Effects of brexpiprazole, a novel serotonin-dopamine activity modulator, on phencyclidine-induced cognitive deficits in mice: A role for serotonin 5-HT1A receptors

Brexpiprazole, a serotonin-dopamine activity modulator, is currently being tested in clinical trials as a new therapy for a number of neuropsychiatric diseases, including schizophrenia and major depressive disorder. Accumulating evidence suggests that 5-hydroxytryptamine (5-HT)1A receptors play a role in cognition. This study was undertaken to examine whether brexpiprazole, a novel drug with 5-HT1A receptor partial agonism, could improve cognitive deficits in mice, induced by repeated administration of the N-methyl-d-aspartate (NMDA) receptor antagonist, phencyclidine (PCP). Subsequent subchronic (14 days) oral administration of brexpiprazole (0.3, 1, or 3 mg/kg/day) significantly attenuated PCP (10 mg/kg/day for 10 days)-induced cognitive deficits in mice, in a dose-dependent manner. The effects of brexpiprazole (3 mg/kg) were significantly antagonized by co-administration of the selective 5-HT1A receptor antagonist, WAY-100,635 (1.0 mg/kg), although WAY-100,635 alone was not effective in this model. These findings suggest that brexpiprazole can ameliorate PCP-induced cognitive deficits in mice via 5-HT1A receptors. Therefore, brexpiprazole could ameliorate cognitive deficits as seen in schizophrenia and other neuropsychiatric diseases.