Potentiation of NMDA receptor currents by dopamine D1 receptors in prefrontal cortex

Interactions between dopamine and N-methyl-D-aspartate receptors (NMDARs) in prefrontal cortex (PFC) and other brain regions are believed to play an important role in normal mental function and neuropsychiatric disorders. In this study, we examined the regulation of NMDAR currents by the dopamine D-1 receptor in PFC pyramidal neurons. Application of the D-1 receptor agonist SKF81297 caused a prominent increase of the steady-state NMDA-evoked current in acutely isolated PFC pyramidal neurons. The D-1 effect on NMDARs was independent of protein kinase A or protein phosphatase 1, but was abolished by incubation of neurons in Ca2+-free medium. Intracellular application of the Ca2+ chelator, calmodulin, or calmodulin inhibitors largely prevented the D, modulation of NMDAR currents. Moreover, inhibiting PKC activity or disrupting PKC association with its anchoring protein also significantly reduced the D-1 effect on NMDAR currents. This upregulation of NMDAR activity by dopamine D-1 receptors and the previous finding on up-regulation of dopamine D-1 receptors by NMDAR activation provide a cellular mechanism for the reciprocal interactions between D-1 and NMDARs. These interactions may play an important role in modulating synaptic plasticity and thus in cognitive and emotional processes.