Potassium channel blockers inhibit D2 dopamine, but not A1 adenosine, receptor-mediated inhibition of striatal dopamine release.
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 microM) 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 3 microM 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 microM) 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.
Cass
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Department of Pharmacology, University of Colorado Health Sciences Center, Denver 80262.
Zahniser
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D015761:4-Aminopyridine / Q000494:pharmacology*; D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism*; D018492:Dopamine Antagonists; D008297:Male; D015221:Potassium Channels / Q000187:drug effects*; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000502:physiology*; D017448:Receptors, Dopamine D2; D011983:Receptors, Purinergic / Q000502:physiology*; D019789:Tetraethylammonium; D013757:Tetraethylammonium Compounds / Q000494:pharmacology*
D018492:Dopamine Antagonists; D015221:Potassium Channels; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D011983:Receptors, Purinergic; D013757:Tetraethylammonium Compounds; D019789:Tetraethylammonium; D015761:4-Aminopyridine