A pharmacological model for psychosis based on N-methyl-D-aspartate receptor hypofunction: molecular, cellular, functional and behavioral abnormalities.
Dan Rujescu, Andreas Bender, Martin Keck, Annette M Hartmann, Frauke Ohl, Hanna Raeder, Ina Giegling, Just Genius, Robert W McCarley, Hans-Jürgen Möller, Heinz Grunze
Biological psychiatry April 15, 2006 DOI: 10.1016/j.biopsych.2005.08.029 via PubMed
Summary
AI-generated from the abstractA chronic, low-dose application of MK-801, a selective noncompetitive NMDA receptor antagonist, in animals produces changes that parallel those seen in schizophrenia. The treatment altered NMDA receptor subunit expression and reduced the number of GABAergic parvalbumin-positive interneurons, matching post-mortem findings from schizophrenic patients. This led to altered inhibition of pyramidal cells and cognitive deficits similar to those in schizophrenia. The findings suggest this animal model may help understand psychosis and aid in developing new treatments.
Study at a glance
| Characteristics | Animal model study Peer reviewed |
|---|---|
| Population | Animals |
| Intervention | MK-801 |
| Dose | low-dose |
| Duration | Chronic |
| Key finding | Chronic low-dose MK-801 in animals produces neurobiological and cognitive changes that parallel schizophrenia, including altered NMDA receptor expression, reduced GABAergic interneurons, and cognitive deficits. |
Abstract
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.