['Cognitive inflexibility in schizophrenia is treatment-resistant and predictive of poor outcome. This study examined the effect of asenapine, a novel psychopharmacologic agent being developed for schizophrenia and bipolar disorder, on cognitive dysfunction in the rat.', 'The objective of this paper was to establish whether asenapine has a beneficial effect on the performance of rats with ibotenic acid-induced lesion of the medial prefrontal cortex (mPFC) in an intradimensional/extradimensional (ID/ED) test of cognitive flexibility.', 'The effect of subcutaneously administered asenapine (0.75, 7.5, 75 microg/kg) on ID/ED performance of controls or mPFC-lesioned rats was examined using a within-subjects, repeated-measures design. In a second experiment, lesioned and control rats were tested with or without asenapine in a modified version of the task, with multiple set-shifts, before brains were processed for Fos-immunoreactivity in the mPFC.', 'The mPFC lesion-induced deficit in the ID/ED task was stable with repeated testing over more than two months. Asenapine (75 microg/kg s.c., p < 0.05) completely restored the performance of lesioned rats. Experiment 2 replicated both lesion and asenapine effects and demonstrated that it is possible to measure set-shifting multiple times within a test session. Asenapine (75 microg/kg s.c.) was associated with differential activation of the neurons in the anterior mPFC of lesioned animals, but was without effect in controls.'] Does asenapine restore cognitive flexibility in rats with medial prefrontal cortex lesions?