Dopamine and glutamate dysfunctions in schizophrenia: role of the dopamine D3 receptor

Abstract

Symptoms of schizophrenia are improved by dopamine antagonists and exacerbated by dopamine-releasing agents, suggesting hyperactivity of dopamine. However, chronic blockade of glutamate neurotransmission by antagonists at the N-methyl-D-aspartate (NMDA) receptor subtype produces a pathophysiological state resembling schizophrenia. A link between cortical glutamate/NMDA deficiency and subcortical dopamine hyperactivity, particularly in the mesolimbic pathway, has been hypothesized in schizophrenia. Here we show that hyperactivity produced by NMDA receptor blockade is dependent upon stimulation of the dopamine D3 receptor subtype. Since D3 receptor antagonists and antipsychotics produced very similar effects, our results add to the growing evidence suggesting that D3 receptor blockade might produce antipsychotic effects.