Effects of several partial dopamine D2 receptor agonists in Cebus apella monkeys previously treated with haloperidol.
Eight Cebus apella monkeys were treated with haloperidol for 2 years. Five monkeys had developed mild oral tardive dyskinesia and all were primed for neuroleptic induced dystonia, thus serving as a model for both chronic and acute extrapyramidal side effects. In this model, the partial dopamine D2 receptor agonists SDZ HDC-912, SDZ HAC-911, terguride, (-)-3-(3-hydroxyphenyl)-N-propylpiperidine) ((-)-3-PPP) and SND 919 were tested for extrapyramidal side-effect liability. Their antipsychotic potential was also tested, using a dose of dextroamphetamine producing mild stereotypy and moderate motoric unrest. For comparison, the dopamine D2 receptor agonist, LY 171555 and antagonist, raclopride were used. In contrast to the other drugs tested, SDZ HAC-911 consistently reduced oral activity, P < 0.05 (at doses from 0.005 to 0.025 mg/kg). The relative dystonic potencies were raclopride > SDZ HDC-912 > SDZ HAC-911 = terguride. Neither (-)-3-PPP nor SND 919 produced dystonia, but had observable dopamine D2 receptor agonistic effects, (-)-3-PPP producing emesis at 1-4 mg/kg and SND 919 producing motoric unrest and stereotypy at 0.05-0.25 mg/kg. Comparing the antiamphetamine effects of the more antagonist-like drugs with raclopride, the relative potencies were terguride = SDZ HAC-911 > SDZ HDC-912 > raclopride. Comparing the antiamphetamine effects of the more agonist-like drugs with LY 171555, the relative potencies were SND 919 > (-)-3-PPP > LY 171555 in relation to motoric unrest, while neither (-)-3-PPP nor LY 171555 produced inhibition of stereotypy.
Peacock
L
L
Research Institute of Biological Psychiatry, St. Hans Hospital, Roskilde, Denmark.
Gerlach
J
J
D000284:Administration, Oral; D000661:Amphetamine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D052160:Benzothiazoles; D002428:Cebus; D004195:Disease Models, Animal; D015259:Dopamine Agents / Q000009:adverse effects / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy*; D004421:Dystonia / Q000139:chemically induced / Q000188:drug therapy*; D004873:Ergolines / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D006220:Haloperidol / Q000009:adverse effects*; D008090:Lisuride / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology; D000077487:Pramipexole; D019257:Quinpirole; D020891:Raclopride; D012457:Salicylamides / Q000008:administration & dosage / Q000494:pharmacology; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology
D014150:Antipsychotic Agents; D052160:Benzothiazoles; D015259:Dopamine Agents; D065127:Dopamine D2 Receptor Antagonists; D004873:Ergolines; D010880:Piperidines; D012457:Salicylamides; D013844:Thiazoles; C062737:N-(2,6-dimethylergoline-8-yl)-2,2-dimethylpropanamide; C059362:N-(2-chloro-6-methylergoline-8-yl)-2,2-dimethylpropanamide; D019257:Quinpirole; C006208:dironyl; D020891:Raclopride; D000077487:Pramipexole; C026539:preclamol; D000661:Amphetamine; D008090:Lisuride; D006220:Haloperidol