Title

Activation of glycogen synthase kinase-3ß is required for hyperdopamine and D2 receptor-mediated inhibition of synaptic NMDA receptor function in the rat prefrontal cortex

Document Type

Article

Publication Date

2009

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-3ß (GSK-3ß) activity, which in turn phosphorylates ß-catenin and disrupts ß-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-3ß inhibitor or D 2 receptor antagonist. These results therefore suggest that GSK-3ß is required for the hyperdopamine/D2 receptor-mediated inhibition of NMDA receptors in the prefrontal neurons and these actions may underlie D2 receptor-mediated psychostimulant effects and hyperdopamine-dependent behaviors in the brain.

Publication Title

Journal of Neuroscience

Volume

29

Issue

49

First Page

15551

Last Page

15563

Comments

This article was published in Journal of Neuroscience, Volume 29, Issue 49, Pages 15551-15563.

The published version is available at http://dx.doi.org/10.1523/JNEUROSCI.3336-09.2009.

Copyright © 2009 Soc. for Neuroscience.

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