Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of the antipsychotic drug perospirone: role of serotonin 5-HT1A receptors

Accumulating evidence suggests that the serotonin 5-HT(1A) receptor may play a role in the pathophysiology of schizophrenia. The present study was undertaken to examine the effects of perospirone, an atypical antipsychotic drug with 5-HT(1A) receptor agonism, on cognitive deficits in mice after repeated administration of the NMDA Receptor Antagonist phencyclidine (PCP). Subsequent subchronic (14 days) administration of perospirone (1.0, 3.0, or 10 mg/kg) significantly attenuated PCP (10 mg/kg)-induced cognitive deficits in mice, in a dose-dependent manner. The effects of perospirone (10 mg/kg) were significantly antagonized by co-administration of the selective 5-HT(1A) receptor antagonist WAY100635 (1.0 mg/kg). Furthermore, hypothermia by the 5-HT(1A) receptor agonist 8-OH DPAT (0.25 mg/kg) was significantly attenuated in mice treated with PCP. Moreover, a receptor binding assay using [(3)H]WAY100635 revealed that levels of 5-HT(1A) receptors in the hippocampus, but not in the frontal cortex, of PCP-treated mice were significantly lower than those of saline-treated mice. These findings suggest that repeated PCP administration alters 5-HT(1A) receptor function in the mouse brain, and that subsequent subchronic administration of perospirone ameliorates PCP-induced cognitive deficits via 5-HT(1A) receptors. Therefore, perospirone could be a potential therapy for the cognitive deficits observed in schizophrenic patients.