The role of G proteins in mediating the coupling of D1 dopamine receptors to inositol phosphate formation was investigated in rat brain striatum. Pertussis toxin-activated ADP-ribosylation ( > or = 95%) did not affect the ability of the D1 agonist SKF38393 to stimulate the generation of inositol phosphates in striatal slices. Stimulation of striatal membranes with dopamine in the presence of [35S]GTP gamma S or [alpha-32P]GTP increased guanine nucleotide binding to G alpha s, G alpha i, and G alpha q in a concentration-dependent fashion. The activation of G alpha s and G alpha q was mimicked by the D1 agonist SKF38393 and blocked by the D1 antagonist SCH23390. In contrast, the D2/3 dopamine receptor agonist quinpirole stimulated guanine nucleotide binding to G alpha i, and dopamine-stimulated activation of G alpha i was attenuated by the D2 antagonist I-sulpiride. Furthermore, antisera directed against G alpha s or G alpha q but not G alpha i, G alpha o, or G alpha z precipitated specific D1-like binding sites labeled with [3H]SCH23390. The D1-like receptors that coprecipitated with G alpha s-but not with G alpha q can be recognized by a specific D1 dopamine receptor antibody. The data provide evidence to suggest that in addition to coupling to Gs/adenylyl cyclase, D1-like dopamine sites that couple to Gq may mediate dopamine-stimulated formation of inositol phosphates in the rat striatum.