Dopamine D4 receptor antagonist reversal of subchronic phencyclidine-induced object retrieval/detour deficits in monkeys.
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]-imidazol e 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 microg/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.
Jentsch
J D
JD
Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06510, USA.
Taylor
J R
JR
Redmond
D E
DE
Elsworth
J D
JD
Youngren
K D
KD
Roth
R H
RH
D000818:Animals; D002522:Chlorocebus aethiops; D003072:Cognition Disorders / Q000139:chemically induced / Q000188:drug therapy*; D004298:Dopamine / Q000134:cerebrospinal fluid; D018492:Dopamine Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D065127:Dopamine D2 Receptor Antagonists; D005260:Female; D006213:Hallucinogens / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D010622:Phencyclidine / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D050638:Receptors, Dopamine D4
D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D006213:Hallucinogens; D007093:Imidazoles; D011743:Pyrimidines; D050638:Receptors, Dopamine D4; C107692:NGD 94-1; D010622:Phencyclidine; D006220:Haloperidol; D004298:Dopamine