Phensy Aarron, Duzdabanian Hasmik E, Brewer Samantha, Panjabi Anurag, Driskill Christopher, Berz Annuska, Peng George, Kroener Sven
School of Behavioral and Brain Sciences, The University of Texas at DallasRichardson, TX, United States.
Front Behav Neurosci. 2017 Jun 6;11:106. doi: 10.3389/fnbeh.2017.00106. eCollection 2017.
Alterations of the normal redox state can be found in all stages of schizophrenia, suggesting a key role for oxidative stress in the etiology and maintenance of the disease. Pharmacological blockade of N-methyl-D-aspartic acid (NMDA) receptors can disrupt natural antioxidant defense systems and induce schizophrenia-like behaviors in animals and healthy human subjects. Perinatal administration of the NMDA receptor (NMDAR) antagonist ketamine produces persistent behavioral deficits in adult mice which mimic a range of positive, negative, and cognitive symptoms that characterize schizophrenia. Here we tested whether antioxidant treatment with the glutathione (GSH) precursor N-acetyl-cysteine (NAC) can prevent the development of these behavioral deficits. On postnatal days (PND) 7, 9 and 11, we treated mice with subanesthetic doses (30 mg/kg) of ketamine or saline. Two groups (either ketamine or saline treated) also received NAC throughout development. In adult animals (PND 70-120) we then assessed behavioral alterations in a battery of cognitive and psychomotor tasks. Ketamine-treated animals showed deficits in a task of cognitive flexibility, abnormal patterns of spontaneous alternation, deficits in novel-object recognition, as well as social interaction. Developmental ketamine treatment also induced behavioral stereotypy in response to an acute amphetamine challenge, and it impaired sensorimotor gating, measured as reduced prepulse inhibition (PPI) of the startle response. All of these behavioral abnormalities were either prevented or strongly ameliorated by NAC co-treatment. These results suggest that oxidative stress is a major factor for the development of the ketamine-induced behavioral dysfunctions, and that restoring oxidative balance during the prodromal stage of schizophrenia might be able to ameliorate the development of several major symptoms of the disease.
在精神分裂症的各个阶段都能发现正常氧化还原状态的改变，这表明氧化应激在该疾病的病因和维持中起着关键作用。N-甲基-D-天冬氨酸（NMDA）受体的药理学阻断可破坏天然抗氧化防御系统，并在动物和健康人类受试者中诱发类似精神分裂症的行为。围产期给予NMDA受体（NMDAR）拮抗剂氯胺酮会在成年小鼠中产生持续的行为缺陷，这些缺陷模拟了精神分裂症的一系列阳性、阴性和认知症状。在这里，我们测试了用谷胱甘肽（GSH）前体N-乙酰半胱氨酸（NAC）进行抗氧化治疗是否可以预防这些行为缺陷的发展。在出生后第7、9和11天，我们用亚麻醉剂量（30 mg/kg）的氯胺酮或生理盐水处理小鼠。两组（氯胺酮处理组或生理盐水处理组）在整个发育过程中也接受了NAC治疗。然后，在成年动物（出生后第70 - 120天）中，我们评估了一系列认知和精神运动任务中的行为改变。氯胺酮处理的动物在认知灵活性任务中表现出缺陷、自发交替模式异常、新物体识别缺陷以及社交互动缺陷。发育期间的氯胺酮处理还会在急性苯丙胺刺激下诱发行为刻板症，并且会损害感觉运动门控，表现为惊吓反应的前脉冲抑制（PPI）降低。NAC联合治疗可预防或显著改善所有这些行为异常。这些结果表明，氧化应激是氯胺酮诱导的行为功能障碍发展的主要因素，并且在精神分裂症前驱期恢复氧化平衡可能能够改善该疾病几种主要症状的发展。
