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 disea se. To study the mechanisms involved in the signal transduction process ind uced by alpha-DHEC on the presynaptic site of the dopaminergic neuron, we i ncubated slices of the rat caudate-putamen with alpha-DHEC and the indicate d substances in static chambers. Following incubation the resulting DA outf low was measured by high-performance-liquid chromatography with electrochem ical detection. The addition of alpha-DHEC (10 mu M-0.1mM) did not modulate basal DA outflow. Activation of voltage-gated sodium channels by veratridi ne (VER) from low to relatively high concentrations (1-10 mu M) led to a co ncentration-dependent increase of DA outflow. Using concentrations as high as 10 mu M a dramatic increase of DA levels (600% of baseline levels) was o bserved. The ability of VER to provoke DA release was sensitive to the addi tion of tetrodotoxin (TTX) and was completely blocked by 1mM TTX. Coincubat ion 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 cour se of VER-induced DA outflow was not modulated by alpha-DHEC. As described in our earlier studies, the specific D2 receptor antagonist (-)sulpiride (S LP) concentration-dependently enhances extracellular DA levels. Addition of alpha-DHEC almost completely blocked SLP-induced DA-outflow. When slices w ere 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 bu t 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 chan nels or D1, D3-receptors are involved in the action of alpha-DHEC at the pr esynaptic site of the dopaminergic neuron. The results give one rationale f or the proposed neuroprotective effect of alpha-DHEC.