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

描述(申请人提供)：N-甲基-D-天冬氨酸受体(NMDAR)介导的谷氨酸传递，以及多巴胺(DA)和3-氨基丁酸(GABA)系统，长期以来一直与精神分裂症有关，但所有常用的抗精神病药物都作用于DA受体。最近的研究表明，代谢性谷氨酸受体(MGluR)激动剂逆转了NMDAR拮抗剂苯环利定(PCP)和地佐西平(MK-801)在动物模型和精神分裂症患者中的行为效应。这些研究表明，mGluR2/3受体激动剂具有抗精神病特性，可能为精神分裂症提供一种新的治疗方法。这一发现令人兴奋，但它提出了一些基本问题：为什么mGluR2/3激动剂具有与D2受体抗精神病药物相同的治疗效果，以及mGluR2/3激动剂通过什么机制改善行为？我们假设mGluR2/3激动剂通过直接调节NMDAR亚单位在前额叶中的表达和运输，恢复了MK-801阻断所致的NMDAR功能中断。我们将使用体内药理药物、体外膜片钳记录和分子技术的综合方法，在MK-801精神分裂症动物模型中验证我们的假设。拟议的实验将为mGluR调节NMDAR介导的传播的潜在机制提供见解，并将有助于更好地理解mGluR激动剂如何在动物模型中逆转NMDAR拮抗剂的行为效应，以及精神分裂症的潜在分子病理生理特征和治疗。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一种新的治疗方法。然而，一个基本的问题是mGluR2/3激动剂使用什么机制来改善行为。这项研究肯定会为mGluR激动剂作为潜在的抗精神病药物的作用提供细胞和分子机制的见解。

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.