DOPAMINE DEFICIT AND SCHIZOPHRENIA

描述：（改编自申请人的摘要） 发生在精神分裂症中的症状可以说是最衰弱的症状， 对药物治疗的抵抗力最强。而非典型的 抗精神病药物，氯氮平，是少数几种成功的药物之一， 治疗精神分裂症的阴性和认知症状， 行动没有得到充分理解，这阻碍了其他发展 比氯氮平更有效且没有其危险性的药物 方面的影响.在人类中，反复使用苯环己哌啶（PCP）通常会引起 患有精神分裂样综合症在猴子身上，我们发现 亚慢性暴露于五氯苯酚诱导多巴酚宁功能下降， 前额叶皮层（PFC），持续一个多月。证明， 神经化学和解剖学特异性。PCP诱导的PFC多巴胺 缺乏与猴子的认知障碍有关， 此外，这些认知缺陷是 通过给予氯氮平部分改善 在老鼠和猴子的技术，这个项目将研究机制 负责反复PCP诱导的神经生物学变化 给药对解剖完整性、神经递质调节和 与PFC相关的行为功能。此外， 参与药理学逆转认知缺陷产生的 将对五氯苯酚的亚慢性接触情况进行评估。 研究计划将针对以下四个具体目标：（1） 神经生物学变化;负责多巴胺功能的减少， PCP重复给药后PFC，（2）氯氮平的能力， 逆转PCP诱导的认知障碍， 增加PFC中的多巴胺周转，以及哪些受体对 这一行动？(3)确定非典型抗精神病药物（或受体） 特异性药物），逆转PCP处理猴的PFC多巴胺缺乏 减轻认知障碍，以及（4）确定是否存在 区域特异性适应性改变小清蛋白GABA能中间神经元 在反复接受五氯酚治疗的猴子体内的PFC。 在这只猴子身上产生的关键神经化学和行为数据 PFC多巴胺缺乏和认知受损的模型将提供重要的 关于额叶皮层相关神经系统的新见解 精神分裂症的认知功能障碍这些数据将有助于开发 改善神经化学和行为缺陷的新策略 在这个潜在的动物模型中，以及与之相关的认知功能障碍中， 患有精神分裂症和其他精神疾病。

DESCRIPTION: (Adapted from applicant's abstract) The cognitive deficits that occur in schizophrenia are arguably the most debilitating of the symptoms, and the most resistant to pharmacological treatment. While the atypical antipsychotic drug, clozapine, is the one of the few drugs with any success in treating the negative and cognitive symptoms of schizophrenia, its mechanism of action is not fully understood and this has hindered development of other agents that are more effective than clozapine and lack its dangerous side effects. In man, repeated use of phencyclidine (PCP) can often induce an enduring schizophrenic-like syndrome. In the monkey, we have found that subchronic exposure to PCP induces a decrease in doparnine function in the prefrontal cortex (PFC), which persists for more than a month. Demonstrates, neurochemical and anatomical specificity. This PCP-induced PFC dopamine deficiency correlates with cognitive impairments in the monkey, which resemble those occurring in schizophrenia Furthermore, these cognitive deficits are partially ameliorated by administration of clozapine Using in vivo and ex vivo techniques in rats and monkeys, this project will examine the mechanisms responsible for the neurobiological changes induced by repeated PCP administration on the anatomical integrity, neurotransmitter regulation and behavioral functions associated with the PFC. In addition, the mechanisms involved in the pharmacological reversal of the cognitive deficits produced by subchronic exposure to PCP will be evaluated. The research plan will address the following four specific aims: (1) What neurobiological changes; responsible for the reduction in dopamine function in the PFC following repeated PCP administration, (2) clozapine's ability to reverse the PCP-induced cognitive impairment mediated by a preferential increase dopamine turnover in the PFC, and what receptors are essential for this action? (3) Determine if atypical antipsychotic drugs (or receptor specific agents) that reverse the PFC dopamine deficit in PCP-treated monkey attenuate the cognitive impairments, and (4) Determine whether there are regionally specific adaptive changes the parvalbumin GABAergic interneurons of the PFC in the monkey repeatedly treated with PCP. The generation of critical neurochemical and behavioral data in this monkey model of PFC dopamine deficiency and impaired cognition will provide important new insights concerning the neural systems relevant the frontal cortical cognitive dysfunction in schizophrenia. These data will aid in the development of novel strategies for ameliorating the neurochemical and behavioral deficits in this potential animal model, and in the cognitive dysfunctions associated with schizophrenia and other psychiatric disorders.