Dopamine D-2 antagonists reverse apomorphine-induced decreased water intake in the rat: prediction of antipsychotic drugs with few extrapyramidal side-effects?
Water intake in water deprived rats was decreased by administration of a low dose of apomorphine (0.1 mg/kg s.c.). This dose is too low to induce hyperactivity and stereotypies. Four different dopamine (DA) D-2 antagonists were used to counteract this effect of apomorphine; haloperidol [an antipsychotic inducing extrapyramidal side-effects (EPS)], sulpiride (an antipsychotic inducing less EPS than haloperidol), metoclopramide (not used as an antipsychotic but inducing EPS) and domperidone (not passing through the blood brain barrier). Domperidone did not counteract the apomorphine effect, indicating a central mechanism of action for apomorphine. Metoclopramide did not counteract the apomorphine effect and, in higher doses, water intake was even further reduced. Sulpiride completely counteracted the apomorphine effect but, in higher doses, did not by itself reduce water intake. Haloperidol counteracted the apomorphine effect in a small dose-range and caused a further reduction in the water intake when given in high doses. The results can be explained by the existence of two subpopulations of D-2 receptors related to different functions. The model described may be used in screening experiments aimed at finding new antipsychotic drugs with a low incidence of EPS.
Ljungberg
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Department of Pharmacology, Karolinska Institute, Stockholm, Sweden.
D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000494:pharmacology*; D001058:Apomorphine / Q000494:pharmacology*; D004294:Domperidone; D004305:Dose-Response Relationship, Drug; D004327:Drinking Behavior / Q000187:drug effects*; D006220:Haloperidol / Q000009:adverse effects / Q000494:pharmacology*; D008297:Male; D008787:Metoclopramide; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects / Q000502:physiology*; D017448:Receptors, Dopamine D2; D013469:Sulpiride
D014150:Antipsychotic Agents; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D004294:Domperidone; D013469:Sulpiride; D006220:Haloperidol; D008787:Metoclopramide; D001058:Apomorphine