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Effect of chronic treatment with NNC 756, a new D-1 receptor antagonist, or raclopride, a D-2 receptor antagonist, in drug-naive Cebus monkeys: dystonia, dyskinesia and D-1/D-2 supersensitivity

St Hans Hospital, Dept. P, Research Institute of Biological Psychiatry, Roskilde, Denmark

Lars Hansen

St Hans Hospital, Dept. P, Research Institute of Biological Psychiatry, Roskilde, Denmark

When given subcutaneously in gradually increasing doses, up to 1 mg/kg, NNC 756, a dopamine (DA) D-1 antagonist, failed to produce dystonia in eight drug-naive Cebus monkeys. In contrast, raclopride, a DA D-2 antagonist, produced dystonia at low doses (0.010-0.015 mg/kg). Following pre-treatment with raclopride, NNC 756 also induced dystonia at low doses (0.015-0.025 mg/kg), but continued treatment caused tolerance, and increasing doses of NNC 756 could be administered without induction of dystonia. NNC 756 induced a dose-dependent parkinsonism (slow, stiff movements and tremor), and more sedation than raclopride. After treatment for 14 weeks, withdrawal of raclopride (0.01 mg/kg) led to mild oral dyskinesia (tardive dyskinesia), while withdrawal of NNC 756 (1.0 mg/kg) led to a special grooming syndrome, but no dyskinesia. Withdrawal of raclopride as well as NNC 756 led to behavioural D-1 and D-2 dopamine supersensitivity in the form of increased dyskinesia (including grooming after NNC 756) induced by D-1 agonist (SKF 81297) and increased arousal induced by D-2 agonist (quinpirole). These results indicate that D-1 antagonists such as NNC 756 elicit fewer extrapyramidal symptoms (both acute and tardive) than D-2 antagonists such as raclopride, although extremely high doses may cause a special grooming withdrawal syndrome.

Key Words: D-1 dopamine antagonists • D-2 dopamine antagonists • NNC 756 • raclopride • dystonia • dyskinesia • dopamine supersensitivity • monkey

Journal of Psychopharmacology, Vol. 7, No. 4, 355-364 (1993)
DOI: 10.1177/026988119300700407


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