The interactions between adenosine A(2A) receptors and dopamine D2 receptors on the modulation of depolarization-evoked [(3)H]-gamma-amino-butyric-acid release (GABA) were examined in slices of the globus pallidus of the rat. The stimulation of release caused by activation of A(2A) receptors was blocked when dopaminergic influences were eliminated with three independent methods: a) antagonism of D2 receptors with sulpiride; b) alkylation of these receptors with N-ethoxycarbonyl-2-ethoxy-1, 2-dihydroquinoline (EEDQ); c) depletion of dopamine with reserpine. In turn, activation of A(2A) receptors modified the response to stimulation of D2 receptors: the EC(50) for quinpirole increased nearly one thousand times when A(2A) receptors were stimulated. Antagonism of A(2A) receptors in the absence of added agonists inhibited [(3)H] GABA release indicating receptor occupancy by endogenous adenosine. The dopamine dependence and the large effects of activating A(2A) receptors on the potency of dopaminergic agonists clarify some of the therapeutic properties of A(2A) antagonists in parkinsonian animals and patients.