D1/D5 dopamine receptor activation differentially modulates rapidly inactivating and persistent sodium currents in prefrontal cortex pyramidal neurons

Dopamine (DA) is a well established modulator of prefrontal cortex (PFC) function, yet the cellular mechanisms by which DA exerts its effects in this region are controversial. A major point of contention is the consequence of D-1 DA receptor activation. Several studies have argued that D-1 receptors enhance the excitability of PFC pyramidal neurons by augmenting voltage-dependent Na+ currents, particularly persistent Na+ currents. However, this conjecture is based on indirect evidence. To provide a direct test of this hypothesis, we combined voltage-clamp studies of acutely isolated layer V-VI prefrontal pyramidal neurons with single-cell RT-PCR profiling. Contrary to prediction, the activation of D-1 or D-5 DA receptors consistently suppressed rapidly inactivating Na+ currents in identified corticostriatal pyramidal neurons. This modulation was attenuated by a D-1/D-5 receptor antagonist, mimicked by a cAMP analog, and blocked by a protein kinase A (PKA) inhibitor. In the same cells the persistent component of the Na+ current was unaffected by D-1/D-5 receptor activation-suggesting that rapidly inactivating and persistent Na+ currents arise in part from different channels. Single-cell RT-PCR profiling showed that pyramidal neurons coexpressed three alpha -subunit mRNAs (Nav1.1, 1.2, and 1.6) that code for the Na+ channel pore. In neurons from Nav1.6 null mice the persistent Na+ currents were significantly smaller than in wild-type neurons. Moreover, the residual persistent currents in these mutant neurons-which are attributable to Nav1.1/1.2 channels-were reduced significantly by PKA activation. These results argue that D-1/D-5 DA receptor activation reduces the rapidly inactivating component of Na+ current in PFC pyramidal neurons arising from Nav1.1/1.2 Na+ channels but does not modulate effectively the persistent component of the Na+ current that is attributable to Nav1.6 Na+ channels.