RO-10-5824 is a selective dopamine D4 receptor agonist that increases novel object exploration in C57 mice

Novelty seeking as a behavioral phenomenon emerges as a compromise between approach and avoidance behavior. Although novelty seeking is thought to play a role in drug abuse and in cognition, the biological basis for this construct is poorly understood. At a genetic level, dopamine D4 receptors (D4R) appear to be critical for the behavioral expression of novelty seeking. In humans, polymorphisms of D4R have been associated with novelty-seeking traits in general and attention deficit-hyperactivity disorder in particular. Similarly, D4R (-/-) mice exhibit less novel object exploration than D4R (+/+) mice. Due to of the paucity of selective D4R ligands for use in behavioral pharmacology studies, few studies have examined the behavioral effects of D4R compounds in animals. The present experiments characterized RO-10-5824, a new, selective D4R partial agonist with minimal affinity for dopamine D2 and D3 receptors, and tested the hypothesis that activation of D4R increases the investigation by mice of a novel object placed in the center of a familiar open field. C57BL/6J and DBA/1J male mice were used in a dose response study of the selective D4R partial agonist RO-10-5824 (0, 1.0, 3.0, or 10.0 mg/kg). While having no effect on the amount of locomotor activity in novel or familiar environments, RO-10-5824 (10.0 mg/kg) increased time spent in the center of the enclosure in the presence of a novel object in C57 but not DBA mice. These results support the hypothesis that stimulation of D4R can enhance novelty seeking in mice and that this effect may be dependent on subtle genetic differences. (C) 2003 Elsevier Science Ltd. All rights reserved.