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、阴性和认知性精神分裂症样症状，并在精神分裂症患者中诱发精神病性反应。这些数据，以及由此产生的NMDA受体功能减退的精神分裂症的假设，提供了一个令人信服的理由，在模型中的NMDA受体功能降低的神经生物学特性的相关性。目前的建议将评估行为和脑代谢表型的NMDA受体功能降低的遗传模型-NMDA R1（NR 1）亚基缺陷小鼠。NR 1亚基是所有NMDA受体的组分，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。假设与NR 1缺陷小鼠模型相关的行为和脑代谢表型将模拟在精神分裂症患者中观察到的某些表型。具体而言，假设NR 1缺陷小鼠将表现出前额叶和边缘区的脑代谢降低，并表现出感觉处理的改变（前脉冲抑制和惊吓习惯化）。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。拟议的工作还将测试以下假设：典型和非典型抗精神病药物的给药将对在NMDA受体功能降低的遗传模型中观察到的行为和局部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效应的启发性价值外，所提出的放射自显影研究类似于人类脑代谢和血流的PET研究，因此提供了将啮齿动物中发现的结果与人类相关联的重要潜在转化机会。拟议的工作不仅有助于了解非典型抗精神病药物的神经生物学作用，而且还将提供范式，其中新的药理学策略可以探索精神分裂症的治疗。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以帮助描述这些模型中的神经化学功能障碍，并通过推断，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.