INVOLVEMENT OF RECEPTOR RESERVE IN D-1 AGONISTIC ACTION OF (-)-STEPHOLIDINE IN LESIONED RATS

(-)-Stepholidine (SPD) is a natural produce. Previous studies had demo nstrated that SPD displayed D-1 agonism in unilaterally 6-hydroxydopam ine (6-OHDA)-lesioned rats and D-1 antagonism in reserpinized rats and normal rats. The aim of the present study was to explain this peculia r pharmacological action based on behavioral and biochemical experimen ts. In the unilaterally 6-OHDA-lesioned rats, SPD (4 mg/kg, s.c.) indu ced contralateral rotation as did apomorphine (APO), but the rotation response to SPD was 60% lower than that to APO (0.5 mg/kg, i.p.). Coad ministration with APO (0.5 mg/kg, i.p.) and SPD (0.5 to 10 mg/kg, s.c. ) produced a biphasic action curve; At low doses (0.5 or 1 mg/kg), SPD potentiated APO action; at high doses (4 or 10 mg/kg), however, SPD s uppressed APO. In striatal homogenate of the unilaterally lesioned rat s, SPD stimulated cyclic AMP (cAMP) formation and produced a maximal r esponse comparable to that of dopamine (DA) in the denervated striatum , but 70% lower than that of DA in the intact striatum. Coadministrati on of 10 mu M DA with various concentrations of SPD yielded different results, with a biphasic response in the intact side and a synergistic effect in the denervated side. Furthermore, based on the determinatio n of receptor mediated cAMP formation, the D-1 receptor reserve was an alyzed in both denervated and intact striatum by using the DA receptor inactivator N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ). Th e results showed that following EEDQ administration, the receptor dens ity [revealed by [H-3]R(+)-7-chloro-8-hydroxy-3-methyl 1-phenyl-2,3,4, 5-tetrahydro-1H-3-benzazepine ([H-3]SCH-23390) binding] and the agonis t-stimulated adenylate cyclase (AC) activity (revealed by cAMP formati on) were reduced concur rently. In the intact striatum, the reduction in SPD-stimulated AC activity paralleled the receptor loss, indicating the absence of receptor reserve, while in the denervated striatum the reduction in AC activity was less than the receptor loss, indicating a significant level of receptor reserve (estimated 16.4%). By comparis on, receptor reserve for DA was 45.7 and 25.3% in the denervated and i ntact striatum, respectively, representing an 80% increase of receptor reserve. In conclusion, SPD is a D-1 partial agonist, and receptor re serve permits SPD to display its D-1 agonistic action in the unilatera lly 6-OHDA-lesioned rats. (C) 1997 Elsevier Science Inc.