Acute extrapyramidal syndrome in Cebus monkeys: development mediated by dopamine D2 but not D1 receptors.
The present study assessed the role of dopamine D1 and D2 receptors in the production of an extrapyramidal syndrome (EPS) in Cebus apella monkeys. Previous studies have shown the development of EPS in both old and new world monkeys with haloperidol administration. We now report that repeated weekly administration of a selective D1 antagonist, SCH 23390, does not produce this syndrome in cebus monkeys. Cebus monkeys were treated with either vehicle (n = 6), the specific D2 antagonist haloperidol (0.3 mg/kg p.o., n = 9) or the specific D1 antagonist SCH 23390 (10.0 mg/kg p.o., n = 9) once a week for approximately 1 year and behavioral effects were observed and scored. The drug doses used in this study produced similar sedative scores when given acutely and sedation increased over the first 12 weeks of the study for both treatment groups. However, by the 12th week of dosing with haloperidol all the monkeys showed a profound EPS characterized by limb extensions, head pushing, tongue protrusions and sometimes severe biting movements. In contrast, none of the SCH 23390-treated monkeys showed any abnormal movements, suggesting D1 antagonists have a low EPS side-effect liability. The profile of the incidence of EPS seen with classical neuroleptic drugs in cebus monkeys and their blockade of EPS by anticholinergic drugs mimics the profile seen in humans. The models presented appear to be predictive of the production of the EPS in humans and could be used to screen neuroleptics for EPS liability. Furthermore, the EPS is probably due to the selective blockade of dopamine D2 receptors with its associated enhancement of cholinergic neurotransmission.(ABSTRACT TRUNCATED AT 250 WORDS)
Coffin
V L
VL
Schering-Plough Research, Bloomfield, New Jersey.
Latranyi
M B
MB
Chipkin
R E
RE
D000818:Animals; D014150:Antipsychotic Agents / Q000037:antagonists & inhibitors / Q000633:toxicity*; D001480:Basal Ganglia Diseases / Q000139:chemically induced*; D001522:Behavior, Animal / Q000187:drug effects; D001552:Benzazepines / Q000633:toxicity*; D002428:Cebus; D006220:Haloperidol / Q000633:toxicity; D008297:Male; D010276:Parasympatholytics / Q000494:pharmacology; D011954:Receptors, Dopamine / Q000187:drug effects*; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2
D014150:Antipsychotic Agents; D001552:Benzazepines; D010276:Parasympatholytics; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D006220:Haloperidol