Inhibition of SKF 38393- and pergolide-induced circling in rats with unilateral 6-OHDA lesion is correlated to dopamine D-1 and D-2 receptor affinities in vitro.
The effects of 30 dopamine (DA) antagonists, including 4 as stereoisomeric pairs, on circling behaviour induced by the D-1 agonist SKF 38393 and the D-2 agonist pergolide in rats with unilateral 6-hydroxy-DA lesions have been studied. SKF 38393-induced circling was selectively blocked by the specific D-1 antagonists SCH 23390 and SKF 83566, and was furthermore blocked by other DA antagonists with potencies correlating to their affinities to D-1 receptors labelled by 3H-SCH 23390 in vitro. Pergolide-antagonistic potencies in contrast correlated to affinities to D-2 receptors labelled by 3H-spiperone in vitro. Pergolide-induced circling was selectively blocked by the specific D-2 antagonists in the benzamide series. No interaction between D-1 and D-2 antagonists was observed in combination experiments with SCH 23390 and YM 09151-2 in both circling models. Among other reference neurotransmitter antagonists acting on alpha- and beta-adrenoceptors, histamine, serotonin and muscarinic receptors, only the alpha 1-adrenoceptor antagonist prazosin was effective in high doses. In contrast, the alpha 2- and beta-adrenoceptor agonists clonidine and clenbuterol as well as the muscarinic agonist RS 86 inhibited circling induced by SKF 38393 as well as pergolide. The 5-HT1A agonist 8-OHDPAT inhibited pergolide-induced circling only. It is concluded that these two behavioural models are selective in vivo measures of relative D-1 and D-2 receptor activity of DA antagonists.
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D018492:Dopamine Antagonists; D004347:Drug Interactions; D006892:Hydroxydopamines / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D016627:Oxidopamine; D010479:Pergolide / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000378:metabolism*; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2
D001552:Benzazepines; D018492:Dopamine Antagonists; D006892:Hydroxydopamines; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D010479:Pergolide; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D016627:Oxidopamine