Dopamine D1/D5 receptor activation modulates a persistent sodium current in rat prefrontal cortical neurons in vitro

The effects of dopamine (DA) on a persistent Na+ current (I-NaP) in layer V-VI prefrontal cortical (PFC) pyramidal cells were studied using whole cell voltage-clamp recordings in rat PFC slices. After blocking K+ and Ca2+ currents, a tetrodotoxin-sensitive I-NaP was activated by slow depolarizing voltage ramps or voltage steps. DA modulated the I-NaP in a voltage-dependent manner: increased amplitude of I-NaP at potentials more negative than -40 mV, but decreased at more positive potentials. DA also slowed the inactivation process of I-NaP. The D1/D5 dopamine receptor agonists SKF 38393, SKF 81297, and dihydrexidine (3-10 mu M), but not the dopamine D2/D3 receptor agonist qiunpirole (1-20 mu M), mimicked the effects of DA on I-NaP. Modulation of I-NaP by D1/D5 agonists was blocked by the D1/D5 antagonist SCH23390. Bath application of specific protein kinase C inhibitor, chelerhythrine, or inclusion of the specific protein kinase C inhibiting peptide([19-36]) in the recording pipette, but not protein kinase A inhibiting peptide([5-24]), blocked the effect of D1/D5 agonists on I-NaP. In current-clamp recordings, D1/D5 receptors activation enhanced the excitability of cortical pyramidal cells. Application of the D1/D5 agonist SKF 81297 induced a long-lasting decrease in the first spike latency in response to depolarizing current ramp. This was associated with a shift in the start of nonlinearity in the slope resistance to more negative membrane potentials. We proposed that this effect is due to a D1/D5 agonist-induced leftward shift in the activation of I-NaP. This enables DA to facilitate the firing of PFC neurons in response to depolarizing inputs.