title: Glutamatergic dysbalance and oxidative stress in in vivo and in vitro models of psychosis based on chronic NMDA receptor antagonism.
abstract: BACKGROUND
  The psychotomimetic effects of N-methyl-D-aspartate (NMDA) receptor antagonists in healthy humans and their tendency to aggravate psychotic symptoms in schizophrenic patients have promoted the notion of altered glutamatergic neurotransmission in the pathogenesis of schizophrenia.
  
  
  METHODS
  The NMDA-receptor antagonist MK-801 was chronically administered to rats (0.02 mg/kg intraperitoneally for 14 days). In one subgroup the antipsychotic haloperidol (1 mg/kg) was employed as a rescue therapy. Glutamate distribution and 3-NT (3-nitrotyrosine) as a marker of oxidative stress were assessed by immunohistochemistry in tissue sections. In parallel, the effects of MK-801 and haloperidol were investigated in primary embryonal hippocampal cell cultures from rats.
  
  
  RESULTS
  Chronic NMDA-R antagonism led to a marked increase of intracellular glutamate in the hippocampus (126.1 +/- 10.4% S.E.M of control; p=0.037), while 3-NT staining intensity remained unaltered. No differences were observed in extrahippocampal brain regions. Essentially these findings could be reproduced in vitro.
  
  
  CONCLUSIONS
  The combined in vivo and in vitro strategy allowed us to assess the implications of disturbed glutamate metabolism for the occurrence of oxidative stress and to investigate the effects of antipsychotics. Our data suggest that oxidative stress plays a minor role in this model than previously suggested. The same applies to apoptosis. Moreover, the effect of haloperidol seems to be mediated through yet unidentified mechanisms, unrelated to D2-antagonism. These convergent lines of evidence indicate that further research should be focused on the glutamatergic system and that our animal model may provide a tool to explore the biology of schizophrenia.
authors.affiliation: Department of Psychiatry, Ludwig-Maximilians University of Munich, Munich, Germany.
authors.forename: Just
authors.initials: J
authors.lastname: Genius
authors.forename: Johanna
authors.initials: J
authors.lastname: Geiger
authors.forename: Anna-Lena
authors.initials: AL
authors.lastname: Dölzer
authors.forename: Jens
authors.initials: J
authors.lastname: Benninghoff
authors.forename: Ina
authors.initials: I
authors.lastname: Giegling
authors.forename: Annette M
authors.initials: AM
authors.lastname: Hartmann
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Möller
authors.forename: Dan
authors.initials: D
authors.lastname: Rujescu
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism*; D006220:Haloperidol / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D020318:Rats, Long-Evans; D017382:Reactive Oxygen Species / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012559:Schizophrenia / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D018691:Excitatory Amino Acid Antagonists; D017382:Reactive Oxygen Species; D016194:Receptors, N-Methyl-D-Aspartate; C002744:3-nitrotyrosine; D018698:Glutamic Acid; D014443:Tyrosine; D016291:Dizocilpine Maleate; D006220:Haloperidol