The modulation of cAMP formation by protein kinase C (PKC), activated by phorbol-12-myristate-13-acetate, and by Ca2+ entry, using the ionophore A23187, was investigated in rat striatal neurons grown in primary dissociated cell culture. Phorbol-12-myristate-13-acetate (PMA) potentiated forskolin-induced and dopamine-induced cAMP formation in a concentration-dependent manner. In contrast, the calcium ionophore A23187 inhibited dopamine-induced cAMP formation. When PMA and A23187 were tested simultaneously, the levels of cAMP were not statistically different from those found in the presence of dopamine alone. Furthermore, the decreasing effect of A23187 on cAMP formation was enhanced when PKC was desensitized by pretreating the neurons with 1 microM PMA for 18 h. These data indicate that in striatal neurons Ca2+ entry and PKC activation exert opposing effect on cAMP production.