ARPP-21 is a cyclic AMP-regulated phosphoprotein (M(r) = 21,000) that has a distribution in brain similar to that of DARPP-32 (dopamine- and cyclic AMP-regulated phosphoprotein, M(r) = 32,000). It is enriched in the medium-sized spiny neurons in the striatum and in the striatonigral nerve terminals in the pars reticulata of the substantia nigra. The present study shows that dopamine D1 agonist SKF 38393 increases the state of phosphorylation of ARPP-21 by 26% in nigral slices and that pretreatment of the slices with D1 antagonist SCH 23390 blocks this effect. These results demonstrate that ARPP-21 is a dopamine-regulated phosphoprotein. Because D1 receptors are localized on nerve terminals of striatonigral pathway, the phosphorylation of ARPP-21 is likely to mediate some of the intracellular effects of dopamine on these terminals.