Dopamine D₄ receptor stimulation contributes to novel object recognition: Relevance to cognitive impairment in schizophrenia

Several atypical antipsychotic drugs (APDs) have high affinity for the dopamine (DA) D₄ receptor, 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 D₄ receptor 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 D₄ agonist, PD168077, and the D₄ antagonist, 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 D₄ antagonist 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. D₄ receptor 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 D₄ receptor, lurasidone.