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GTP Regulation of (-) Stepholidine Binding to RH of D1 Dopamine Receptors in Calf Striatum
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(-) Stepholidine (SPD) exhibits antagonist effects on normosensitive dopamine (DA) recep-tors, but it has an agonist action on rotation in unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats. The present work endeavors to further elucidate the mechanism of its agonist action on D1receptors. [3H] R (+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2, 3, 4, 5-tetrahydro-lH-3-benzazepine ( [3H] SCH-23390) and [3H] spiper-one were used, respectively, as radioligands in D1 and D2 DA receptor binding assays in calf striatal membranes. Experimental data were analyzed by a non-linear regression computer program, GraphPAD InPlot 3.15. The competition curves were fitted first by a single-site equation and then by a two-site equation. The results showed that both apomorphine (APO) and SPD competitively inhibited [3H] SCH-23390 binding. Their competition curves fitted best ro the two-site equation (P<0.05) with a high-affinity site (RH) and a low-affinity site (R) to DA receptors. The K, and K, values (nM) were 2.7±0.45 and 378±62 for APO, and 3.9±2.2 and 126±25 for SPD, respectively. In contrast, the competition curve of SCH-23390, a selective D1DA receptor antagonist, fitted best to a single-site model with a K, value of 1.7±0.5nM. The RH of APO or SPD could be decreased by the addition of 450μM GTP. In the [3H] spiperone binding test, the APO curve was modeled best by the two-site equation, while the SPD curve fitted best to a single-site model. In the rotational behavior test, APO induced 44±20 turns/30 min in the 6-OHDA-lesioned rats, and SPD induced 310±42 turns/30 min, while SCH-23390 antagonized the SPD-induced rotation but did not induce rotational behavior. These results suggest that SPD possesses agonist actions on D1 but antagonist effects on D2 DA receptors. BIOCHEM PHARMACOL 54; 2: 227-232, 1997. 1997 Elsevier Science Inc.
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