Maj Institute of Pharmacology Polish Academy of Sciences, Department of Pharmacology, Cracow, Poland.
Maj Institute of Pharmacology, Polish Academy of Sciences, Department of Neurochemistry, Cracow, Poland.
J Physiol Pharmacol. 2021 Oct;72(5). doi: 10.26402/jpp.2021.5.05. Epub 2022 Feb 12.
Recent studies suggest that impaired glutathione synthesis and dopaminergic transmission are important factors in the pathophysiology of schizophrenia. Moreover, some studies have suggested that antidepressants are able to increase the activity of atypical antipsychotics which may efficiently improve the treatment of negative and some cognitive symptoms of schizophrenia. In the present study, we investigated the influence of repeated co-treated with mirtazapine and aripiprazole on the schizophrenia-like behavior and brain-derived neurotrophic factor (BDNF) mRNA expression in adult rats exposed to glutathione deficit during early postnatal development. Between the postnatal days p5-p16, male pups were treated with the inhibitor of glutathione synthesis, BSO (L-buthionine-(S,R)-sulfoximine) and the dopamine uptake inhibitor, GBR 12909 alone or in combination. Mirtazapine and aripiprazole were given repeatedly, once daily for 21 days before the tests. The behavioral and biochemical tests were performed in p90-92 rats. BSO given alone and in combination with GBR 12909 induced deficits in the studied behavioral tests and decreased the expression of BDNF mRNA. Repeated aripiprazole administration at a higher dose reversed these behavioral deficits. Co-treatment with an ineffective dose of aripiprazole and mirtazapine also abolished the behavioral deficits and biochemical changes, especially in the hippocampus in these rats. The present study indicated that the inhibition of glutathione synthesis in early postnatal development induced long-term deficits corresponding to schizophrenia-like behavior and decreased the BDNF mRNA expression in adult rats, and these behavioural and biochemical deficits were reversed by repeated treatment with a higher dose of aripiprazole and also by co-treatment with an ineffective dose of aripiprazole and mirtazapine. The above data suggest that this neurodevelopment rat model of schizophrenia-induced by glutathione deficit evoked by repeated treatment with BSO alone and together with GBR 12909 in early postnatal life may be useful for studies on the pathomechanism of schizophrenia.
最近的研究表明，谷胱甘肽合成和多巴胺能传递受损是精神分裂症病理生理学的重要因素。此外，一些研究表明，抗抑郁药能够增加非典型抗精神病药物的活性，从而有效地改善精神分裂症的阴性症状和一些认知症状的治疗效果。在本研究中，我们研究了在早期 postnatal 发育期间暴露于谷胱甘肽缺乏的成年大鼠中，重复联合使用米氮平和阿立哌唑对类精神分裂症行为和脑源性神经营养因子 (BDNF) mRNA 表达的影响。在 postnatal 第 5-16 天期间，雄性幼鼠接受谷胱甘肽合成抑制剂 BSO（L-丁硫氨酸-（S，R）-亚砜亚胺）和多巴胺摄取抑制剂 GBR 12909 的单独或联合治疗。米氮平和阿立哌唑反复给予，在测试前每日一次共 21 天。在 p90-92 大鼠中进行行为和生化测试。BSO 单独和与 GBR 12909 联合使用会导致研究行为测试中的缺陷，并降低 BDNF mRNA 的表达。重复给予较高剂量的阿立哌唑可逆转这些行为缺陷。联合给予无效剂量的阿立哌唑和米氮平也消除了这些大鼠的行为缺陷和生化变化，特别是在海马区。本研究表明，早期 postnatal 发育期间谷胱甘肽合成的抑制会导致长期的类似精神分裂症的行为缺陷，并降低成年大鼠的 BDNF mRNA 表达，而这些行为和生化缺陷可通过重复给予较高剂量的阿立哌唑以及联合给予无效剂量的阿立哌唑和米氮平来逆转。上述数据表明，由早期 postnatal 生活中重复给予 BSO 单独和与 GBR 12909 联合引起的谷胱甘肽缺乏引起的这种神经发育大鼠精神分裂症模型可能有助于研究精神分裂症的发病机制。
