title: Dopamine D4receptor stimulation contributes to novel object recognition: Relevance to cognitive impairment in schizophrenia.
abstract: Several atypical antipsychotic drugs (APDs) have high affinity for the dopamine (DA) D4receptor, but the relevance to the efficacy for the treatment of cognitive impairment associated with schizophrenia (CIAS) is poorly understood. The aim of this study was to investigate the effects of D4receptor stimulation or blockade on novel object recognition (NOR) in normal rats and on the sub-chronic phencyclidine (PCP)-induced novel object recognition deficit. The effect of the D4agonist, PD168077, and the D4antagonist, L-745,870, were studied alone, and in combination with clozapine and lurasidone. In normal rats, L-745,870 impaired novel object recognition, whereas PD168077 had no effect. PD168077 acutely reversed the sub-chronic phencyclidine-induced novel object recognition deficit. Co-administration of a sub-effective dose (SED) of PD168077 with a sub-effective dose of lurasidone also reversed this deficit, but a sub-effective dose of PD168077 with a sub-effective dose of clozapine, a more potent D4antagonist than lurasidone, did not reverse the sub-chronic phencyclidine-induced novel object recognition deficit. At a dose that did not induce a novel object recognition deficit, L-745,870 blocked the ability of clozapine, but not lurasidone, to reverse the novel object recognition deficit. D4receptor agonism has a beneficial effect on novel object recognition in sub-chronic PCP-treated rats and augments the cognitive enhancing efficacy of an atypical antipsychotic drug that lacks affinity for the D4receptor, lurasidone.
authors.affiliation: 1 Department of Psychiatry and Behavioral Sciences, Northwestern Feinberg School of Medicine, Chicago, USA.|2 Sumitomo Dainippon Pharma Co. Ltd, Suita, Osaka, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Miyauchi
authors.affiliation: 1 Department of Psychiatry and Behavioral Sciences, Northwestern Feinberg School of Medicine, Chicago, USA.
authors.forename: Nichole M
authors.initials: NM
authors.lastname: Neugebauer
authors.affiliation: 1 Department of Psychiatry and Behavioral Sciences, Northwestern Feinberg School of Medicine, Chicago, USA.
authors.forename: Herbert Y
authors.initials: HY
authors.lastname: Meltzer
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology; D003024:Clozapine / Q000494:pharmacology; D060825:Cognitive Dysfunction / Q000188:drug therapy* / Q000378:metabolism*; D005260:Female; D000069056:Lurasidone Hydrochloride / Q000494:pharmacology; D010622:Phencyclidine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D050638:Receptors, Dopamine D4 / Q000378:metabolism*; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism*; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology
chemical_list: C099630:3-((4-(4-chlorophenyl)piperazin-1-yl)methyl)-1H-pyrrolo(2,3-b)pyridine; D014150:Antipsychotic Agents; D001549:Benzamides; C477501:N-((4-(2-cyanophenyl)-1-piperazinyl)methyl)-3-methylbenzamide; D010879:Piperazines; D011725:Pyridines; D011758:Pyrroles; D058825:Serotonin 5-HT1 Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; D050638:Receptors, Dopamine D4; D010622:Phencyclidine; D003024:Clozapine; D000069056:Lurasidone Hydrochloride
keywords: Antipsychotic; dopamine D4 receptor; memory; phencyclidine; schizophrenia