Differential alteration of striatal D-1 and D-2 receptors induced by the long-term administration of haloperidol, sulpiride or clozapine to rats.
Rats received haloperidol, sulpiride, or clozapine in their daily drinking water for up to 1 year in clinically equivalent doses. After 12 months' drug intake, and while drug administration continued, striatal dopamine function was assessed. Haloperidol induced D-2 receptor hypersensitivity as shown by enhanced apomorphine-induced stereotypy, elevated Bmax for specific 3H-spiperone and 3H-NPA binding, and an increase in striatal acetylcholine content. D-1 receptor sites appeared unaffected, since dopamine-stimulated adenylate cyclase and specific 3H-piflutixol binding were not altered. In contrast, neither sulpiride nor clozapine enhanced apomorphine-induced stereotypy or increased Bmax for 3H-spiperone binding. Sulpiride, but not clozapine, increased Bmax for 3H-NPA binding; clozapine, but not sulpiride, elevated striatal acetyl choline concentrations. In general, both sulpiride and clozapine enhanced D-1 function as assessed by dopamine-stimulated adenylate cyclase or 3H-piflutixol binding. On acute administration sulpiride and clozapine appear to act at D-2 sites, but continuous chronic administration of these compounds does not result in the development of striatal D-2 receptor hypersensitivity. The absence of change in D-2 function during chronic treatment, coupled with an ability to enhance D-1 function, may contribute to the low incidence of tardive dyskinesia produced by these drugs in man.
Jenner
P
P
Rupniak
N M
NM
Marsden
C D
CD
D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D003024:Clozapine / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects*; D003984:Dibenzazepines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008134:Long-Term Care; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects* / Q000378:metabolism; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D013134:Spiperone / Q000378:metabolism; D013239:Stereotyped Behavior / Q000187:drug effects; D013469:Sulpiride / Q000494:pharmacology*; D013892:Thioxanthenes / Q000378:metabolism
D003984:Dibenzazepines; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D013892:Thioxanthenes; D013134:Spiperone; D013469:Sulpiride; C015448:piflutixol; D003024:Clozapine; D006220:Haloperidol; D001058:Apomorphine