Agonist-induced desensitization of adenosine A1 and A2 receptors was studied in rat striatum slices maintained in carbo-oxygenated Krebs buffer. Slices were exposed to adenosine analogues (either cyclo-pentyl-adenosine or N-ethyl-carboxamido-adenosine) for selected time periods (15-60 min) and repeatedly washed at the end of agonist exposure. Agonist-induced changes of adenosine receptors were then evaluated in P2 fractions prepared from slices by measuring A1 and A2 receptor-regulated adenylate cyclase. A1 receptors were rapidly desensitized by agonist exposure, as shown by a gradual loss of A1 receptor-mediated inhibition of basal cyclase activity and cAMP formation, which was evident within 15-30 min after addition of the adenosine analogue. Agonist-induced desensitization of A1 receptors was dose- and time-dependent, and seemed quicker in onset with cyclo-pentyl-adenosine, according to the higher A1 selectivity of this receptor agonist, with respect to N-ethyl-carboxamido-adenosine. Binding of the A1-selective agonist [3H]cyclo-hexyl-adenosine was unaffected by the desensitization procedure at any of the exposure periods utilized, suggesting that an uncoupling of A1 receptors from their transduction system is indeed responsible for the loss of functional activity. Loss of A1 receptor function was accompanied by a time-dependent amplification of A2 receptor-mediated stimulation of adenylate cyclase activity, likely due to an 'unmasking' of A2 stimulatory receptor function as a consequence of the desensitization of A1 inhibitory receptors. All these effects could be completely counteracted by the concomitant exposure to an adenosine receptor antagonist, and specifically involved the coupling mechanisms of adenosine receptors with their effector system.(ABSTRACT TRUNCATED AT 250 WORDS)