213 85 85 3 3 Jørn Arnt John Hyttel Department of Pharmacology and toxicology H. Lundbeck A/S Ottiliavej 7-9 DK-2500 Copenhagen-Valby Denmark Abstract The antagonistic effect of dopamine (DA) D-1 and D-2 antagonists against circling behaviour induced by various DA agonists in 6-OHDA-lesioned rats has been investigated. DA D-1/D-2 selectivity of agonists in vitro was measured by the stimulatory effect on DA-sensitive adenylate cyclase in rat striatal homogenates (D-1), the inhibitory effect on electrically-induced release of 3 H-DA in rabbit striatal slices (D-2) and the affinity to 3 H-piflutixol (D-1) and 3 H-spiroperidol (D-2) binding sites in rat striatal membranes. The contralateral circling behaviour induced by the DA D-1 agonist SK & F 38393 was blocked by the DA D-1 antagonist, SCH 23390, and by the mixed DA D-1/D-2 antagonist cis (Z)-flupentixol, but was not influenced by the DA D-2 antagonists spiroperidol and clebopride. In contrast, circling behaviour induced by the preferential DA D-2 agonists pergolide and LY 171555 was blocked by clebopride, spiroperidol, and cis (Z)-flupentixol, but weakly or not influenced by SCH 23390. Apomorphine-induced circling behaviour was blocked by cis (Z)-flupentixol, partially antagonized by SCH 23390 and clebopride but not inhibited by spiroperidol, although the time-course of circling was changed. Combinations of SCH 23390 with spiroperidol or clebopride in low doses completely blocked the effect of apomorphine. These results indicate that DA D-1 and D-2 receptors mediate circling behaviour through separate mechanisms which can be independently manipulated with respective agonists and antagonists. Furthermore, the results indicate that both DA D-1 and D-2 receptors are involved in the effect of apomorphine, since selective antagonists induced maximally 50% inhibition. Complete blockade was only found in combination experiments and by the mixed D-1/D-2 antagonists cis (Z)-flupentixol, cis (Z)-clopenthixol, and clozapine.
Psychopharmacology – Springer Journals
Published: Mar 1, 1985
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