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Journal article
Activation of Glycogen Synthase Kinase-3 beta Is Required for Hyperdopamine and D-2 Receptor-Mediated Inhibition of Synaptic NMDA Receptor Function in the Rat Prefrontal Cortex
The Journal of neuroscience, v 29(49), pp 15551-15563
09 Dec 2009
PMID: 20007479
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The interactions between dopamine and glutamate systems play an essential role in normal brain functions and neuropsychiatric disorders. The mechanism of NMDA receptor regulation through high concentrations of dopamine, however, remains unclear. Here, we show the signaling pathways involved in hyperdopaminergic regulation of NMDA receptor functions in the prefrontal cortex by incubating cortical slices with high concentration of dopamine or administering dopamine reuptake inhibitor 1-(2-[bis-(4-fluorophenyl)methoxy]ethyl)4-(3-phenylpropyl) piperazine (GBR12909) in vivo. We found that, under both conditions, the synaptic NMDA receptor-mediated currents were significantly attenuated by excessive dopamine stimulation through activation of D-2 receptors. Furthermore, high dose of dopamine failed to affect NMDA receptor-mediated currents after blockade of NR2B subunits but triggered a dynamin-dependent endocytosis of NMDA receptors. The high-dose dopamine/D-2 receptor-mediated suppression of NMDA receptors was involved in the increase of glycogen synthase kinase-3 beta (GSK-3 beta) activity, which in turn phosphorylates beta-catenin and disrupts beta-catenin-NR2B interaction, but was dependent on neither Gq11 nor PLC (phospholipase C). Moreover, the hyperdopamine induced by GBR12909 significantly decreased the expression of both surface and intracellular NR2B proteins, as well as NR2B mRNA levels, suggesting an inhibition of protein synthesis. These effects were, however, completely reversed by administration of either GSK-3 beta inhibitor or D-2 receptor antagonist. These results therefore suggest that GSK-3 beta is required for the hyperdopamine/D-2 receptor-mediated inhibition of NMDA receptors in the prefrontal neurons and these actions may underlie D-2 receptor-mediated psychostimulant effects and hyperdopamine-dependent behaviors in the brain.
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Details
- Title
- Activation of Glycogen Synthase Kinase-3 beta Is Required for Hyperdopamine and D-2 Receptor-Mediated Inhibition of Synaptic NMDA Receptor Function in the Rat Prefrontal Cortex
- Creators
- Yan-Chun Li - Drexel UniversityDong Xi - Drexel UniversityJoy Roman - Drexel UniversityYue-Qiao Huang - Drexel UniversityWen-Jun Gao - Drexel University
- Publication Details
- The Journal of neuroscience, v 29(49), pp 15551-15563
- Publisher
- Soc Neuroscience
- Number of pages
- 13
- Grant note
- R01MH085666 / NATIONAL INSTITUTE OF MENTAL HEALTH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Mental Health (NIMH) National Alliance for Research on Schizophrenia and Depression (NARSAD) Young Investigator Award; NARSAD Drexel University College of Medicine R21MH232307; R01MH085666 / National Institutes of Health (NIH); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Neurobiology and Anatomy
- Web of Science ID
- WOS:000272736400022
- Scopus ID
- 2-s2.0-71849083984
- Other Identifier
- 991019167552704721
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- Web of Science research areas
- Neurosciences