Sensitization of neuronal A2A adenosine receptors after persistent D2 dopamine receptor activation

Acute activation of Galpha(i/o)-coupled D-2 dopamine receptors inhibits A(2A) adenosine receptor stimulation of adenylate cyclase. This antagonistic interaction between D-2 dopamine and A(2A) adenosine receptors has been well documented; however, the effects of persistent activation of D-2 dopamine receptors on subsequent A(2A) adenosine receptor signaling have not been explored. The present study investigated the effects of short-term (3-h) and long-term (18-h) activation of D-2L dopamine receptors on subsequent A(2A) adenosine receptor stimulation of adenylate cyclase in CAD-D-2L and NS20Y-D-2L neuroblastoma cells. Short- and long-term activation of D-2L dopamine receptors markedly increased 5'-N-methylcarboxamidoadenosine (MECA)-stimulated cyclic AMP accumulation 1.4-fold and 1.7-fold, respectively. D-2L receptor-induced sensitization of A(2A)-stimulated cyclic AMP accumulation was blocked by the D-2 antagonist spiperone and pertussis toxin pretreatment. In addition, persistent activation of A(2A) adenosine receptors resulted in 50% desensitization of subsequent MECA-stimulated cyclic AMP accumulation; however, MECA-induced desensitization of A(2A) adenosine receptors did not prevent completely quinpirole-induced sensitization of adenylate cyclase. These studies revealed a novel mode of regulation between D-2L dopamine and A(2A) adenosine receptors and suggest a cooperative interaction in the regulation of cyclic AMP signaling.