Dopamine and Glutamate Hypotheses of Schizophrenia

Abstract

The original dopamine hypothesis of schizophrenia posits that psychosis is associated with a hyperactive dopamine transmission. This hypothesis has been revised through the years to account for the cognitive and negative symptoms that are increasingly recognized as the core features of schizophrenia. The critical support for this hypothesis stems from the fact that until recently it was assumed that all antipsychotic drugs block dopamine receptors; however, decades of research have failed to provide solid evidence for a primary dopaminergic disruption in schizophrenia. An alternative hypothesis, based on glutamate transmission, was developed after discovering that the psychotomimetic agent phencyclidine is an antagonist of glutamate NMDA receptors. Further clinical and basic research has provided support for the notion that various genetic and cellular susceptibility factors in schizophrenia may converge at the level of NMDA receptor dysfunction. This hypothesis predicts that a disrupted glutamatergic transmission causes the core cognitive deficits of schizophrenia and may lead to a secondary disruption in dopamine transmission that in turn causes psychosis. This hypothesis has provided novel therapeutic targets for schizophrenia that modulate glutamatergic transmission through a number of mechanisms including metabotropic and AMPA receptors and glycine modulatory site on NMDA receptors.