Abstract
Pharmacological intervention targeting mGluRs has emerged as a potential treatment for schizophrenia, whereas the mechanisms involved remain elusive. We explored the antipsychotic effects of an mGluR2/3 agonist in the MK-801 model of schizophrenia in the rat prefrontal cortex. We found that the mGluR2/3 agonist LY379268 effectively recovered the disrupted expression of NMDA receptors induced by MK-801 administration. This effect was attributable to the direct regulatory action of LY379268 on NMDA receptors via activation of the Akt/GSK-3Β signaling pathway. As occurs with the antipsychotic drug clozapine, acute treatment with LY379268 significantly increased the expression and phosphorylation of NMDA receptors, as well as Akt and GSK-3Β. Physiologically, LY379268 significantly enhanced NMDA-induced current in prefrontal neurons and a GSK-3Β inhibitor occluded this effect. In contrast to the widely proposed mechanism of modulating presynaptic glutamate release, our results strongly argue that mGluR2/3 agonists modulate the function of NMDA receptors through postsynaptic actions and reverse the MK-801-induced NMDA dysfunction via the Akt/GSK-3Β pathway. This study provides novel evidence for postsynaptic mechanisms of mGluR2/3 in regulation of NMDA receptors and presents useful insights into the mechanistic actions of mGluR2/3 agonists as potential antipsychotic agents for treating schizophrenia.
Original language | English (US) |
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Pages (from-to) | 1260-1274 |
Number of pages | 15 |
Journal | Neuropsychopharmacology |
Volume | 36 |
Issue number | 6 |
DOIs | |
State | Published - May 2011 |
Externally published | Yes |
Keywords
- Antipsychotics
- NMDA antagonism
- NMDA receptors
- metabolic glutamate receptors
- schizophrenia
- signaling pathway
ASJC Scopus subject areas
- Pharmacology
- Psychiatry and Mental health