Laboratório de Neurofisiologia, Departamento de Ciências Fisiológicas, Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado do Rio de Janeiro (UERJ), Av. Prof. Manuel de Abreu 444, 5 andar, Vila Isabel, Rio de Janeiro, RJ, 20550-170, Brazil.
Departamento de Ciências, Faculdade de Formação de Professores da Universidade do Estado do Rio de Janeiro (UERJ), RJ, São Gonçalo, Brazil.
Psychopharmacology (Berl). 2023 Oct;240(10):2111-2129. doi: 10.1007/s00213-023-06434-3. Epub 2023 Aug 2.
Sex-biased differences in schizophrenia are evident in several features of the disease, including symptomatology and response to pharmacological treatments. As a neurodevelopmental disorder, these differences might originate early in life and emerge later during adolescence. Considering that the disruption of the glutamatergic system during development is known to contribute to schizophrenia, we hypothesized that the neonatal phencyclidine model could induce sex-dependent behavioral and neurochemical changes associated with this disorder during adolescence. C57BL/6 mice received either saline or phencyclidine (5, 10, or 20 mg/kg) on postnatal days (PN) 7, 9, and 11. Behavioral assessment occurred in late adolescence (PN48-50), when mice were submitted to the open field, social interaction, and prepulse inhibition tests. Either olanzapine or saline was administered before each test. The NMDAR obligatory GluN1 subunit and the postsynaptic density protein 95 (PSD-95) were evaluated in the frontal cortex and hippocampus at early (PN30) and late (PN50) adolescence. Neonatal phencyclidine evoked dose-dependent deficits in all analyzed behaviors and males were more susceptible. Males also had reduced GluN1 expression in the frontal cortex at PN30. There were late-emergent effects at PN50. Cortical GluN1 was increased in both sexes, while phencyclidine increased cortical and decreased hippocampal PSD-95 in females. Olanzapine failed to mitigate most phencyclidine-evoked alterations. In some instances, this antipsychotic aggravated the deficits or potentiated subthreshold effects. These results lend support to the use of neonatal phencyclidine as a sex-biased neurodevelopmental preclinical model of schizophrenia. Olanzapine null effects and deleterious outcomes suggest that its use during adolescence should be further evaluated.
精神分裂症存在性别偏向差异，表现在疾病的多个特征中，包括症状和对药物治疗的反应。作为一种神经发育障碍，这些差异可能起源于生命早期，并在青春期后期出现。考虑到谷氨酸能系统在发育过程中的中断已知会导致精神分裂症，我们假设新生期苯环己哌啶模型可能会在青春期引发与该疾病相关的性别依赖性行为和神经化学变化。C57BL/6 小鼠在出生后第 7、9 和 11 天接受生理盐水或苯环己哌啶（5、10 或 20mg/kg）。行为评估发生在青春期晚期（PN48-50），此时小鼠接受旷场、社交互动和条件性回避测试。在每次测试前，给予奥氮平或生理盐水。在青春期早期（PN30）和晚期（PN50）评估前额叶皮层和海马中的 NMDA 必需 GluN1 亚基和突触后密度蛋白 95（PSD-95）。新生期苯环己哌啶引起所有分析行为的剂量依赖性缺陷，雄性更为敏感。雄性在 PN30 时前额叶皮层的 GluN1 表达也减少。在 PN50 时出现后期出现的影响。皮质 GluN1 在两性中均增加，而苯环己哌啶增加女性皮质 GluN1 而减少海马 PSD-95。奥氮平未能减轻大多数苯环己哌啶引起的变化。在某些情况下，这种抗精神病药物会加剧缺陷或增强亚阈值效应。这些结果支持使用新生期苯环己哌啶作为精神分裂症性别偏向神经发育性临床前模型。奥氮平无效和有害结果表明，在青春期使用应进一步评估。
