title: The emerging role of glutamate in the pathophysiology and treatment of schizophrenia.
abstract: OBJECTIVE
  Research has implicated dysfunction of glutamatergic neurotransmission in the pathophysiology of schizophrenia. This review evaluates evidence from preclinical and clinical studies that brain glutamatergic neurotransmission is altered in schizophrenia, may affect symptom expression, and is modulated by antipsychotic drugs.
  
  
  METHODS
  A comprehensive review of scientific articles published over the last decade that address the role of glutamate in the pathophysiology of schizophrenia was carried out.
  
  
  RESULTS
  Glutamatergic neurons are the major excitatory pathways linking the cortex, limbic system, and thalamus, regions that have been implicated in schizophrenia. Postmortem studies have revealed alterations in pre- and postsynaptic markers for glutamatergic neurons in several brain regions in schizophrenia. The N-methyl-D-aspartic acid (NMDA) subtype of glutamate receptor may be particularly important as blockade of this receptor by the dissociative anesthetics reproduces in normal subjects the symptomatic manifestations of schizophrenia, including negative symptoms and cognitive impairments, and increases dopamine release in the mesolimbic system. Agents that indirectly enhance NMDA receptor function via the glycine modulatory site reduce negative symptoms and variably improve cognitive functioning in schizophrenic subjects receiving typical antipsychotics.
  
  
  CONCLUSIONS
  Dysfunction of glutamatergic neurotransmission may play an important role in the pathophysiology of schizophrenia, especially of the negative symptoms and cognitive impairments associated with the disorder, and is a promising target for drug development.
authors.affiliation: Schizophrenia Program, Massachusetts General Hospital, Boston, USA.
authors.forename: D C
authors.initials: DC
authors.lastname: Goff
authors.forename: J T
authors.initials: JT
authors.lastname: Coyle
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects* / Q000503:physiopathology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000503:physiopathology; D003072:Cognition Disorders / Q000188:drug therapy / Q000503:physiopathology; D003342:Corpus Striatum / Q000187:drug effects / Q000503:physiopathology; D005971:Glutamates / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008032:Limbic System / Q000187:drug effects / Q000503:physiopathology; D051381:Rats; D017470:Receptors, Glutamate / Q000187:drug effects / Q000502:physiology; D012559:Schizophrenia / Q000188:drug therapy* / Q000503:physiopathology*; D012565:Schizophrenic Psychology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D013788:Thalamus / Q000187:drug effects / Q000503:physiopathology
chemical_list: D014150:Antipsychotic Agents; D005971:Glutamates; D017470:Receptors, Glutamate