To investigate whether adenosine A2a agonists modulate dopamine D2 receptor binding in vivo, we have analyzed the effects of intraperitoneally administered 2-[p-(carboxyethyl)phenylethylamino]-5'-N-ethylcarboxamidoadenosin e (CGS 21680) on the ability of dopamine to compete at [125I]iodosulpride (0.25 nM) binding sites in filter-wiped cryostat sections of the rat forebrain and on [3H]L-(-)-N-propylnorapomorphine ([3H]NPA) binding (1 nM) using quantitative receptor autoradiography. CGS 21680 (1-3 mg/kg) decreased the IC50 value of dopamine on [125I]iodosulpride binding, and the decrease at 1 mg/kg was blocked by the A2 antagonist 3,7-dimethyl-1-propargylxanthine (DMPX; 5 mg/kg). The decrease in the IC50 value of dopamine was due to a decrease in the KL value whereas the KH value and the proportion of high-affinity binding sites were unaffected. The binding of [3H]NPA was significantly increased in the rostral and caudal parts of the caudate-putamen and in the rostral part of the olfactory tubercle, whereas no change could be demonstrated in the nucleus accumbens and in the caudal part of the olfactory tubercle. These results indicate that stimulation of A2a receptors in vivo causes alterations in the binding characteristics of D2 receptors in certain regions of the basal ganglia.