Dual actions of (-)-stepholidine on the dopamine receptor-mediated adenylate cyclase activity in rat corpus striatum

(-)-Stepholidine (SPD) is an antagonist of normosensitive dopamine (DA) receptors, but it exhibits D1agonistic action on rotational behavior in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra pars compacta (SNC). In the present study, agonistic and antagonistic effects of SPD on the DA receptor-mediated synaptosomal adenylate cyclase (AC) activity in rat striatum were investigated. After blockade of D2receptors, SPD augmented AC activity dose-dependently. The EC50value was 41.1 ± 8.6 μmol/L. At the concentration of 10 μmol/L, SPD increased cAMP formation from a basal level (50.8 ± 10.3 pmol/mg protein/min) to 133.7 ± 31.8 pmol/mg protein/min. The SPD-induced stimulation of AC activity was almost completely reversed by 10 μmol/L Sch23390. These results indicate that SPD possesses an agonistic action on the D1receptor. Forskolin- stimulated adenylate cyclase (FSAC) activity was used as a model to elucidate the effect of SPD on D2receptors. The results indicate that DA inhibited FSAC activity dose-dependently, while SPD partially restored FSAC activity. Taken together, these results support the conclusion that SPD has dual actions on DA receptors that mediate AC activity, i.e., an agonistic action on D1receptors and an antagonistic action on D2receptors.