TY - JOUR
T1 - Dopamine D4 receptor stimulation contributes to novel object recognition
T2 - Relevance to cognitive impairment in schizophrenia
AU - Miyauchi, Masanori
AU - Neugebauer, Nichole M.
AU - Meltzer, Herbert Y.
N1 - Publisher Copyright:
© British Association for Psychopharmacology.
PY - 2017/4/1
Y1 - 2017/4/1
N2 - 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.
AB - 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.
KW - Antipsychotic
KW - dopamine D receptor
KW - memory
KW - phencyclidine
KW - schizophrenia
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U2 - 10.1177/0269881117693746
DO - 10.1177/0269881117693746
M3 - Article
C2 - 28347261
AN - SCOPUS:85018395336
SN - 0269-8811
VL - 31
SP - 442
EP - 452
JO - Journal of Psychopharmacology
JF - Journal of Psychopharmacology
IS - 4
ER -