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

When given subcutaneously in gradually increasing doses, up to 1 mg/kg, NNC 756, a dopamine (DA) D-l 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-l and D-2 dopamine supersensitivity in the form of increased dyskinesia (including grooming after NNC 756) induced by D-l agonist (SKF 81297) and increased arousal induced by D-2 agonist (quinpirole). These results indicate that D-l 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.