, 202:295 | Cite as

Asenapine restores cognitive flexibility in rats with medial prefrontal cortex lesions

  • David S. Tait
  • Hugh M. Marston
  • Mohammed Shahid
  • Verity J. Brown
Original Investigation



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 μg/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 μg/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 μg/kg s.c.) was associated with differential activation of the neurons in the anterior mPFC of lesioned animals, but was without effect in controls.


Asenapine can ameliorate mPFC lesion-induced impairment in attentional set-shifting, and is associated with a greater activation of the spared neurons in the anterior mPFC. These data suggest that asenapine may benefit impaired cognitive flexibility in disorders such as schizophrenia.


Schizophrenia ID/ED Attentional set-shifting Ibotenic acid 


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Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • David S. Tait
    • 1
  • Hugh M. Marston
    • 2
  • Mohammed Shahid
    • 2
  • Verity J. Brown
    • 1
  1. 1.School of PsychologyUniversity of St AndrewsSt AndrewsUK
  2. 2.Department of PharmacologySchering-Plough CorporationNewhouseUK

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