Novel application potential of lisdexamfetamine for visual discrimination and reversal learning improvement in rats: A translational cognitive research

Impairments in visual discrimination and cognitive flexibility are prevalent in several neuropsychiatric disorders. Here, we explored the effects of lisdexamfetamine, the prodrug of d-amphetamine, on visual discrimination and cognitive flexibility using touchscreen-based visual discrimination and reversal learning task, a translational cross-species cognitive paradigm in rats. A single administration of 1.0 mg/kg lisdexamfetamine significantly improved the accuracy of visual discrimination. Furthermore, repeated treatment with 1.0 mg/kg lisdexamfetamine during the visual discrimination training period significantly shortened training sessions to achieve 80 % accuracy. However, neither acute nor chronic administration of d-amphetamine (0.05–0.5 mg/kg) significantly improved visual discrimination performance in rats. Furthermore, both 3.0 mg/kg lisdexamfetamine and 1.5 mg/kg d-amphetamine significantly improved reversal learning. Given the crucial involvement of N-methyl-D-aspartic acid glutamate receptors (NMDARs) in discrimination learning process, the membranous/cytosolic distribution of NMDARs after chronic treatment with lisdexamfetamine and d-amphetamine was tested using Western Blotting. Lisdexamfetamine (1.0 mg/kg), rather than d-amphetamine (0.05–0.5 mg/kg) significantly increased the membranous distribution of GluN1, GluN2A, GluN2B, the main subunits of NMDARs in hippocampus, the key brain region associated with learning process, but not in medial prefrontal cortex. Together, these results revealed that lisdexamfetamine improved visual discrimination and cognitive flexibility in rats. The chronic effects of lisdexamfetamine on enhancing visual discrimination learning may be partly related to increase membranous NMDARs distribution in the hippocampus. The present study suggests a novel potential application of lisdexamfetamine for improving visual discrimination and cognitive flexibility, which may facilitate the clinical application to address certain cognitive deficits in neuropsychiatric disorders.