Effects of Lisdexamfetamine, a Prodrug of D-Amphetamine, on Locomotion, Spatial Cognitive Processing and Neurochemical Profiles in Rats: A Comparison With Immediate-Release Amphetamine

Abstract

D-amphetamine has been used to enhance cognitive performance over the last few decades. Due to the rapid absorption after administration, d-amphetamine shows narrow effective window and severe abuse potential. Lisdexamfetamine, a prodrug of d-amphetamine, reduces the magnitude of plasma d-amphetamine concentration and prolongs the action duration when compared with immediate-release d-amphetamine at equimolar doses. However, the differences of these two drugs, which produce distinct pharmacokinetic characteristics, in cognition improvement still unclear. In present study, we compared the effects of d-amphetamine (i.p) and lisdexamfetamine (p.o) at equimolar doses (0.2, 0.5, 1.5, 4.5, and 13.5 mg/kg of d-amphetamine base) on locomotion, spatial working memory and recognition memory in rats. Given the crucial involvement of dopamine neurotransmitter system within the medial prefrontal cortex (mPFC) in cognitive processing, microdialysis was conducted to profile the difference in neurochemical characteristics between the two drugs. In our results, d-amphetamine ranges from 0.5 to 1.5 mg/kg significantly increased locomotor activity. However, d-amphetamine ranges from 0.2 to 13.5 mg/kg failed to improve spatial working memory and recognition memory in Y-maze-based spontaneous alternation and two-trial delayed alternation tasks of rats, respectively. In contrast, lisdexamfetamine with 4.5 mg/kg significantly increased the locomotion and improved both spatial working and recognition memory. Further, microdialysis showed that lisdexamfetamine induced lower magnitude and longer duration of extracellular dopamine increase than that of d-amphetamine. These results suggest that lisdexamfetamine was more effective than d-amphetamine in improving spatial cognitive performance, which was attributed to the steady and lasting dopamine release pattern within the mPFC.

Keywords: d-amphetamine; dopamine; lisdexamfetamine; pharmacokinetic characteristics; spatial cognition.

FIGURE 1

The effects of d-amphetamine and lisdexamfetamine on locomotor activity. (A) Total distances induced by d-amphetamine within 180 min (median ± interquartile, Kruskal-Wallis test). (B) Distances induced by d-amphetamine with 15-min interval (mean ± SEM, Repeated measure ANOVA followed by Bonferroni test). (C) Total distances induced by lisdexamfetamine within 180 min (median ± interquartile, Kruskal-Wallis test). (D) Distances induced by lisdexamfetamine with 15-min interval (mean ± SEM, Repeated measure ANOVA followed by Bonferroni test). Ctrl: control; Amp: d-amphetamine; Lis: lisdexamfetamine. *P < 0.05, **P < 0.01, ***P < 0.001 vs. Ctrl, n = 9 in each group.

FIGURE 2

The effects of d-amphetamine and lisdexamfetamine on Y-maze-based spontaneous alternation. (A) The effect of d-amphetamine on percentage of Alteration/5min (median ± interquartile, Kruskal-Wallis test). (B) The effect of d-amphetamine on transform times within 5 min (median ± interquartile, Kruskal-Wallis test). (C) The effect of lisdexamfetamine on percentage of Alteration/5 min (mean ± SEM, One-way ANOVA, followed by Dunnett-t test). (D) The effect of lisdexamfetamine on transform times within 5 min (median ± interquartile, Kruskal-Wallis test). Ctrl: control; Amp: d-amphetamine; Lis: lisdexamfetamine. *P < 0.05, **P < 0.01 vs. Ctrl, n = 10 in each group.

FIGURE 3

The effects of d-amphetamine on Tow-trial Y-maze based delayed alternation. (A) The effect of d-amphetamine on percentage of novel arm visit times (median ± interquartile, Kruskal-Wallis test). (B) The percentage of each arm visits (mean ± SEM, Repeated measure ANOVA followed by Bonferroni test). (C) The effect of d-amphetamine on percentage of novel arm retention (median ± interquartile, Kruskal-Wallis test). (D) The percentage of each arm retention (mean ± SEM, Repeated measure ANOVA followed by Bonferroni test). Ctrl: control; Amp: d-amphetamine. (A,C) *P < 0.05, ***P < 0.001 vs. Ctrl; (B,D) *P < 0.05, ***P < 0.001 vs. Novel arm, n = 10 in each group.

FIGURE 4

The effects of lisdexamfetamine on Tow-trial Y-maze based delayed alternation. (A) The effect of lisdexamfetamine on percentage of novel arm visit times (mean ± SEM, One-way ANOVA, followed by Dunnett-t test). (B) The percentage of each arm visits (mean ± SEM, Repeated measure ANOVA followed by Bonferroni test). (C) The effect of lisdexamfetamine on percentage of novel arm retention (mean ± SEM, One-way ANOVA, followed by Dunnett-t test). (D) The percentage of each arm retention (mean ± SEM, Repeated measure ANOVA followed by Bonferroni test). Ctrl: control; Caf: caffeine; Lis: lisdexamfetamine. (A,C) *P < 0.05, **P < 0.01, ***P < 0.001 vs. Ctrl; (B,D) *P < 0.05, **P < 0.01, ***P < 0.001 vs. novel arm, n = 10 in each group.

FIGURE 5

The effects of d-amphetamine and lisdexamfetamine on catecholamine neurotransmitters and the metabolites in mPFC. (A) The implantation location of the microdialysis guide cannula. (B) The effects of d-amphetamine and lisdexamfetamine on DA efflux. (C) The effects of d-amphetamine and lisdexamfetamine on DOPAC efflux. (D) The effects of d-amphetamine and lisdexamfetamine on HVA efflux. Amp: d-amphetamine; Lis: lisdexamfetamine. Data are presented by mean ± SEM, n = 5 in each group.