A Pharmacological Model for Psychosis Based on N-methyl-D-aspartate Receptor Hypofunction: Molecular, Cellular, Functional and Behavioral Abnormalities

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...

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Bibliographic Details
Published in:Biological psychiatry (1969) 2006-04, Vol.59 (8), p.721-729
Main Authors: Rujescu, Dan, Bender, Andreas, Keck, Martin, Hartmann, Annette M., Ohl, Frauke, Raeder, Hanna, Giegling, Ina, Genius, Just, McCarley, Robert W., Möller, Hans-Jürgen, Grunze, Heinz
Format: Article
Language:English
Subjects:
Adult and adolescent clinical studies
animal model
Animals
Animals, Newborn
Behavior, Animal - drug effects
Biological and medical sciences
Calbindin 2
Choice Behavior - drug effects
Choice Behavior - physiology
Disease Models, Animal
Dizocilpine Maleate - pharmacology
DNA, Recombinant - metabolism
Electric Stimulation - methods
Excitatory Amino Acid Antagonists - pharmacology
Gene Expression - drug effects
Gene Expression - physiology
glutamate
hippocampus
Hippocampus - pathology
Immunohistochemistry - methods
In Vitro Techniques
Male
Medical sciences
Membrane Potentials - drug effects
Membrane Potentials - physiology
Membrane Potentials - radiation effects
Mental Disorders - genetics
Mental Disorders - metabolism
Mental Disorders - physiopathology
MK-801
Motor Activity - drug effects
Motor Activity - physiology
Neural Networks (Computer)
Neurons - physiology
NMDA
Other psychotic disorders
Parvalbumins - metabolism
Patch-Clamp Techniques - methods
Psychology. Psychoanalysis. Psychiatry
Psychopathology. Psychiatry
Psychoses
Psychosis
Rats
Rats, Long-Evans
Receptors, N-Methyl-D-Aspartate - genetics
Receptors, N-Methyl-D-Aspartate - metabolism
Reverse Transcriptase Polymerase Chain Reaction - methods
RNA, Messenger - metabolism
S100 Calcium Binding Protein G - metabolism
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Summary: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. 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. 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. 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.
ISSN:0006-3223
1873-2402
DOI:10.1016/j.biopsych.2005.08.029