Long-term treatment with low doses of the D1 antagonist NNC 756 and the D2 antagonist raclopride in monkeys previously exposed to dopamine antagonists.
Eight Cebus apella monkeys previously exposed to D1 and D2 antagonists were treated subcutaneously for 8 weeks with the D1 antagonist NNC 756 (0.01 mg/kg), followed by a wash-out period of 4 weeks and treatment with the D2 antagonist raclopride for 8 weeks (end doses 0.01 mg/kg). NNC 756 induced no dystonia, while marked dystonia was induced by raclopride. Mild tolerance to the dystonia-inducing effect of raclopride slowly developed. Both drugs induced significant sedation and mild bradykinesia. Sedation induced by NNC 756 was stronger than that of raclopride, while no differences were found regarding bradykinesia. The sedative effect of both NNC 756 and raclopride increased over time during chronic treatment. No changes in bradykinesia developed. No significant dyskinesia was induced by NNC 756, while raclopride significantly induced both acute and tardive oral dyskinesia. Furthermore, raclopride-induced acute dyskinesia worsened during chronic treatment. Concomitant treatment with NNC 756 tended to reduce the D1 agonist SKF 81297-induced dyskinesia and grooming, while concomitant treatment with raclopride increased SKF 81297-induced dyskinesia and tended to decrease SKF 81297-induced grooming. Chronic treatment with raclopride induced supersensitivity to both the D2/D3 agonist LY 171555 and SKF 81297, while chronic NNC 756 treatment only induced supersensitivity to SKF 81297. The findings indicate that D1 antagonists may induce less dystonia and oral dyskinesia as compared with D2 antagonists and support the hypothesis of both a permissive and an inhibitory interaction between D1 and D2 receptor systems.
St Hans Hospital, Department P, Roskilde, Denmark.
H
H
Lublin
J
J
Gerlach
F
F
Mørkeberg
D000818:Animals; D001480:Basal Ganglia Diseases / Q000139:chemically induced / Q000523:psychology; D001522:Behavior, Animal / Q000187:drug effects*; D001552:Benzazepines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D001572:Benzofurans / Q000494:pharmacology*; D002428:Cebus; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D004409:Dyskinesia, Drug-Induced / Q000523:psychology; D004873:Ergolines / Q000494:pharmacology; D006120:Grooming / Q000187:drug effects; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D019257:Quinpirole; D020891:Raclopride; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000037:antagonists & inhibitors*; D017448:Receptors, Dopamine D2 / Q000819:agonists; D012457:Salicylamides / Q000494:pharmacology*
D001552:Benzazepines; D001572:Benzofurans; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D004873:Ergolines; D006993:Hypnotics and Sedatives; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D012457:Salicylamides; D019257:Quinpirole; D020891:Raclopride; C067113:SK&F 81297; C075357:odapipam