Cited by 437Schizophrenia research and treatmentNeurotransmitter Receptor Influence on BehaviorNeuroscience and Neuropharmacology Research

Glutamate, Dopamine, and Schizophrenia: From Pathophysiology to Treatment

LARUELLE, MARC, KEGELES, LAWRENCE S., ABI‐DARGHAM, ANISSA·2003·Annals of the New York Academy of Sciences

Abstract

A bstract: 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) D 2 receptors, (2) deficient stimulation of prefrontal DA D 1 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 D 2 receptors rests on strong pharmacological evidence and has recently received support from brain imaging studies. The hypothesis of deficient prefrontal cortex (PFC) D 1 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.

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Crossref · 10.1196/annals.1300.063

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  • Elevated prefrontal E/I ratio may result from alterations in multiple pathways implicated in schizophrenia, including GABAergic deficits, increased background input from other areas, or abnormal levels of neuromodulators.

    “Elevated prefrontal E/I ratio may result from alterations in multiple pathways that are implicated in schizophrenia.These include GABAergic deficits, such as reduced GAD67 production (Lewis et al. 2005); increased background input from other areas such as the thalamus or hippocampus (Lisman et al. 2008); or abnormal levels of neuromodulators (Laruelle et al. 2003).”

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Authors
LARUELLE, M., KEGELES, L. S., & ABI‐DARGHAM, A.
Affiliations
Columbia University Irving Medical Center (US)
Corresponding author
LARUELLE, MARC
Venue
Annals of the New York Academy of Sciences
Publisher
Wiley
Published
2003-11
Volume
1003
Issue
1
Pages
138-158
ISSN
  • 0077-8923 (ISSN-L)
  • 1749-6632
OpenAlex
W2120481681
Cited by
437
References
136
Citations by year
2026: 4 · 2025: 3 · 2024: 2 · 2023: 7 · 2022: 9 · 2021: 7 · 2020: 15 · 2019: 14 · 2018: 9 · 2017: 16 · 2016: 19 · 2015: 19 · 2014: 22 · 2013: 24 · 2012: 26
FWCI
3.95
Type
journal article
Language
en
Open access
closed
Locations
  • Annals of the New York Academy of Sciences (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (5k08mh001594-05, 5k02mh064178-03)
  • National Institute of Mental Health (K02 MH064178-01A2, K02MH01603-01, K02MH001603, K08 MH01594-01)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
schizophrenia, glutamate, dopamine, NMDA receptor hypofunction, prefrontal connectivity, dopamine-glutamate interaction, striatum, prefrontal cortex, neuroimaging, synaptic plasticity
MeSH terms
Animals, Cerebral Cortex, Dopamine, Glutamates, Humans, Schizophrenia, Receptors, N-Methyl-D-Aspartate, Neostriatum, Prefrontal Cortex

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