Antipsychotic Mechanisms of mGluR Agonists in the MK-801 Model of Schizophrenia

描述（由申请人提供）：N-甲基-D-天冬氨酸受体（NMDAR）介导的谷氨酸传递，沿着多巴胺（DA）和3-氨基丁酸（GABA）系统，长期以来一直与精神分裂症相关，但所有常用的抗精神病药物均作用于DA受体。最近的研究表明，在动物模型和精神分裂症患者中，代谢型谷氨酸受体（mGluR）激动剂逆转了NMDAR拮抗剂苯环己哌啶（PCP）和地佐环平（MK-801）的行为效应。这些研究表明，mGluR 2/3受体激动剂具有抗精神病特性，可能为精神分裂症提供新的治疗方法。这一发现令人兴奋，但它提出了一些基本问题：为什么mGluR 2/3激动剂具有与D2受体抗精神病药物相同的治疗效果，以及mGluR 2/3激动剂通过何种机制改善行为？我们假设mGluR 2/3激动剂通过直接调节前额回路中NMDAR亚基的表达和运输来恢复MK- 801阻断诱导的NMDAR功能中断。一个综合的方法，在体内药物，体外膜片钳记录，和分子技术将被用来测试我们的假设在MK-801精神分裂症动物模型。拟议的实验将提供深入了解的潜在机制mGluR调节NMDAR介导的传输，并将有助于更好地了解如何mGluR激动剂逆转行为的影响NMDAR拮抗剂在动物模型和潜在的分子病理生理学特征和治疗精神分裂症。公共卫生相关性：最近的研究表明，mGluR激动剂具有抗精神病特性，可能为精神分裂症提供新的治疗方法。然而，一个根本的问题是mGluR 2/3激动剂使用什么机制来改善行为。这项研究肯定会提供深入了解mGluR激动剂作为潜在的抗精神病药物的作用所涉及的细胞和分子机制。

DESCRIPTION (provided by applicant): N-methyl-D-aspartate receptor (NMDAR)-mediated glutamate transmission, along with dopamine (DA) and 3-aminobutyric acid (GABA) systems, has long been linked to schizophrenia, but all commonly prescribed antipsychotic agents act on DA receptors. Recent studies indicate that metabotropic glutamate receptor (mGluR) agonists reverse the behavioral effects of the NMDAR antagonist phencyclidine (PCP) and dizocilpine (MK-801) in animal models and in patients with schizophrenia. These studies suggest that mGluR2/3 receptor agonists have antipsychotic properties and may provide a new treatment of schizophrenia. This finding is exciting, but it raises some fundamental questions: Why do mGluR2/3 agonists have the same therapeutic efficacy as D2 receptor antipsychotic agents and by what mechanisms do mGluR2/3 agonists ameliorate behavior? We hypothesize that mGluR2/3 agonists restore the disrupted NMDAR function induced by the MK- 801 blockade by directly regulating the expression and trafficking of NMDAR subunits in the prefrontal circuitry. An integrated approach of in vivo pharmacologic agents, in vitro patch clamp recording, and molecular techniques will be used to test our hypothesis in the MK-801 animal model of schizophrenia. The proposed experiments will provide insights into the underlying mechanisms of mGluR regulation of NMDAR-mediated transmission and will contribute to a better understanding of how mGluR agonists reverse behavioral effects of NMDAR antagonists in animal models and of the underlying molecular pathophysiological characteristics and treatment of schizophrenia. PUBLIC HEALTH RELEVANCE: Recent studies indicate that mGluR agonists have antipsychotic properties and may provide a new treatment of schizophrenia. However, a fundamental question raised is what mechanisms the mGluR2/3 agonists use to ameliorate behaviors. This study will certainly provide insights into the cellular and molecular mechanisms involved in actions of mGluR agonists as potential antipsychotics.