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Glutamate and dopamine components in schizophrenia.
1Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada. philip.seeman@utoronto.ca
Journal of Psychiatry & Neuroscience : JPN
|March 10, 2009
Summary
Schizophrenia treatment may shift from dopamine blockers to glutamate agonists. Glutamate agonists show antipsychotic effects by interacting with dopamine D(2) receptors.
Area of Science:
- Neuroscience
- Psychiatry
- Pharmacology
Background:
- Current schizophrenia treatment relies on dopamine (DA) D(2) receptor blockers, suggesting a hyperdopamine state.
- Emerging evidence, including the efficacy of glutamate agonist LY404039, suggests a hypoglutamate state in schizophrenia.
Purpose of the Study:
- To investigate the potential hypoglutamate basis of schizophrenia.
- To explore the mechanism of action for glutamate agonists as antipsychotics.
- To reconcile the roles of glutamate and dopamine in psychosis.
Main Methods:
- Analysis of basic and clinical findings on phencyclidine and LY glutamate agonists.
- Utilizing Dreiding models to assess receptor interactions.
- Examining the relationship between dissociation constants and antipsychotic efficacy.
Main Results:
- Phencyclidine exhibits dopamine D(2) agonist actions, challenging a purely hypoglutamate model.
- Accurate Dreiding models show phencyclidine and LY agonists fit the D(2) receptor model.
- Metabotropic glutamate agonists demonstrate D(2) agonism, with doses correlating to dissociation constants.
Conclusions:
- The antipsychotic action of glutamate agonists may stem from their ability to interfere with dopamine neurotransmission.
- Glutamate agonists may act as partial agonists at dopamine D(2) receptors.
- This suggests a complex interplay between glutamate and dopamine systems in schizophrenia pathophysiology.
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