Potassium Channel Blockers Inhibit D₂ Dopamine, but Not A₁Adenosine, Receptor‐Mediated Inhibition of Striatal Dopamine Release

Abstract: D₂ dopamine autoreceptors and A₁ adenosine heteroreceptors inhibit the evoked release of dopamine from rat striatum. We examined the role of potassium channels in this modulation by determining the effects of two potassium channel blockers, 4‐aminopyridine and tetraethylammonium, on the modulation of electrically stimulated release of endogenous dopamine from rat striatal slices. Maximally effective concentrations of the D₂ dopamine receptor agonist N‐0437 (10 nM) and of adenosine (50 μM) caused a 30% inhibition of evoked dopamine overflow, and their effects were additive. When coperfused with N‐0437, both 4‐aminopyridine and tetraethylammonium blocked the inhibition caused by N‐0437 in a dose‐dependent manner. 4‐Aminopyridine was approximately three orders of magnitude more potent than tetraethylammonium, with complete blockade occurring at 3μM and 1 mM, respectively. Binding experiments confirmed that neither 4‐aminopyridine nor tetraethylammonium was a direct‐acting D₂ dopamine receptor antagonist at the concentration necessary to block the release‐modulatory effect of D₂ receptor activation. In contrast, the inhibitory modulation produced by adenosine was not affected by 4‐aminopyridine (30 μM) or tetraethylammonium (1 mM). These results suggest that D₂ dopamine and A₁ adenosine receptors inhibit dopamine release in the striatum by different mechanisms. D₂ dopamine autoreceptor action appears to involve potassium channels, whereas A₁ adenosine receptor action does not.