Prefrontal cortex (PFC)-mediated executive function is crucial for other higher-order cognitions, such as decision making, thinking and planning (D'esposito and Postle, 2015; Keeler and Robbins, 2011; Thiele and Bellgrove, 2018). Improvement in the core domains of executive function, including working memory, attention and inhibitory control (Doebel, 2020) are beneficial for the enhancement of working efficiency of individuals who are engaged in special vocations, as well as treatment for the patients suffered from neurological and psychological diseases (Husain and Mehta, 2011).

Currently, cognitive enhancers are regarded as the major therapeutic medication for cognition improvement, which contain a class of drugs targeting several neurotransmitter systems (i.e., catecholaminergic, cholinergic and glutamatergic) (Berridge and Devilbiss, 2011; Bisagno et al., 2016; Hosking et al., 2014; Warburton, 1992; Hsu et al., 2018; Zhang et al., 2013). Among them, drugs acting on the catecholamine neurotransmitter system are well-characterized (Barch and Carter, 2005; Pietrzak et al., 2010). D-amphetamine, served as the first clinical medicine of this system, was used to improve attention and inhibitory control on both health population (Dolder et al., 2018; Roberts et al., 2020) and patients diagnosed with attention-deficit hyperactivity disorder (ADHD) in the last decades (Cherkasova et al., 2014; Piña et al., 2020). In addition, lisdexamfetamine, covalently synthesized by linking d-amphetamine to l-lysine (Hutson et al., 2014), also has been approved for the treatment of ADHD (Frampton, 2016), and the only therapeutic medication for binge eating disorder (Heo and Duggan, 2017). However, whether it improves executive function under non-disease condition keep unclear.

Recently, the development of novel translational cognitive paradigms provides approach to credible prediction of drugs efficacy (Wallace et al., 2015). Unlike traditional open water or dry maze (i.e., T-maze or Morris water maze), these paradigms offer a series of advantages. First, these tasks are fully automated, allowing simultaneously conduct a larger number of trials and minimized variability of experimental environment and operators (Scott et al., 2019). More importantly, they are translational across species, which the behaviors of rodent closely predict the corresponding cognitive domains in human (Hvoslef-Eide et al., 2015). Specifically, for executive function assessment, trial unique non-matching to location (TUNL) task and five-choice serial reaction time task (5-CSRTT) are two well-established paradigms in rats. TUNL task, a touchscreen-based platform, is modified from T-maze delayed alteration task and employed for spatial working memory evaluation (Bennett et al., 2023; Nakamura et al., 2021). Besides, 5-CSRTT, adapting from the human version of continuous performance test (CPT) (Robbins, 2002), is applied for attention and inhibitory control assessment (Fang and Frohlich, 2023; Flores-Dourojeanni et al., 2023).

In the present study, TUNL task and 5-CSRTT were employed to assess the effects of lisdexamfetamine on executive function, aiming to explore whether lisdexamfetamine (per os [p.o]) improve executive function under normal conditions. Since lisdexamfetamine has different pharmacokinetic (PK) and neurochemical profiles than that of d-amphetamine (Heal et al., 2013a; Kaland and Klein-Schwartz, 2015; Rowley et al., 2012), the effects of d-amphetamine (intraperitoneal [i.p]) on executive function were also explored to clarify the relationship between certain PK and neurochemical properties and executive function. Further, liquid chromatography-tandem mass spectrometry (LC-MS/MS) and high-performance liquid chromatography-electrochemical detection (HPLC-ECD), as well as Western Boltting were employed to profile the PK and neurochemical characteristics of both drugs.