Phencyclidine-induced Cognitive Impairments

描述（由申请人提供）：尽管精神分裂症的治疗取得了重大进展，但事实上，认知障碍是决定功能结果的最重要因素。尽管有更有效的抗精神病药物，但患者在社会和职业功能方面的恢复率仍保持在与20世纪30年代相似的水平，因此，认知缺陷是精神分裂症恢复的主要限制因素，但对这些缺陷的病因知之甚少。重要的是建立一个临床前模型来阐明这些缺陷的分子基础，并筛选能够治疗这些缺陷的药物。研究行为和药物作用的分子相关性的一种方法是使用基因靶向敲除和转基因动物。这种技术允许对选择性药理学制剂不存在的受体进行操纵。由于这些突变仅在小鼠中可用，因此有必要首先使用小鼠进行临床前分析，以便使用这些技术。目前的建议是这一进程中重要的第一步。C57BL/6小鼠将亚慢性给药苯环利定，慢性滥用者会产生类似精神分裂症的认知缺陷。小鼠将在空间记忆任务中进行评估，并评估谷氨酸NMDA、NR1和NR2亚基表达的变化。非典型抗精神病药奥氮平对PCP的行为影响和PCP对额叶皮质和海马NMDA受体表达的影响的能力将被评估。

DESCRIPTION (provided by applicant): Despite major advances in treatment of schizophrenia, cognitive impairments are, in fact, the, most important determination of functional outcome. Rates of patient recovery in areas of social and vocational function remain at levels similar to those seen in the 1930s in spite of more effective antipsychotic drugs, thus, cognitive deficits are a major limiting factor, in recovery from schizophrenia, but little is known about the etiology of these deficits. It is important to develop a preclinical model to elucidate the molecular basis of these deficits and to screen drugs capable of treating these deficits. One approach for investigating the molecular correlates of behavior and drug action is the use of gene-targeted-knockout and transgenic animals. This technique allows for the manipulation of receptors for which selective pharmacological agents do not exist. Because these mutations are only available in mice, it is necessary to first develop preclinical assays using mice in order to use these techniques. The current proposal is an important first step in this process. C57BL/6-mice will be subchronically administered phencyclidine, which produces schizophrenia-like cognitive deficits in chronic abusers. The mice will be evaluated in a spatial memory task, and, changes in the expression of glutamate NMDA, NR1, and NR2 subunits will be assessed. The ability of the atypical antipsychotic olanzapine to attenuate PCP's behavioral effects and PCP's effects on expression of NMDA receptors in frontal cortex and hippocampus will then be assessed.