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

Abstract

(−)-Stepholidine (SPD) is an antagonist of normosensitive dopamine (DA) receptors, but it exhibits D 1 agonistic action on rotational behaviour 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 D 2 receptors, SPD augmented AC activity dose-dependently. The EC 50 value 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 D 1 receptor. Forskolin-stimulated adenylate cyclase (FSAC) activity was used as a model to elucidate the effect of SPD on D 2 receptors. 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 D 1 receptors and an antagonistic action on D 2 receptors.