The dopamine D3 receptor antagonist, S33138, counters cognitive impairment in a range of rodent and primate procedures

• Published in: The international journal of neuropsychopharmacology 2010-09, Vol.13 (8), p.1035-1051
• Main Authors: Millan, Mark J., Buccafusco, Jerry J., Loiseau, Florence, Watson, David J. G., Decamp, Emmanuel, Fone, Kevin C. F., Thomasson-Perret, Nitza, Hill, Michael, Mocaer, Elisabeth, Schneider, Jay S.
• Format: Article
• Language: English
• Subjects: Acetanilides - metabolism; Acetanilides - pharmacology; Acetanilides - therapeutic use; Animals; Benzopyrans - metabolism; Benzopyrans - pharmacology; Benzopyrans - therapeutic use; Cognition Disorders - drug therapy; Cognition Disorders - metabolism; Cognition Disorders - psychology; Dopamine Antagonists - metabolism; Dopamine Antagonists - pharmacology; Dopamine Antagonists - therapeutic use; Dose-Response Relationship, Drug; Female; Macaca mulatta; Male; Primates; Rats; Rats, Wistar; Receptors, Dopamine D3 - antagonists & inhibitors; Receptors, Dopamine D3 - metabolism; Species Specificity
• ISSN: 1461-1457; 1469-5111
• DOI: 10.1017/S1461145710000775

Although dopamine D3 receptor antagonists have been shown to enhance frontocortical cholinergic transmission and improve cognitive performance in rodents, data are limited and their effects have never been examined in primates. Accordingly, we characterized the actions of the D3 receptor antagonist, S33138, in rats and rhesus monkeys using a suite of procedures in which cognitive performance was disrupted by several contrasting manipulations. S33138 dose-dependently (0.01–0.63 mg/kg s.c.) blocked a delay-induced impairment of novel object recognition in rats, a model of visual learning and memory. Further, S33138 (0.16–2.5 mg/kg s.c.) similarly reduced a delay-induced deficit in social novelty discrimination in rats, a procedure principally based on olfactory cues. Adult rhesus monkeys were trained to perform cognitive procedures, then chronically exposed to low doses of 1–methyl-4-phenyl-1,2,3,6-tetrahydropyridine which produced cognitive impairment without motor disruption. In an attentional set-shifting task of cognitive flexibility involving an extra-dimensional shift, deficits were reversed by S33138 (0.04 and 0.16 mg/kg p.o.). S33138 also significantly improved accuracy (0.04 and 0.16 mg/kg p.o.) at short (but not long) delays in a variable delayed-response task of attention and working memory. Finally, in a separate set of experiments performed in monkeys displaying age-related deficits, S33138 significantly (0.16 and 0.63 mg/kg p.o.) improved task accuracies for long delay intervals in a delayed matching-to-sample task of working memory. In conclusion, S33138 improved performance in several rat and primate procedures of cognitive impairment. These data underpin interest in D3 receptor blockade as a strategy for improving cognitive performance in CNS disorders like schizophrenia and Parkinson's disease.