D1/D5Dopamine Receptor Activation Differentially Modulates Rapidly Inactivating and Persistent Sodium Currents in Prefrontal Cortex Pyramidal Neurons

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Abstract
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 D1 DA receptor activation. Several studies have argued that D1 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 D1 or D5 DA receptors consistently suppressed rapidly inactivating Na+ currents in identified corticostriatal pyramidal neurons. This modulation was attenuated by a D1/D5 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 D1/D5 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 α-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 D1/D5 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.