The International Journal of Neuropsychopharmacology

Thematic Section: Memory and Cognition

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

Mark J. Millana1 c1, Jerry J. Buccafuscoa2, Florence Loiseaua1, David J. G. Watsona3, Emmanuel Decampa4, Kevin C. F. Fonea3, Nitza Thomasson-Perreta6, Michael Hilla5, Elisabeth Mocaera6 and Jay S. Schneidera4

a1 Institut de Recherches Servier, Croissy sur Seine, France

a2 Department of Pharmacology and Toxicology Medical College of Georgia, Augusta, GA, USA; Charlie Norwood VA Medical Centre, Augusta, USA

a3 School of Biomedical Sciences, Queen's Medical Centre, Nottingham University, Nottingham, UK

a4 Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA

a5 Motac Cognition Inc., PO Box 451, Cherry Hill, NJ, USA

a6 IRIS Servier 6, Courbevoie Cedex, France

Abstract

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.

(Received October 07 2009)

(Reviewed November 15 2009)

(Revised May 25 2010)

(Accepted June 01 2010)

(Online publication July 22 2010)

Correspondence:

c1 Address for correspondence: Dr M. J. Millan, Institut de Recherches Servier, 125 Chemin de Ronde, 78290 Croissy sur Seine, France. Tel.: 00.33.1.55.72.24.25 Fax: 00.33.1.55.72.20.82 Email: mark.millan@fr.netgrs.com

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