Transient N-methyl-D-aspartate receptor blockade in early development causes lasting cognitive deficits relevant to schizophrenia

Biol Psychiatry. 2005 Feb 15;57(4):433-6. doi: 10.1016/j.biopsych.2004.11.031.


Background: Aberrant N-methyl-D-aspartate (NMDA) receptor-mediated glutamatergic transmission has been implicated in schizophrenia. We studied whether transient inhibition of NMDA receptor activity during early postnatal development would produce a behavioral phenotype resembling that of individuals who are susceptible to develop schizophrenia.

Methods: Rat pups were given injections of the NMDA channel blocker MK801 on postnatal days 7 through 10. This period is akin to the prenatal second trimester of primate development. Cognitive function was tested in adulthood.

Results: Treatment with MK801 impaired cognitive flexibility and working memory. The impairment in cognitive flexibility was due to increased perseverative behavior. Treatment did not affect locomotor activity or recognition memory.

Conclusions: These results suggest that a brief disruption of NMDA receptors during a sensitive period of cortical development is sufficient to produce selective cognitive deficits that are relevant to schizophrenia.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Age Factors
  • Animals
  • Animals, Newborn
  • Behavior, Animal / drug effects
  • Cognition Disorders / chemically induced*
  • Cognition Disorders / complications
  • Discrimination, Psychological / drug effects
  • Dizocilpine Maleate / adverse effects*
  • Exploratory Behavior / drug effects
  • Locomotion / drug effects
  • Male
  • Memory, Short-Term / drug effects
  • Neuropsychological Tests
  • Psychomotor Performance / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Schizophrenia / etiology*


  • Receptors, N-Methyl-D-Aspartate
  • Dizocilpine Maleate