DOPAMINE-D-1 RECEPTOR MODULATES THE VOLTAGE-GATED SODIUM CURRENT IN RAT STRIATAL NEURONS THROUGH A PROTEIN KINASE-A

1. Whole-cell recordings were made from striatal neurones obtained fro m neonatal rats and maintained in primary cultures. The effects of dop amine D-1 receptor activation mere studied on the voltage-gated sodium current. 2. Bath application of a specific D-1 agonist, SKF38393 (1 m u M), reduced the neuronal excitability recorded in current-clamp by i ncreasing the threshold for. generation of action potentials. 3. In vo ltage-clamp recordings, SKF38393 (1 mu M) reversibly reduced the peak amplitude of the sodium current by 37.8 +/- 4.95%. This effect was rev ersed by the D-1 antagonist SCH23390 and was blocked by the intracellu lar loading of GDP-beta-S (2 mM) suggesting GTP-binding protein involv ement. 4. The D-1 agonist reduced the peak amplitude of the sodium cur rent without significantly affecting (i) the voltage dependence of the current-voltage relationship, (ii) the voltage dependence of the stea dy-state activation and inactivation, (iii) the kinetics of the time-d ependent inactivation, and (iv) the kinetics of recovery from inactiva tion. 5. The peak amplitude of the sodium current was progressively re duced by intracellular loading of cyclic AMP-dependent protein kinase (100 U ml(-1)). 6. Diffusion of a specific peptide inhibitor of the cy clic AMP-dependent protein kinase (PKI; 10 mu M) into the cytosol of n eurones blocked the effect of the D-1 agonist on the sodium current am plitude. 7. These results demonstrate that dopamine acting at the D-1 receptor reduces the amplitude of the sodium current without modifying its voltage- and time-dependent properties. This effect involves acti vation of the cyclic AMP-dependent protein kinase and results in a dep ression of the striatal neuronal excitability by increasing the thresh old for generation of action potentials.