TY - JOUR T1 - Activation of Glycogen Synthase Kinase-3β Is Required for Hyperdopamine and D<sub>2</sub> Receptor-Mediated Inhibition of Synaptic NMDA Receptor Function in the Rat Prefrontal Cortex JF - The Journal of Neuroscience JO - J. Neurosci. SP - 15551 LP - 15563 DO - 10.1523/JNEUROSCI.3336-09.2009 VL - 29 IS - 49 AU - Yan-Chun Li AU - Dong Xi AU - Joy Roman AU - Yue-Qiao Huang AU - Wen-Jun Gao Y1 - 2009/12/09 UR - http://www.jneurosci.org/content/29/49/15551.abstract N2 - 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 D2 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/D2 receptor-mediated suppression of NMDA receptors was involved in the increase of glycogen synthase kinase-3β (GSK-3β) activity, which in turn phosphorylates β-catenin and disrupts β-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-3β inhibitor or D2 receptor antagonist. These results therefore suggest that GSK-3β 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. ER -