Disruptions of the oxytocin system impair sociability and cognitive flexibility in a subchronic phencyclidine model of schizophrenia.

Abstract

Previous research suggests that the oxytocin (Oxt) system may play a role in the etiology of schizophrenia. To investigate, we used a subchronic phencyclidine (PCP) mouse model to test how disruption of Oxt or the Oxt receptor (Oxtr) affects schizophrenia-related behaviors. Specifically, we assessed how subchronic PCP impacted sociability, hyperlocomotion, and depressive-like behaviors in male Oxt and Oxtr knockout (-/-) and wildtype (+/+) mice. Additionally, we evaluated immediate early gene activation in Oxtr -/- and +/+ mice to identify brain regions where the Oxt system might impact schizophrenia-associated behaviors. Lastly, we investigated cognitive flexibility in Oxtr -/- and +/+ mice. We found that subchronic PCP treatment decreased social interactions in Oxt -/- mice as compared to Oxt +/+ mice, with no genotypic differences in the Oxtr line of mice. Increased c-Fos expression was observed in Oxtr -/- mice relative to Oxtr +/+ controls in the medial amygdala and the paraventricular nucleus of the hypothalamus following a forced swim test. Finally, we found deficits in cognitive flexibility in Oxtr -/- mice treated with PCP, relative to Oxtr +/+ mice. These findings are consistent with the hypothesis that Oxt may buffer against some of the schizophrenia-associated symptoms induced by subchronic PCP treatment. Based on the data, we speculate that compensatory mechanisms may be able to accommodate the loss of the Oxt system, depending on the origin of the dysfunction and the behavioral endpoint in question. These findings also add support to data linking disruption of Oxt system signaling to schizophrenia.