Review
Models of schizophrenia in humans and animals based on inhibition of NMDA receptors

https://doi.org/10.1016/j.neubiorev.2008.03.012Get rights and content

Abstract

The research of the glutamatergic system in schizophrenia has advanced with the use of non-competitive antagonists of glutamate NMDA receptors (phencyclidine, ketamine, and dizocilpine), which change both human and animal behaviour and induce schizophrenia-like manifestations. Models based on both acute and chronic administration of these substances in humans and rats show phenomenological validity and are suitable for searching for new substances with antipsychotic effects. Nevertheless, pathophysiology of schizophrenia remains unexplained. In the light of the neurodevelopmental model of schizophrenia based on early administration of NMDA receptor antagonists it seems that increased cellular destruction by apoptosis or changes in function of glutamatergic NMDA receptors in the early development of central nervous system are decisive for subsequent development of psychosis, which often does not manifest itself until adulthood. Chronic administration of antagonists initializes a number of adaptation mechanisms, which correlate with findings obtained in patients with schizophrenia; therefore, this model is also suitable for research into pathophysiology of this disease.

Section snippets

Introduction—N-methyl-d-aspartate receptor in schizophrenia

An important role of the glutamatergic neutrotransmitter system in the etiopathogenesis of schizophrenia has been supported by findings on various levels from molecular interactions up to the structural layout of neuronal network in the human brain (Goff and Coyle, 2001, Owen et al., 2004). Glutamate acts through several types of both ionotropic and metabotropic receptors (review Dingledine et al., 1999, Petrovič et al., 2005). In particular, the change of function of the ionotropic glutamate N

Neurodevelopmental model of schizophrenia

Neurodevelopmental hypothesis of the origin of schizophrenia assumes that a disorder in pre- or perinatal development of the brain will result in manifestation of the disease in early adulthood (Weinberger, 1996). This hypothesis also includes a neurodegenerative aspect. That is to say, several studies suggest a possible assault to the brain during development, which results in schizophrenia in early adulthood (Lipska et al., 1995, Howland et al., 2004; review Deutsch et al., 2001).

Genetic model of schizophrenia based on inhibition of NMDA receptor

The genetic model inspired by a hypothetical NMDA dysfunction in schizophrenia is based on a decrease in expression of the NR1 subunit or of other NMDA receptor subunits. Mohn and colleagues showed that an insertion of a gene of resistance to neomycine into intron 20 of the NR1 locus reduced expression of the NR1 subunit by 90% in homogenates from the cerebral cortex of mice that were genetically adjusted this way (Mohn et al., 1999). Mice with full deletion of the gene for the NR1 subunit die

Pharmacological model of schizophrenia: hypofunction of NMDA receptors in adults

This model consists in acute or chronic administration of NMDA receptor antagonists to adults (Table 2), and is based on the glutamatergic hypothesis of schizophrenia (Javitt and Zukin, 1991, Carlsson et al., 2001). This hypothesis presumes that by inhibition of NMDA receptors, the mesolimbic dopaminergic system becomes secondarily activated which in turn causes psychosis. Besides affecting the dopamine system, blockade of NMDA receptors reduces the firing rate of fast-spiking inhibitor

Conclusions

The non-competitive NMDA receptor antagonists exert potential for modeling psychotic behaviour. Models based on acute or chronic administration of these substances both in humans and rats show phenomenological validity and are usable in the testing of new substances with potential antipsychotic effect. Nevertheless, pathophysiology of schizophrenia remains unexplained. With respect to the neurodevelopmental model of schizophrenia based on early administration of NMDA antagonists it seems that

Acknowledgements

This research was supported by grant NR-8792-3 and MZ0PCP2005 from the Grant Agency of the Ministry of Health, the Czech Republic and by the projects 1M0517 from the Ministry of Education, Youth and Sports the Czech Republic.

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