Antipsychotic Actions in Models of NMDA Hypofunction
NMDA 功能减退模型中的抗精神病作用
基本信息
- 批准号:6734720
- 负责人:
- 金额:$ 25.46万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2003
- 资助国家:美国
- 起止时间:2003-04-10 至 2008-01-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
DESCRIPTION (provided by applicant): Clinical studies have demonstrated that NMDA receptor antagonists induce positive, negative and cognitive schizophrenic-like symptoms in healthy subjects and precipitate psychotic reactions in patients with schizophrenia. These data, and the resulting NMDA receptor hypofunction hypothesis of schizophrenia, provide a compelling rationale for characterizing neurobiological correlates in models of reduced NMDA receptor function. The present proposal will assess behavioral and brain metabolic phenotypes in a genetic model of reduced NMDA receptor function-the NMDA R1 (NR1) subunit deficient mouse. The NR1 subunit is a component of all NMDA receptors and reduced expression of this subunit will therefore result in a chronic state of NMDA receptor hypofunction. It is hypothesized that the behavioral and brain metabolic phenotypes associated with the NR1 deficient mouse model will mimic certain phenotypes observed in schizophrenic patients. Specifically, it is hypothesized that the NR1 deficient mice will exhibit reduced brain metabolism in prefrontal and limbic regions, and exhibit alterations in sensory processing (prepulse inhibition and startle habituation). If these hypotheses are correct, the mouse models could represent an approach to explore potential preventative strategies for schizophrenia. The proposed work also will test the hypothesis that administration of typical and atypical antipsychotic drugs will have different effects on the alterations in behavior and regional brain metabolic activity observed in the genetic model of reduced NMDA receptor function In addition to the heuristic value of the work for understanding differential effects of typical and atypical antipsychotic drugs, the proposed autoradiographic studies are analogous to human PET studies of brain metabolism and blood flow, and therefore offer an important potential translational opportunity to relate results found in rodents to humans. The proposed work will not only contribute to the understanding of neurobiological actions of atypical antipsychotic drugs, but also will provide paradigms in which novel pharmacological strategies could be explored for the treatment of schizophrenia. In addition, characterizing neurobiological actions of antipsychotic drugs in the genetic model of NMDA receptor hypofunction could help delineate neurochemical dysfunction in these models, and by inference, potential pathophysiological processes in schizophrenia.
描述(申请人提供):临床研究表明,NMDA 受体拮抗剂会在健康受试者中诱发阳性、阴性和认知性精神分裂症样症状,并在精神分裂症患者中引发精神病性反应。这些数据以及由此产生的精神分裂症 NMDA 受体功能减退假说,为表征 NMDA 受体功能降低模型中的神经生物学相关性提供了令人信服的理由。本提案将评估 NMDA 受体功能降低的遗传模型——NMDA R1 (NR1) 亚基缺陷小鼠的行为和大脑代谢表型。 NR1 亚基是所有 NMDA 受体的组成部分,因此该亚基表达减少将导致 NMDA 受体功能减退的慢性状态。据推测,与 NR1 缺陷小鼠模型相关的行为和大脑代谢表型将模仿在精神分裂症患者中观察到的某些表型。具体而言,假设 NR1 缺陷小鼠的前额叶和边缘区域的脑代谢降低,并表现出感觉处理的改变(前脉冲抑制和惊吓习惯)。如果这些假设正确,小鼠模型可以代表一种探索精神分裂症潜在预防策略的方法。拟议的工作还将检验这样的假设,即使用典型和非典型抗精神病药物将对 NMDA 受体功能降低的遗传模型中观察到的行为和区域脑代谢活动的改变产生不同的影响。除了该工作对于理解典型和非典型抗精神病药物的差异作用的启发价值外,拟议的放射自显影研究类似于脑代谢和血液的人类 PET 研究 流,因此提供了一个重要的潜在转化机会,将啮齿动物中发现的结果与人类联系起来。拟议的工作不仅有助于理解非典型抗精神病药物的神经生物学作用,而且还将提供探索治疗精神分裂症的新药理学策略的范例。此外,在 NMDA 受体功能减退的遗传模型中表征抗精神病药物的神经生物学作用可能有助于描述这些模型中的神经化学功能障碍,并由此推断精神分裂症的潜在病理生理过程。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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Gary E Duncan其他文献
Olanzapine and Clozapine Increase the GABAergic Neuroactive Steroid Allopregnanolone in Rodents
奥氮平和氯氮平增加啮齿动物中的γ-氨基丁酸能神经活性甾体孕烯醇酮
- DOI:
10.1038/sj.npp.1300015 - 发表时间:
2003-12-16 - 期刊:
- 影响因子:7.100
- 作者:
Christine E Marx;Margaret J VanDoren;Gary E Duncan;Jeffrey A Lieberman;A Leslie Morrow - 通讯作者:
A Leslie Morrow
Gary E Duncan的其他文献
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{{ truncateString('Gary E Duncan', 18)}}的其他基金
Antipsychotic Actions in Models of NMDA Hypofunction
NMDA 功能减退模型中的抗精神病作用
- 批准号:
7013100 - 财政年份:2003
- 资助金额:
$ 25.46万 - 项目类别:
Antipsychotic Drug Effects on Neuropsychological and Brain Metabolic Responses
抗精神病药物对神经心理学和大脑代谢反应的影响
- 批准号:
6980598 - 财政年份:2003
- 资助金额:
$ 25.46万 - 项目类别:
Antipsychotic Actions in Models of NMDA Hypofunction
NMDA 功能减退模型中的抗精神病作用
- 批准号:
6607932 - 财政年份:2003
- 资助金额:
$ 25.46万 - 项目类别:
Antipsychotic Actions in Models of NMDA Hypofunction
NMDA 功能减退模型中的抗精神病作用
- 批准号:
7172955 - 财政年份:2003
- 资助金额:
$ 25.46万 - 项目类别:
Antipsychotic Actions in Models of NMDA Hypofunction
NMDA 功能减退模型中的抗精神病作用
- 批准号:
6879724 - 财政年份:2003
- 资助金额:
$ 25.46万 - 项目类别:
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