Cystine-Glu Antiporter & PCP Model of Schizophrenia

描述（由申请人提供）：精神分裂症是一种使人衰弱的疾病，影响世界上近1%的人口。不幸的是，目前的抗精神病药引起严重的副作用，并且在治疗精神分裂症的许多症状方面无效。更有效的药物治疗的发展将可能等待更好地了解精神分裂症的神经生物学。本实验将研究一种新的谷氨酸来源，特别是非囊泡谷氨酸释放胱氨酸-谷氨酸反向转运蛋白，苯环己哌啶（PCP），这是最常用的精神分裂症动物模型之一的行为和神经化学作用的贡献。第一个目标中的实验将测试使用半胱氨酸前药N-乙酰半胱氨酸靶向胱氨酸-谷氨酸反向转运蛋白代表精神分裂症的新治疗策略的假设。具体而言，这些实验将检查N-乙酰半胱氨酸治疗对由PCP急性和亚慢性给药减少的自发活动、工作记忆缺陷和社交退缩的影响。这些行为以前曾被用来深入了解精神分裂症的神经生物学。在这一目标的其他实验将利用体内微透析来评估N-乙酰半胱氨酸管理的能力，以扭转PCP在内侧前额叶皮层的神经化学作用。第二个目标中的实验将检验这样的假设，即胱氨酸-谷氨酸反向转运蛋白的活性失调有助于PCP的病理生理学，并可能导致精神分裂症。具体而言，这些实验将检查是否急性或重复管理的PCP改变细胞外或组织水平的胱氨酸和谷胱甘肽在内侧前额叶皮层。总的来说，这些实验有可能确定胱氨酸-谷氨酸反向转运蛋白作为一种新的细胞机制，在精神分裂症的病理生理学，以及证明潜在的抗精神病特性的N-乙酰半胱氨酸。

DESCRIPTION (provided by applicant): Schizophrenia is a debilitating disorder that affects almost 1% of the world's population. Unfortunately, current antipsychotics induce severe side effects and are ineffective in treating a number of the symptoms of schizophrenia. The development of more effective pharmacotherapies will likely await a better understanding of the neurobiology of schizophrenia. The present experiments will examine the contribution of a novel source of glutamate, specifically nonvesicular glutamate release from cystine-glutamate antiporters, to the behavioral and neurochemical effects of phencyclidine (PCP), which represents one of the most commonly used animal models of schizophrenia. The experiments in the first aim will test the hypothesis that targeting the cystine-glutamate antiporter using the cysteine prodrug N-acetylcysteine represents a novel treatment strategy for schizophrenia. Specifically, these experiments will examine the impact of N-acetylcysteine treatment on locomotor activity, deficits in working memory and social withdrawal) reduced by acute and subchronic administration of PCP. These behaviors have been used previously to gain insight into the neurobiology of schizophrenia. Additional experiments in this aim will utilize in vivo microdialysis to assess the capacity of N-acetylcysteine administration to reverse the neurochemical effects of PCP in the medial prefrontal cortex. The experiments in the second aim will test the hypothesis that a dysregulation in the activity of cystine-glutamate antiporters contributes to the pathophysiology of PCP, and potentially schizophrenia. Specifically these experiments will examine whether acute or repeated administration of PCP alters extracellular or tissue levels of cystine and glutathione in the medial prefrontal cortex. Collectively, these experiments have the potential to identify the cystine-glutamate antiporter as a novel cellular mechanism in the pathophysiology of schizophrenia, as well as to demonstrate the potential antipsychotic properties of N-acetylcysteine.