It has been claimed recently that, in several cell types, ATP can induce a stimulation of cAMP production which is sensitive to methylxanthine inhibition and is not mediated by the ATP degradation product, adenosine. One explanation for these results would be direct activation of adenosine A2 receptors by ATP itself. We have therefore investigated whether adenine nucleotides are ligands of adenosine A2A receptors from bovine striatum. We show here that ATP, ADP, AMP and their phosphorothioates analogues (ATP gamma S, ADP beta S and AMP alpha S), at a 100 microM concentration, produced a 83-91% inhibition of the binding of [3H]CGS21680, an adenosine A2A receptor agonist, to striatum membranes. However, this action was inhibited by adenosine deaminase or by adenosine 5'-O-(alpha, beta-methylene)diphosphate (APCP), an inhibitor of 5'-nucleotidase-mediated AMP degradation. The effects of adenosine deaminase and APCP were dependent on their concentration. These results indicate that ATP, ADP and even AMP can exert an effect on the adenosine A2A receptors only through their breakdown into adenosine by ectonucleotidases.