Dopamine Receptor Agonist- and Antagonist-Induced Behaviors in Primates Previously Treated with Dopamine Receptor Antagonists

Abstract

Eight Cebus apella monkeys previously treated with dopamine D1 and D2 receptor antagonists were used to elucidate the pathophysiology of acute oral dyskinesia. Five monkeys had mild oral tardive dyskinesia because of previous antagonist treatment. Interactions between the dopamine (DA) D1 receptor agonist SKF 81297 and the DA D2/D3 receptor agonist quinpirole, DA D1 and D2 receptor antagonists, and the anticholinergic biperiden were investigated. SKF 81297, 0.3 mg/kg, induced acute oral dyskinesia and grooming, which were each inhibited by the DA D1 receptor antagonist NNC 756 in a dose-dependent manner. The DA D2 receptor antagonist raclopride enhanced SKF 81297-induced acute oral dyskinesia and suppressed SKF 81297-induced grooming, each with bell-shaped dose-effect curves. Quinpirole, 0.1 mg/kg, induced a hyperarousal syndrome (i.e., increased arousal, stereotypy, and locomotion). Concomitant treatment with SKF 81297 and quinpirole caused an extreme hyperarousal syndrome but antagonized acute oral dyskinesia and grooming, suggesting a synergistic effect of high-efficacy DA D1 and D2/D3 receptor agonists regarding the induction of the hyperarousal syndrome and the antagonism of acute oral dyskinesia and grooming. Biperiden, 0.25 mg/kg, antagonized both the SKF 81297-induced and raclopride-induced acute oral dyskinesia. The results suggest that oral dyskinesia and grooming are independent but most often simultaneously occurring behaviors. Grooming is induced by DA D1 receptor agonists and antagonized by D1 and D2 antagonists and D2/D3 agonists. Acute oral dyskinesia is induced by D1 agonists and lower doses of D2 antagonists, but antagonized by D1 antagonists, D2/D3 agonists, and anticholinergics. These results suggest varying interactions between dopaminergic receptor subtypes in different types of dopaminergic behaviors.