title: A pharmacological model for psychosis based on N-methyl-D-aspartate receptor hypofunction: molecular, cellular, functional and behavioral abnormalities.
abstract: BACKGROUND
  The psychotomimetic effects of N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine (PCP) in healthy humans and their ability to exacerbate psychotic symptoms in schizophrenic patients have promoted a view of schizophrenia as being related to altered glutamatergic neurotransmission.
  
  
  METHODS
  This prompted us and others to develop animal models for psychosis based on a glutamatergic approach. Pharmacological induction of a state of impaired glutamatergic neurotransmission based on chronic, low-dose application of MK-801, a highly selective noncompetitive NMDA antagonist, revealed marked parallels between schizophrenia and our animal model.
  
  
  RESULTS
  MK-801 altered the expression of NR1 splice variants and NR2 subunits of the NMDA receptor in a pattern partially resembling the alterations detected in schizophrenia. Ultrastructurally, the number of gamma-aminobutyric-acid (GABA)ergic parvalbumin-positive interneurons was relatively decreased, a finding which again parallels observations in post mortem brain from schizophrenic patients. As a functional consequence, local inhibition of pyramidal cells which is largely mediated by recurrent axon collaterals, originating from GABAergic interneurons, was altered. Not unexpectedly, these animals showed cognitive deficits resembling findings in schizophrenic humans.
  
  
  CONCLUSIONS
  These convergent lines of evidence suggest that our approach has a significant potential of serving as a model of the pathobiology of several aspects of psychosis and consequently could contribute to the development of new therapeutic strategies.
authors.affiliation: Division of Molecular and Clinical Neurobiology, Department of Psychiatry, Ludwig-Maximilians-University, Munich, Germany. Dan.Rujescu@med.uni-muenchen.de
authors.forename: Dan
authors.initials: D
authors.lastname: Rujescu
authors.forename: Andreas
authors.initials: A
authors.lastname: Bender
authors.forename: Martin
authors.initials: M
authors.lastname: Keck
authors.forename: Annette M
authors.initials: AM
authors.lastname: Hartmann
authors.forename: Frauke
authors.initials: F
authors.lastname: Ohl
authors.forename: Hanna
authors.initials: H
authors.lastname: Raeder
authors.forename: Ina
authors.initials: I
authors.lastname: Giegling
authors.forename: Just
authors.initials: J
authors.lastname: Genius
authors.forename: Robert W
authors.initials: RW
authors.lastname: McCarley
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Möller
authors.forename: Heinz
authors.initials: H
authors.lastname: Grunze
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000187:drug effects; D064032:Calbindin 2; D002755:Choice Behavior / Q000187:drug effects / Q000502:physiology; D004274:DNA, Recombinant / Q000378:metabolism; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004558:Electric Stimulation / Q000379:methods; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000473:pathology; D007150:Immunohistochemistry / Q000379:methods; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D001523:Mental Disorders / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D016571:Neural Networks, Computer; D009474:Neurons / Q000502:physiology; D010320:Parvalbumins / Q000378:metabolism; D018408:Patch-Clamp Techniques / Q000379:methods; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics* / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D064030:S100 Calcium Binding Protein G / Q000378:metabolism
chemical_list: D064032:Calbindin 2; D004274:DNA, Recombinant; D018691:Excitatory Amino Acid Antagonists; D010320:Parvalbumins; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D064030:S100 Calcium Binding Protein G; D016291:Dizocilpine Maleate