这里，使用大鼠的试验独特的非匹配位置任务和五选择串行反应时间任务，我们发现赖右苯丙胺（po）增强了各种认知负荷条件下的空间工作记忆和持续注意力，而d-安非他明（ip）仅改善这些认知表现是在一定的高认知负荷条件下的。此外，与右旋苯丙胺相比，赖右苯丙胺引起的冲动性较小，表明对抑制控制的不利影响较低。药代动力学表明，赖右苯丙胺在血浆和脑组织中产生相对稳定和持久的苯丙胺碱释放，而d-苯丙胺注射液引起苯丙胺碱水平快速增加和急剧下降。微透析显示，赖右苯丙胺引起内侧前额皮质（mPFC）内多巴胺的持续释放，而右旋安非他明则产生快速增加，然后下降到多巴胺水平。此外，赖右苯丙胺比d-苯丙胺引起更明显的去甲肾上腺素外流。通过蛋白质印迹法检测，不同的神经化学特征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。综上所述，由于其特定的药代动力学和儿茶酚胺释放特性，赖右苯丙胺在改善执行功能方面产生了更好的药理作用。我们的发现为安非他明类精神兴奋剂在认知增强方面的理想药代动力学和神经化学特征提供了有价值的证据。