Glutamate, dopamine, and schizophrenia: from pathophysiology to treatment

Ann N Y Acad Sci. 2003 Nov;1003:138-58. doi: 10.1196/annals.1300.063.


The fundamental pathological process(es) associated with schizophrenia remain(s) uncertain, but multiple lines of evidence suggest that this condition is associated with (1) excessive stimulation of striatal dopamine (DA) D2 receptors, (2) deficient stimulation of prefrontal DA D1 receptors and, (3) alterations in prefrontal connectivity involving glutamate (GLU) transmission at N-methyl-d-aspartate (NMDA) receptors. This chapter first briefly discusses the current knowledge status for these abnormalities, with emphasis on results derived from clinical molecular imaging studies. The evidence for hyperstimulation of striatal D2 receptors rests on strong pharmacological evidence and has recently received support from brain imaging studies. The hypothesis of deficient prefrontal cortex (PFC) D1 receptor stimulation is almost entirely derived from preclinical studies. Preliminary imaging data compatible with this hypothesis have recently emerged. The NMDA hypofunction hypothesis originates mainly from indirect pharmacological data. The interactions between DA and GLU systems relevant to schizophrenia are then reviewed. Animal and imaging data supporting the general model that the putative DA imbalance in schizophrenia (striatal excess and cortical deficiency) might be secondary to NMDA hypofunction in the PFC and its connections are presented. Equally important are the potential consequences of this DA imbalance for NMDA function in the striatum and the cortex, which are subsequently discussed. In conclusion, it is proposed that schizophrenia is associated with strongly interconnected abnormalities of GLU and DA transmission: NMDA hypofunction in the PFC and its connections might generate a pattern of dysregulation of DA systems that, in turn, further weakens NMDA-mediated connectivity and plasticity.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Animals
  • Cerebral Cortex / physiopathology
  • Dopamine / physiology*
  • Glutamates / physiology*
  • Humans
  • Neostriatum / physiopathology
  • Prefrontal Cortex / physiopathology
  • Receptors, N-Methyl-D-Aspartate / physiology
  • Schizophrenia / drug therapy*
  • Schizophrenia / pathology
  • Schizophrenia / physiopathology*


  • Glutamates
  • Receptors, N-Methyl-D-Aspartate
  • Dopamine