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 D₄ receptor (one of the principal targets of antipsychotic drugs). Application of the D₄ 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 D₄ 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 D₄ 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, PD 168077 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 D₄ and NMDA receptors in PFC pyramidal neurons, suggesting that D₄ receptors may play an important role in modulating synaptic plasticity and thus cognitive and emotional processes in PFC circuits.