Dopamine D4 receptor antagonist reversal of subchronic phencyclidine-induced object retrieval/detour deficits in monkeys

Abstract

D₄ dopamine receptors (DRs) are enriched in the primate prefrontal cortex, a brain region implicated in cognitive processes, and mesoprefrontal dopaminergic systems appear to be involved in modulating some cognitive functions of the prefrontal cortex. Despite anatomical localization of D₄ DRs within the frontal cortex, the role of these receptors, specifically, in the regulation of cognition or behavior in primates is unknown. In these studies, we sought to learn whether specific antagonism of D₄ DRs would affect performance of a task dependent on the frontostriatal system. The effects of NGD94-1 (2-phenyl-4(5)-[4-(2-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazole dimaleate), a potent and selective D₄ DR antagonist and haloperidol, a non-specific D₂-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 subjects repeatedly exposed to phencyclidine (PCP), to induce frontal cortical dopaminergic and cognitive dysfunction. NGD94-1 (1–5 mg/kg) reversed the cognitive deficits of PCP pre-treated monkeys, whereas haloperidol (25 μg/kg) exacerbated PCP-induced performance impairments. A low dose of NGD94-1 failed to affect performance of control subjects, while both haloperidol and a high dose of NGD94-1 impaired control performance. These data show, for the first time, that D₄ DRs modulate the cognitive functions of the frontostriatal system.