Targeting the NMDA receptor-nitric oxide-cyclic GMP pathway to develop non-dopaminergic antipsychotic medications for schizophrenia

Abstract

Schizophrenia is a devastating disorder that occurs in about 1% of the population worldwide. For over 30 years, it has been considered to be the result of dysfunctional brain dopaminergic pathways. However, dopaminergic antipsychotic drugs have proven effective for only some of the symptoms found in schizophrenia patients. Recent evidence suggests that dopaminergic abnormalities may be secondary to dysfunctions in multi-neurotransmitter systems modulating dopamine. One of the key neurotransmitters thought to be involved in schizophrenia is glutamate, and there is strong support for the involvement of a hypoactivity of N-methyl-D-aspartate (NMDA) glutamate receptors in the pathogenesis of schizophrenia. However, research with NMDA receptor agonists for the treatment of schizophrenia has produced inconsistent results, which may be due to the development of rapid tolerance to these compounds secondary to down-regulation of NMDA receptors. Perhaps the development of drugs that act on targets downstream NMDA receptors, such as nitric oxide (NO), could avoid the problem of the down-regulation of these receptors.