NMDA receptor dependence of reversal learning and the flexible use of cognitively demanding search strategies in mice

Prog Neuropsychopharmacol Biol Psychiatry. 2019 Mar 2;90:235-244. doi: 10.1016/j.pnpbp.2018.12.003. Epub 2018 Dec 6.


Cognitive flexibility helps organisms to respond adaptively to environmental changes. Deficits in this executive function have been associated with a variety of brain disorders, and it has been shown to rely on various concomitant neurobiological mechanisms. However, the involvement of the glutamatergic system in general, and NMDA receptors in particular, has been debated. Therefore, we injected C57BL/6 mice repeatedly with low-doses of the non-competitive NMDA receptor antagonist MK-801 (dizocilpine, 0.1 mg/kg, i.p.). Reversal learning and the use of specific cognitive strategies were assessed in a non-spatial discrimination touchscreen task and the Morris water maze (MWM) spatial learning task. In addition, mice were subjected to a non-mnemonic test battery. Although initial acquisition learning was not affected by MK-801 administration, it did induce deficits in reversal learning, both in the non-spatial and spatial task. Defects in non-spatial reversal learning appeared to be caused by perseverative errors. Also, MK-801 administration induced perseverative behaviours as well as inefficient spatial strategy use during MWM reversal learning. These effects could not be reduced to changes in exploratory (anxiety-related) behaviours, nor to motor deficits. This was consistent with results in the non-mnemonic test battery, during which MK-801 evoked hyperlocomotion and subtle motor defects, but failed to alter general motor activity and exploratory behaviours. In conclusion, NMDA receptors appear to be involved in the flexible cognitive processes that underlie reversal learning in spatial as well as non-spatial tasks. Our results also indicate that reversal learning as well as the use of cognitively demanding strategies are more sensitive to NMDA receptor blockage than some other functions that have been suggested to be NMDA receptor dependent.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Discrimination, Psychological / drug effects
  • Discrimination, Psychological / physiology
  • Dizocilpine Maleate / pharmacology
  • Excitatory Amino Acid Antagonists / pharmacology
  • Executive Function / drug effects
  • Executive Function / physiology
  • Female
  • Maze Learning / drug effects
  • Maze Learning / physiology
  • Mice, Inbred C57BL
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Reversal Learning / drug effects
  • Reversal Learning / physiology*


  • Excitatory Amino Acid Antagonists
  • Receptors, N-Methyl-D-Aspartate
  • Dizocilpine Maleate