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，影响着世界上近1%的人口。不幸的是，目前的抗精神病药物会引起严重的副作用，并且对治疗精神分裂症的一些症状无效。更有效的药物治疗的发展可能需要对精神分裂症的神经生物学有更好的了解。本实验将研究一种新的谷氨酸来源，特别是从胱氨酸-谷氨酸反转运体中释放的非囊状谷氨酸，对苯环利定（PCP）的行为和神经化学作用的贡献，苯环利定是最常用的精神分裂症动物模型之一。第一个目标的实验将验证假设，即使用半胱氨酸前药n -乙酰半胱氨酸靶向半胱氨酸-谷氨酸反转运蛋白代表了一种新的治疗精神分裂症的策略。具体来说，这些实验将检验n -乙酰半胱氨酸治疗对急性和亚慢性给药PCP减少的运动活动、工作记忆缺陷和社交退缩的影响。这些行为之前已经被用来深入了解精神分裂症的神经生物学。本研究的其他实验将利用体内微透析来评估n -乙酰半胱氨酸给药逆转内侧前额皮质PCP神经化学作用的能力。第二个目标的实验将检验一种假设，即胱氨酸-谷氨酸反转运蛋白活性的失调有助于PCP的病理生理，并可能导致精神分裂症。具体来说，这些实验将检验急性或反复给药PCP是否会改变内侧前额叶皮层中胱氨酸和谷胱甘肽的细胞外或组织水平。总的来说，这些实验有可能确定胱氨酸-谷氨酸反转运蛋白作为精神分裂症病理生理中的一种新的细胞机制，并证明n -乙酰半胱氨酸的潜在抗精神病特性。

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.