Efeitos sexo-dependentes do modelo de esquizofrenia pela exposição neonatal de camundongos à fenciclidina

Abstract

Schizophrenia affects 0.9% of the world population. It is considered a neurodevelopmental disorder, although its full manifestation and diagnosis occur often between late adolescence and early adulthood. After its establishment, three types of symptoms are observed: positive, negative, and cognitive. There are marked sexual differences in schizophrenia, with a higher and earlier incidence in men, who also have more severe negative and cognitive symptoms and a worse response to antipsychotics. Despite these differences, no established animal models mimic them, making it difficult to understand the sex-dependent pathophysiologic mechanisms of schizophrenia and to develop more efficient treatments. Thus, in this study, we used a developmental model of schizophrenia by the neonatal administration of phencyclidine (nPCP), an NMDA receptor antagonist, to investigate whether it induces behavioral and neurochemical changes in a sex-dependent manner. We also evaluated the impact of olanzapine, an atypical antipsychotic, on these changes. C57BL/6 mice of both sexes received subcutaneous injections of phencyclidine at doses of 5, 10, or 20mg/kg (nPCP5, nPCP10, nPCP20), or saline, at postnatal days (PN) 7, 9, and 11. A Naïve group was used to assess the impact of stress associated with injections. At PN30, early adolescence, we quantified by Western Blotting, the NR1 subunit of the NMDA receptor and the postsynaptic protein PSD-95 in the frontal cortex and hippocampus. From PN48 to PN50, the animals were submitted to the following behavioral tests: open field (OF), to check for locomotor hyperactivity associated with positive symptoms; social interaction (SI) to measure a change associated with a negative symptom; and prepulse inhibition (PPI) to assess sensorimotor gate integrity. Olanzapine was administered 30min before each test. There were no differences between Naive and Salina animals, which were pooled in subsequent analyses. In the OF, both nPCP males and females were hypoactive, but males were more sensitive, expressing hypoactivity even at the lowest dose of nPCP. In the SI, impairments in social interaction were identified only in males; in nPCP5 and nPCP20 animals. In the PPI, nPCP males and females showed deficits, with signs of greater severity in males, as they showed a reduction in the percentage of inhibition by the pre-pulse of lower intensity. Olanzapine failed to reverse the behavioral changes caused by nPCP and, in some situations, its administration intensified the effects of the neonatal model. Olanzapine caused more severe hypolocomotion in nPCP males and, particularly in the SI, nPCP10 males only showed deficits if exposed to this antipsychotic. Consistent with the data obtained in the behavioral assessments, we identified a decrease in NR1 protein expression in the frontal cortex only in males. These results suggest that nPCP can be used to model sex-dependent differences identified in patients with schizophrenia. The ineffectiveness and the behavioral damage associated with the protocol adopted for the administration of olanzapine also suggest the need for further studies with the aim of investigating the efficacy and safety of this drug during adolescence