Long-term behavioral and neurodegenerative effects of perinatal phencyclidine administration: Implications for schizophrenia
Long-term behavioral and neurodegenerative effects of perinatal phencyclidine administration: Implications for schizophrenia
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DOI：
10.1016/s0306-4522(01)00384-0
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发表时间：
2001-01-01
期刊：
影响因子：
3.3
通讯作者：
Johnson, KM
中科院分区：
文献类型：
--
作者：
Wang, C;McInnis, J;Johnson, KM
已提出急性和慢性施用N-甲基-D-天冬氨酸（NMDA）受体拮抗剂如苯环己哌啶和地佐环平来模拟精神分裂症的一些症状。本研究的目的是，第一，表征长期的行为和神经退行性影响的亚慢性管理苯环利定围产期大鼠和第二。以确定奥氮平预处理是否可以减轻这些影响。产后7天。在施用盐水或苯环己哌啶（10 mg/kg）之前，用糖胶树胶或奥氮平预处理9和11只大鼠幼仔。一些幼鼠在出生后第12天被杀死进行生化测定，其他幼鼠在出生后第24-28天进行声惊吓前脉冲抑制试验，在出生后第42天进行苯环己哌啶诱导的自发活动试验，在出生后第33 - 70天进行延迟空间学习任务的采集试验。苯环利定治疗导致额叶和嗅皮质中片段化DNA的大量增加，这与通过凋亡机制的神经变性一致。NMDA受体NR 1亚基mRNA的增加也观察到在皮层。凝胶位移分析表明，苯环利定也增加了核因子-kappaB蛋白在前额叶皮层的核转位。在额叶皮层的组织中。Western印迹分析显示苯环利定处理增加Bax蛋白和减少Bcl-X-L蛋白。在发育后期，观察到围产期苯环利定治疗显著延迟了断奶后不久测量的声惊吓的基线前脉冲抑制。在42日龄大鼠中，发现用2 mg/kg苯环利定激发可显著增加已用苯环利定预处理的大鼠的自发活动。同样，围产期苯环利定治疗显着延迟收购的延迟空间交替任务。奥氮平预处理显著抑制了上述每种变化（空间学习任务除外，未对其进行测试）。一种抗精神病药物，已知对精神分裂症的阳性和阴性症状都有效。进一步.在苯环利定给药后奥氮平治疗12天也能够逆转苯环利定诱导的基线前脉冲抑制缺陷。这些数据一起表明，苯环利定的围产期给药导致长期行为变化，其可能与在额叶皮层中观察到的凋亡性神经变性机制相关。据推测，这些赤字可以模拟在精神分裂症中观察到的前额叶功能减退，这种模型可能有助于设计适当的药物治疗。(C)2001 IBRO，由Elsevier Science Ltd.出版。保留所有权利。
Both acute and chronic administration of N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine and dizocilpine have been proposed to mimic some of the symptoms of schizophrenia. The purposes of the present study were first, to characterize the long-term behavioral and neurodegenerative effects of subchronic administration of phencyclidine to perinatal rats and second. to determine whether pretreatment with olanzapine could attenuate these effects. On postnatal days 7. 9 and I I rat pups were pretreated with either chicle or olanzapine prior to administration of either saline or phencyclidine (10 mg/kg). Some pups were killed on postnatal day 12 for biochemical determinations and others were tested on postnatal days 24-28 for prepulse inhibition of acoustic startle, on postnatal day 42 for phencyclidine-induced locomotor activity and between postnatal days 33 and 70 for acquisition of a delayed spatial learning task. Phencyclidine treatment resulted in a substantial increase in fragmented DNA in the frontal and olfactory cortices consistent with neurodegeneration by an apoptotic mechanism. An increase in the NMDA receptor NR1 subunit mRNA was also observed in the cortex. Gel shift assays showed that phencyclidine also increased the nuclear translocation of nuclear factor-kappaB proteins in the prefrontal cortex. In tissue from the frontal cortex. western blot analysis revealed that phencyclidine treatment increased Bax and decreased Bcl-X-L proteins. Later in development, it was observed that perinatal phencyclidine treatment significantly retarded baseline prepulse inhibition of acoustic startle measured shortly after weaning. In 42-day-old rats, it was found that challenge with 2 mg/kg phencyclidine increased locomotor activity to a significantly greater extent in the rats that had been pretreated with phencyclidine. Similarly, perinatal phencyclidine treatment significantly delayed the acquisition of a delayed spatial alternation task. Each of the aforementioned changes (except for the spatial learning task, which was not tested) was significantly inhibited by olanzapine pretreatment. an antipsychotic drug known to be effective against both positive and negative symptoms of schizophrenia. Further. olanzapine treatment for 12 days following the administration of phencyclidine was also able to reverse the phencyclidine-induced deficit in baseline prepulse inhibition,Together these data suggest that perinatal administration of phencyclidine results in long-term behavioral changes that may be mechanistically related to the apoptotic neurodegeneration observed in the frontal cortex. It is postulated that these deficits may model the hypofrontality observed in schizophrenia and that this model may be helpful in designing appropriate pharmacotherapy. (C) 2001 IBRO, Published by Elsevier Science Ltd. All rights reserved.