The effects of D1 and D2 dopamine ligands on protein kinase C (PKC) activity were examined in synaptoneurosomes. Incubation with D1 agonists (SKF 38393, fenodopam), in the presence of calcium, decreased the soluble and increased the particulate PKC activity. These effects were reversed by SCH 23390, which by itself had the opposite effect of increasing the soluble and decreasing the particulate PKC activity. In contrast, incubation with the D2 agonists [LY 171555, (+)-3-(3-hydroxyphenyl)-N-n-propylpiperidine, RU 24213] increased the soluble and decreased the particulate PKC activity. These effects were reversed by sulpiride. (-)-3-(3-Hydroxyphenyl)-N-n-propylpiperidine had a D2 antagonist profile. Apomorphine showed a biphasic dose-response change; i.e., it decreased particulate PKC activity at the D2 receptor at low concentrations (0.1 microM) and increased it at the D1 receptor at higher concentrations (10 microM). Pretreatment with tetrodotoxin or omission of calcium in the incubation medium did not alter the responses of the D2 agonists, but it reversed the changes in PKC activity induced by the D1 agonists and converted the biphasic response of apomorphine to a monophasic inhibition. These results indicate that (1)D1 and D2 dopamine receptors are negatively coupled to PKC and (2) the increase in particulate PKC activity seen with the D1 drugs in the presence of calcium is mediated indirectly via a transneuronal effect.