Partial and full dopamine D1 receptor agonists in mice and rats: relation between behavioural effects and stimulation of adenylate cyclase activity in vitro.
The dopamine (DA) D1 agonists, SK&F 83959, SK&F 75670, SK&F 38993, SK&F 81297 and SK&F 80723, had variable abilities to stimulate adenylate cyclase activity in rat striatal homogenates. Their efficacies, in relation to the effect of 100 microM DA were 0, 33, 69, 68 and 81%, respectively. In rats, all compounds induced (1) contralateral circling behaviour after unilateral 6-hydroxy-DA lesions, (2) ipsilateral circling behaviour after midbrain hemitransection after cotreatment with the D2 agonist quinpirole and (3) oral stereotypies after their combination with quinpirole. Maximum effects and rank order of potencies were similar in the three test models. In mice SK&F 83959, SK&F 75670 and SK&F 38393 inhibited methylphenidate-induced gnawing behaviour and induced no or only weak hypermotility. SK&F 81297 induced marked hypermotility which was partially inhibited by SK&F 83959 and SK&F 75670 and was completely blocked by the D1 antagonist, SCH 23390. It is concluded that no relation could be demonstrated between the efficacy to stimulate adenylate cyclase and to induce circling behaviours and stereotypies in rats. In contrast, a relation between biochemical and behavioural efficacies was found in the mouse models. The results suggest that different subtypes of D1 receptors mediate the behavioural effects reported in this study.
Arnt
J
J
H. Lundbeck A/S, Copenhagen-Valby, Denmark.
Hyttel
J
J
Sánchez
C
C
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology; D015259:Dopamine Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008297:Male; D008774:Methylphenidate / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D009043:Motor Activity / Q000187:drug effects; D016627:Oxidopamine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000502:physiology*; D017447:Receptors, Dopamine D1; D013239:Stereotyped Behavior / Q000187:drug effects*
D015259:Dopamine Agents; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D008774:Methylphenidate; D016627:Oxidopamine; D000262:Adenylyl Cyclases