Regulation of NMDA receptors by dopamine D4 signaling in prefrontal cortex

Increasing evidence has suggested that the interaction between dopaminergic and glutamatergic systems in prefrontal cortex (PFC) plays an important role in normal mental functions and neuropsychiatric disorders. In this study, we examined the regulation of NMDA-type glutamate receptors by the PFC dopamine D-4 receptor (one of the principal targets of antipsychotic drugs). Application of the D-4 receptor agonist PD168077 caused a reversible decrease of the NMDA receptor (NMDAR)-mediated current in acutely isolated and cultured PFC pyramidal neurons, an effect that was blocked by selective D-4 receptor antagonists. Furthermore, application of PD168077 produced a potent reduction of the amplitude (but not paired-pulse ratio) of evoked NMDAR EPSCs in PFC slices. The D-4 modulation of NMDA receptors in PFC involved the inhibition of protein kinase A, activation of protein phosphatase 1 and the ensuing inhibition of active Ca2+-calmodulin-dependent kinase II (CaMKII). Moreover, PD168077 reduced the surface expression of NMDARs and triggered the internalization of NMDARs in a manner dependent on CaMKII activity. These results identify a mechanistic link between D-4 and NMDA receptors in PFC pyramidal neurons, suggesting that D-4 receptors may play an important role in modulating synaptic plasticity and thus cognitive and emotional processes in PFC circuits.