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

• 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
• ISSN: 0006-3223; 1873-2402
• DOI: 10.1016/j.biopsych.2005.08.029

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.