ObjectiveCognitive impairment, especially impaired social cognition, is largely responsible for the deterioration of the social life of patients with schizophrenia (SZ). Oxytocin (OT) is a neuropeptide that offers promising therapy for SZ. This study aimed to explore whether OT could affect dizocilpine (MK801)-induced cognitive impairment and to investigate the effect of exogenous OT on the endogenous OT system in the hippocampus. MethodsThe SZ mouse model was established by repeated administration of dizocilpine [MK801, 0.6mg/kg, intraperitoneal (i.p.)], and then OT (6–60μg/kg, intranasal) or risperidone (0.3mg/kg, i.p.) was administered to explore the effect of OT on cognitive impairment. ResultsOT at a dose of 6μg/kg alleviated MK801-induced hyperactivity, sociability impairment, and spatial memory impairment. OT at a dose of 20 or 60μg/kg attenuated the hyperactivity and social novelty impairment. In MK801-injected mice, the compensatory upregulation of OT mRNA in the hippocampus was reversed by three OT doses, whereas 60μg/kg OT reversed the compensatory upregulation of CD38 protein expression. ConclusionOT alleviated cognitive impairment in the SZ mouse model to varying degrees, reversing the compensatory upregulation of OT signaling in the hippocampus.