DOPAMINE DEFICIT AND SCHIZOPHRENIA

描述：(改编自申请者的摘要)认知缺陷 发生在精神分裂症中的症状可以说是最令人虚弱的，而且 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为数不多的在治疗中取得成功的药物之一 治疗精神分裂症阴性症状和认知症状的作用机制 行动没有被完全理解，这阻碍了其他方面的发展 比氯氮平更有效且没有其危险方面的药物 效果。在人类中，重复使用苯环利定(PCP)通常会导致 持久的精神分裂样综合症。在猴子身上，我们发现 亚慢性接触五氯苯酚可导致大鼠脑内多巴宁功能下降 前额叶皮质(PFC)，持续一个多月。演示， 神经化学和解剖学上的特异性。五氯苯酚诱导的PFC多巴胺 缺乏症与猴子的认知障碍有关，类似于 此外，这些认知缺陷是 氯氮平在体内和体外给药部分改善 在老鼠和猴子身上的技术，这个项目将检验这种机制 重复PCP引起的神经生物学改变 在解剖完整性、神经递质调节和 与PFC相关的行为功能。此外，这些机制 参与药物逆转由阿司匹林引起的认知缺陷 将对亚慢性暴露于五氯苯酚进行评估。 研究计划将涉及以下四个具体目标：(1)什么 神经生物学变化；导致脑部多巴胺功能降低 重复服用PCP后的PFC，(2)氯氮平的能力 优先给药逆转PCP所致认知功能障碍 增加PFC中的多巴胺周转率，以及哪些受体是必不可少的 这一作用？(3)确定非典型抗精神病药物(或受体) 特异性药物)逆转PCP治疗猴的PFC多巴胺缺乏 减轻认知障碍，以及(4)确定是否有 局部适应性改变小白蛋白GABA能中间神经元 用PCP反复治疗猴的PFC。 这只猴子的关键神经化学和行为数据的产生 PFC多巴胺缺乏和认知受损模型将提供重要的 关于额叶皮质相关神经系统的新见解 精神分裂症患者的认知功能障碍。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 在这种潜在的动物模型中，与认知功能障碍相关 患有精神分裂症和其他精神障碍。

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.