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
• 负责人: Gary E Duncan
• 金额: $ 23.96万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-10 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6607932
• 关键词: NMDA receptors; antipsychotic agents; autoradiography; brain mapping; brain metabolism; cognition disorders; immunocytochemistry; inhibitor /antagonist; laboratory mouse; limbic system; mental disorder chemotherapy; neural information processing; nonhuman therapy evaluation; prefrontal lobe /cortex; schizophrenia

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受体拮抗剂在健康受试者中诱导阳性、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反应。这些数据以及由此产生的精神分裂症NMDA受体功能低下假说，为描述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论基础。目前的建议将评估NMDA受体功能降低的遗传模型-NMDA R1(NR1)亚单位缺陷小鼠的行为和脑代谢表型。NR1亚单位是所有NMDA受体的组成部分，因此该亚单位的表达减少将导致NMDA受体功能低下的慢性状态。假设与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。具体地说，假设NR1缺陷小鼠将表现出前额叶和边缘区域大脑新陈代谢降低，并表现出感觉处理的改变(脉冲前抑制和惊吓习惯化)。如果这些假设是正确的，小鼠模型可能代表着一种探索精神分裂症潜在预防策略的方法。这项拟议的工作还将检验这样一个假设，即服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局部大脑代谢活动的变化产生不同的影响。除了了解典型和非典型抗精神病药物的不同影响的工作的启发式价值外，拟议的放射自显影术研究类似于人类脑代谢和血流的PET研究，因此提供了一个重要的潜在翻译机会，将在啮齿动物身上发现的结果与人类相关。这项拟议的工作不仅将有助于理解非典型抗精神病药物的神经生物学作用，还将为探索治疗精神分裂症的新药理学策略提供范例。此外，在NMDA受体功能低下的遗传模型中表征抗精神病药物的神经生物学作用有助于描绘这些模型中的神经化学功能障碍，并由此推断精神分裂症潜在的病理生理过程。