A pharmacological model for psychosis based on N-methyl-D-aspartate receptor hypofunction: molecular, cellular, functional and behavioral abnormalities.
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.
Rujescu
Dan
D
Division of Molecular and Clinical Neurobiology, Department of Psychiatry, Ludwig-Maximilians-University, Munich, Germany. Dan.Rujescu@med.uni-muenchen.de
Bender
Andreas
A
Keck
Martin
M
Hartmann
Annette M
AM
Ohl
Frauke
F
Raeder
Hanna
H
Giegling
Ina
I
Genius
Just
J
McCarley
Robert W
RW
Möller
Hans-Jürgen
HJ
Grunze
Heinz
H
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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