Alterations of hippocampal and prefrontal GABAergic interneurons in an animal model of psychosis induced by NMDA receptor antagonism

Schizophr Res. 2007 Dec;97(1-3):254-63. doi: 10.1016/j.schres.2007.05.005. Epub 2007 Jun 29.


Some behavioral symptoms and neuropathological features of schizophrenia, like alterations of local GABAergic interneurons, could be emulated in an animal model of psychosis based on prolonged low-dose exposure to N-methyl-D-aspartate (NMDA) receptor antagonists, e.g. MK-801. Employing this model, we examined distinct subpopulations of GABAergic interneurons within the hippocampus and prefrontal cortex. Compared to saline control, animals receiving MK-801 exhibited a decreased density of hippocampal parvalbumin-positive interneurons. A co-administration of the antipsychotic drug haloperidol ameliorated this effect of MK-801 on PV(+) interneurons in the hippocampus, but led to a marked reduction of PV immunoreactivity in the prefrontal cortex, when comparing with saline, MK-801 or haloperidol treatment alone. Neither calretinin immunoreactivity nor nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase staining, representing neuronal nitric oxide synthase activity mostly detectable in interneurons, was altered by either treatment. With special reference to the hippocampus, these data show that a prolonged application of low-dose NMDA receptor antagonist could, in part, mimic some neuropathologic findings in human schizophrenia, thus strengthening the idea that (sub-) chronic NMDA receptor antagonism in animals is a viable approach in mimicking aspects of schizophrenia. Moreover, this study provides further evidence for regional differences in the response of GABAergic interneurons to NMDA receptor antagonism and antipsychotic treatment.

MeSH terms

  • Animals
  • Antipsychotic Agents / pharmacology
  • Disease Models, Animal*
  • Dizocilpine Maleate*
  • Haloperidol / pharmacology
  • Hippocampus / drug effects
  • Hippocampus / pathology*
  • Interneurons / drug effects
  • Interneurons / pathology*
  • Male
  • Neural Inhibition / drug effects
  • Neural Inhibition / physiology
  • Neurons / pathology
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / pathology*
  • Psychotic Disorders / pathology*
  • Rats
  • Rats, Long-Evans
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Schizophrenia / chemically induced
  • Schizophrenia / pathology
  • gamma-Aminobutyric Acid / metabolism*


  • Antipsychotic Agents
  • Receptors, N-Methyl-D-Aspartate
  • gamma-Aminobutyric Acid
  • Dizocilpine Maleate
  • Haloperidol