Manipulations of D1- or D2-dopamine receptors have differential and selective effects on the striatonigral and striatopallidal output pathways of the striatum, respectively. However, combined stimulation of these receptors produces synergistic responses. To examine the locus of this interaction in vivo, we infused D1- or D2-receptor agents into the striatum of freely moving, dopamine-depleted rats given systemic injections of the D1 agonist SKF 38393 and the D2 agonist quinpirole. Expression of the immediate early genes zif268 and c-fos, as determined by in situ hybridization histochemistry, was used as a measure of changes in the function of striatal neurons. Systemic administration of SKF 38393 produced a dose-dependent increase in the expression of immediate early genes in the dopamine-depleted striatum. Quinpirole, on the other hand, decreased the basal expression of zif268 in both the lesioned and intact striatum. However, combined administration of quinpirole with SKF 38393 significantly enhanced immediate early gene expression in the dopamine-depleted striatum relative to that seen with SKF 38393 alone. Intrastriatal infusion of SKF 38393 produced a concentration-dependent increase in immediate early gene expression in the striatum. Furthermore, intrastriatal application of the D1-receptor antagonist SCH 23390 blocked the induction of immediate early genes by SKF 38393 given systemically either alone or with quinpirole. The induction of immediate early genes by co-administration of SKF 38393 and quinpirole was also significantly attenuated by intrastriatal administration of the D2-receptor antagonist eticlopride. These data show that D1-D2 synergy is operative in the dopamine-depleted striatum, is reflected in increases in the expression of the immediate early genes zif268 and c-fos, and is a consequence of activation of both D1 and D2 receptors within the striatum rather than in extrastriatal sites. The data further suggest that the enhanced induction of immediate early genes in the dopamine-depleted striatum of rats receiving SKF 38393 with quinpirole reflects a D2-mediated potentiation of a D1-dependent process.