Dopamine D-4 receptor antagonist reversal of subchronic phencyclidine induced object retrieval detour deficits in monkeys

D-4 dopamine receptors (DRs) are enriched in the primate prefrontal cortex, a brain region implicated in cognitive processes, and mesoprefrontal dopam inergic systems appear to be involved in modulating some cognitive function s of the prefrontal cortex. Despite anatomical localization of D-4 DRs with in the frontal cortex. the role of these receptors, specifically, in the re gulation of cognition or behavior in primates is unknown. In these studies, we sought to learn whether specific antagonism of D-4 DRS would affect per formance of a task dependent on the frontostriatal system. The effects of N GD94-1 (2-phenyl-4(5)-[4-(2-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazole dimaleate), a potent and selective D-4 DR antagonist and haloperidol. a non -specific D-2-like DR antagonist. on the performance of an object retrieval /detour task by monkeys were examined. The effects of these antagonists on the object retrieval task were evaluated in normal control monkeys and in s ubjects repeatedly exposed to phencyclidine (PCP), to induce frontal cortic al dopaminergic and cognitive dysfunction. NGD94-1 (1-5 mg/kg) reversed the cognitive deficits of PCP pre-treated monkeys, whereas haloperidol (25 mu g/kg) exacerbated PCP-induced performance impairments A low dose of NGD94-1 failed to affect performance of control subjects, while both haloperidol a nd a high dose of NGD94-1 impaired control performance These data show for the first time, that D-4 DRs modulate the cognitive functions of the fronto striatal system.