The dopamine D2 antagonist remoxipride acts in vivo on a subpopulation of dopamine D2 receptors.
Dopamine D2 receptors were inactivated by N-ethoxycarbonyl-2-ethoxy-1,2,-dihydroxy-quinoline (EEDQ) (6 mg/kg i.p.). The reduction in dopamine receptors was monitored by quantitative receptor autoradiography using [125I]iodosulpiride or [3H]raclopride as radioligands. Pretreatment of male rats with haloperidol (0.3-3 mumol/kg i.p.) produced a dose-related, complete protection against the decrease in [125I]iodosulpiride binding induced by EEDQ in the dorsal and ventral striata and in all cortical areas examined. Raclopride (0.25-10 mumol/kg i.p.) produced the same pattern of effect as haloperidol but had a weaker effect. In contrast, remoxipride (1-40 mumol/kg i.p. or s.c.) only produced a partial protection against the dopamine D2 receptor inactivation by EEDQ. The results in the EEDQ test were related to the potency to block d-amphetamine-induced hyperlocomotion and the ability to induce bar-test catalepsy in the rat. The potencies in the behavioural tests were found to correspond to the in vivo occupancy for dopamine D2 receptors as evaluated by the EEDQ-induced decrease in D2 binding. However, remoxipride differed from both haloperidol and raclopride by showing a much reduced occupancy of dopamine D2 receptors at doses with behaviourally equipotent effects. The results support earlier suggestions that remoxipride in vivo may act on a subpopulation of dopamine D2 receptors.
Karolinska Institute, Department of Neuroscience, Stockholm, Sweden.
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Ogren
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Rosén
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D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002375:Catalepsy / Q000139:chemically induced; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D003913:Dextroamphetamine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000378:metabolism / Q000494:pharmacology; D008032:Limbic System / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D011804:Quinolines / Q000494:pharmacology*; D020891:Raclopride; D051381:Rats; D011954:Receptors, Dopamine / Q000145:classification / Q000187:drug effects*; D017330:Remoxipride / Q000378:metabolism / Q000494:pharmacology*; D012457:Salicylamides / Q000378:metabolism / Q000494:pharmacology; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism
D011804:Quinolines; D011954:Receptors, Dopamine; D012457:Salicylamides; D017330:Remoxipride; D020891:Raclopride; C000470:EEDQ; D006220:Haloperidol; D003913:Dextroamphetamine