The dopamine D2 receptor agonist alpha-dihydroergocryptine modulates voltage-gated sodium channels in the rat caudate-putamen

Alpha-Dihydroergocryptine (alpha-DHEC), a Dopamine (DA) D2 receptor agonist, is widely used as dopaminergic drug in the treatment of Parkinson's disease. To study the mechanisms involved in the signal transduction process induced by alpha-DHEC on the presynaptic site of the dopaminergic neuron, we incubated slices of the rat caudate-putamen with alpha-DHEC and the indicated substances in static chambers. Following incubation the resulting DA outflow was measured by high-performance-liquid chromatography with electrochemical detection. The addition of alpha-DHEC (10 mu M-0.1mM) did not modulate basal DA outflow. Activation of voltage-gated sodium channels by veratridine (VER) from low to relatively high concentrations (1-10 mu M) led to a concentration-dependent increase of DA outflow. Using concentrations as high as 10 mu M a dramatic increase of DA levels (600% of baseline levels) was observed. The ability of VER to provoke DA release was sensitive to the addition of tetrodotoxin (TTX) and was completely blocked by 1mM TTX. Coincubation of alpha-DHEC (10 mu M-0.1mM) and VER (10 mu M) reduced VER-stimulated DA outflow in a concentration-dependent manner. The time-concentration course of VER-induced DA outflow was not modulated by alpha-DHEC. As described in our earlier studies, the specific D2 receptor antagonist (-)sulpiride (SLP) concentration-dependently enhances extracellular DA levels. Addition of alpha-DHEC almost completely blocked SLP-induced DA-outflow. When slices were incubated with the non-selective DA receptor agonist haloperidol (HLP, 0.1 mM) the effect of alpha-DHEC on VER-induced DA outflow was partially but not completely abolished. These data strongly suggest that the effect of alpha-DHEC on the presynaptic site implies an activation of D2 receptors as well as an inhibitory action on voltage-gated sodium channels, alpha-DHEC seems to modulate voltage-gated sodium channels in part independently from DA receptors since blockade of D2 receptors with saturating concentrations of haloperidol did not completely abolish its effect. Based on our data we have no evidence that voltage-gated potassium channels, N-type calcium channels or D1, D3-receptors are involved in the action of alpha-DHEC at the presynaptic site of the dopaminergic neuron. The results give one rationale for the proposed neuroprotective effect of alpha-DHEC.