Methods and Findings in Experimental and Clinical Pharmacology
Vol. 25, Suppl. A, 2003
ISSN 0379-0355
Copyright 2003 Prous Science, S.A.
CCC: 0379-0355/2003
http://www.prous.com

Glutamate and Schizophrenia

C. Matute

Departamento de Neurociencias, Universidad del País Vasco, Vizcaya, Spain

Glutamate is the most important neurotransmitter in brain regions such as the cerebral cortex and hippocampus, which are crucial for the integration of emotional responses and whose function appears to be compromised in schizophrenia. Several studies have demonstrated that brain glutamatergic neurotransmission is altered in schizophrenia. Indeed, different psychomimetic drugs such as phencyclidine bind to the intrachannel site of the N-methyl-d-aspartate (NMDA) receptor, blocking normal receptor activity. Mice expressing low levels of the NMDAR1 subunit display behavioral characteristics related to schizophrenia, which are ameliorated by atypical antipsychotic treatment. In addition, schizophrenic brains present significant alterations in glutamate receptors in different areas. Furthermore, changes in the expression of excitatory amino acid transporters in the thalamus and in the striatum of patients with schizophrenia have been reported. Therefore, dysfunction of glutamatergic neurotransmission appears to play an important role in the pathophysiology of schizophrenia and is thus a promising target for drug development.

We have recently carried out studies on the alteration of glutamate signaling in both experimental animals treated with antipsychotics and in human postmortem prefrontal cortex using DNA arrays, electrophysiology and histology. The results indicate that antipsychotics, in addition to blocking dopaminergic and serotoninergic receptors, regulate excitability in the central nervous system by modulating glutamate signaling mechanisms at the level of receptors and transporters. In turn, studies in the human prefrontal cortex indicate that glutamate transporter expression is altered in non-medicated patients and that antipsychotics appear to modulate the expression of this gene family. Taken together, these results inicate that antipsychotics interfere with glutamate signaling at multiple sites and suggest that the therapeutic benefit and/or side effects observed in patients treated with these drugs may be due, at least in part, to these interactions.

ACKNOWLEDGMENTS

Supported by the Gobierno Vasco.

Methods and Findings in Experimental and Clinical Pharmacology Vol. 25, Suppl. A, 2003
ISSN 0379-0355 Copyright 2003 Prous Science, S.A. CCC: 0379-0355/2003 http://www.prous.com