Perinatal Neurodegeneration and Schizophrenia

围产期神经退行性疾病和精神分裂症

• 批准号: 6608831
• 负责人: KENNETH Maurice JOHNSON
• 金额: $ 26.08万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-14 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6608831
• 关键词: NMDA receptors; apoptosis; behavioral /social science research tag; corpus striatum; disease /disorder model; enzyme linked immunosorbent assay; gel mobility shift assay; immunocytochemistry; in situ hybridization; laboratory rat; mental disorder chemotherapy; model design /development; neural degeneration; neuropharmacology; neuropsychology; neurotoxicology; neurotransmitter receptor; newborn animals; nonhuman therapy evaluation; perinatal; phencyclidine; protein structure function; schizophrenia; temporal lobe /cortex; terminal nick end labeling; western blottings

DESCRIPTION (provided by applicant): Recent studies on the behavioral and neurotoxic effects of NMDA receptor antagonists such as MK-801 and phencyclidine (PCP) have led to the suggestion that glutamatergic hypofunction may be part of the etiology of schizophrenia. Imaging and postmortem studies have pointed to diminished cortical function in schizophrenia, possibly resulting from altered development stemming from an undefined late prenatal insult. This laboratory has found that perinatal PCP administration (PN7, 9, 11) results in evidence of selective cortical apoptosis (PN 12) associated with behavioral changes including diminished baseline prepulse inhibition of acoustic startle (PN 24-28) and a sensitized locomotor response to PCP challenge (PN 42). Each of these effects was prevented by olanzapine pretreatment. Thus, it is proposed that PCP-induced neurotoxicity plays a significant role in the mechanism inderlying the behavioral alterations. This application is to test this, and other related hypotheses. First, the time course and dose- response for PCP-induced neurotoxicity and behavioral effects will be compared in an effort to separate these phenomena. Then, several selective receptor antagonists will be tested in an effort to again separate the behavioral and neurotoxic effects and to provide information concerning the neurotransmitter receptors involved. Specific antagonists of nitric oxide synthase and superoxide anion will also be tested to try to link the neurotoxic mechanism with the behaviors. The role of NMDA receptor upregulation and function in these processes will be tested using a pharmacological approach. Premature loss of striatal PSA-NCAM at PN 15 suggested the possibility that PCP treatment results in altered striatal function. Measurement of striatal glutamatergic innervation and transmitter release regulation will test this hypothesis. Finally, preliminary data suggesting that superoxide anion, SF-KB nuclear translocation and altered expression of Bax and Bcl-XL are involved in PCP-induced apoptosis will be further pursued and ultimately tested pharmacologically to determine their role in the in vivo effects of PCP. These data will increase the understanding of the mechanisms of PCP-induced neuro- and behavioral toxicity in the newborn rat and could provide a model of schizophrenia with both construct and face validity. These data will also provide information about the possible consequences of abuse of NMDA antagonists including PCP and ethanol late in pregnancy.

描述（由申请人提供）：有关行为和行为的最新研究 NMDA受体拮抗剂（如MK-801和）的神经毒性作用 苯克林（PCP）提出了谷氨酸能功能功能的建议 可能是精神分裂症病因的一部分。成像和验尸研究 已经指出精神分裂症的皮质功能降低，可能 由于未定义的晚期产前的发展而导致的发展变化 侮辱。该实验室发现围产期PCP给药（PN7、9，， 11）导致选择性皮质凋亡的证据（PN 12） 行为改变，包括基线预硫 声学惊吓（PN 24-28）和对PCP的敏感运动反应 挑战（第42页）。这些效果都被奥氮平阻止了 预处理。因此，提议PCP诱导的神经毒性发挥作用 在行为改变的机制中的重要作用。这 应用是为了测试这一点和其他相关的假设。首先，时间 PCP引起的神经毒性和行为效应的课程和剂量反应 将比较以分离这些现象。然后，几个 选择性受体拮抗剂将进行测试，以再次分开 行为和神经毒性作用，并提供有关 涉及神经递质受体。一氧化氮的特定拮抗剂 合成酶和超氧化阴离子也将测试以尝试连接神经毒性 具有行为的机制。 NMDA受体上调和 这些过程中的功能将使用药理学方法测试。 PN 15处纹状体PSA-NCAM的过早损失表明PCP的可能性 治疗导致纹状体功能改变。纹状体的测量 谷氨酸能神经支配和发射机释放调节将测试 假设。最后，初步数据表明超氧化阴离子SF-KB 核转运和BAX和BCL-XL的表达改变参与 PCP诱导的细胞凋亡将进一步追捕并最终测试 从药理上确定它们在PCP体内效应中的作用。这些 数据将增加对PCP诱导的神经机制的理解 和新生大鼠的行为毒性，可以提供 具有构造和面部有效性的精神分裂症。这些数据也将 提供有关滥用NMDA的可能后果的信息 怀孕后期，包括PCP和乙醇在内的拮抗剂。