Antipsychotic Actions in Models of NMDA Hypofunction

描述（由申请人提供）：临床研究表明，NMDA受体拮抗剂在健康受试者中诱导阳性、阴性和认知精神分裂症样症状，并在精神分裂症患者中诱发精神病反应。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论依据。本提案将在NMDA受体功能降低的遗传模型- NMDA R1 （NR1）亚基缺陷小鼠中评估行为和脑代谢表型。NR1亚基是所有NMDA受体的组成部分，因此该亚基的表达减少将导致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脑代谢表型将模仿精神分裂症患者中观察到的某些表型。具体来说，假设NR1缺陷小鼠将表现出前额叶和边缘区域的脑代谢减少，并表现出感觉处理的改变（脉冲前抑制和惊吓习惯）。如果这些假设是正确的，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。该研究还将验证一个假设，即典型和非典型抗精神病药物的使用对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有不同的影响，此外，该研究还将为理解典型和非典型抗精神病药物的不同作用提供启发价值。拟议的放射自显影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转化机会，将在啮齿动物中发现的结果与人类联系起来。这项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，而且还将为探索精神分裂症治疗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。

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.