OBJECTIVE Metergoline is an ergot-derived psychoactive drug that acts as a ligand for serotonin and dopamine receptors. The aim of this study was to investigate the regulatory effects of metergoline on the neuronal Nav1.2 voltage-dependent Na(+) channels in vitro. METHODS Xenopus oocytes were injected with cRNAs encoding rat brain Nav1.2 α and β1 subunits. Voltage-activated Na(+) currents were recorded using two-electrode voltage clamp technique. Drugs were applied though perfusion. RESULTS Both metergoline and lidocaine reversibly and concentration-dependently inhibited the peak of Na(+) currents with IC50 values of 3.6 ± 4.2 and 916.9 ± 98.8 μmol/L, respectively. Metergoline (3 μmol/L) caused a 6.8 ± 1.2 mV depolarizing shift of the steady-state activation curve of the Na(+) currents, and did not alter the inactivation curve. In contrast, lidocaine (3 μmol/L) caused a 12.7 ± 1.2 mV hyperpolarizing shift of the inactivation curve of the Na(+) currents without changing the steady-state activation curve. Both metergoline and lidocaine produced tonic and use-dependent inhibition on the peak of Na(+) currents. CONCLUSIONS Metergoline exerts potent inhibition on the activity of neuronal Nav1.2 channels, which may contribute to its actions on the central nervous system.