Chronic PCP Primate PFC Dopamine Deficit and Schizophrenia

描述（由申请人提供）：精神分裂症中发生的认知缺陷可以说是最令人衰弱的症状，并且对药物治疗最具抵抗力。虽然非典型抗精神病药物（APD）氯氮平是少数几种成功治疗精神分裂症阴性和认知症状的药物之一，但其作用机制尚未完全了解，这阻碍了比氯氮平更有效且没有危险副作用的其他药物的开发。在人类中，反复使用苯环己哌啶（PCP）往往会引起持久的精神分裂症样综合征。在猴子中，我们发现亚慢性暴露于五氯苯酚会导致前额叶皮层（PFC）多巴胺功能下降，持续时间超过一个月，并表现出神经化学和解剖学特异性。这种PCP诱导的PFC多巴胺缺乏与猴子的认知障碍有关，这类似于精神分裂症中发生的认知障碍。此外，这些认知缺陷通过给予氯氮平部分改善。五氯苯酚还可导致大鼠PFC第V层的棘突触数量和树突棘密度减少。本项目将利用大鼠和猴的体内和离体技术，从解剖结构完整性、神经递质调节和与PFC相关的行为功能等方面研究五氯苯酚重复给药引起的神经生物学变化的机制。将对药理学逆转因亚慢性接触五氯苯酚而产生的认知缺陷的机制进行评价。研究计划将解决以下问题：多巴胺是否在PCP诱导的树突棘密度降低和啮齿动物PFC中观察到的棘突触丢失中起关键作用？这些解剖学变化可以被非典型APD逆转吗？在大鼠中观察到的脊柱突触数量减少和脊柱密度降低以及多巴胺调节的这种效应是否在猴子中保留？PCP和MPTP诱导的PFC中树突棘突触的丧失以及随后的认知缺陷是否可以通过长期给予非典型APD来逆转？什么样的受体是必不可少的氯氮平的能力，以正常的多巴胺周转在PFC的PCP治疗的猴子？非典型APD（或受体特异性药物）逆转PCP治疗的猴子PFC多巴胺缺乏是否会减轻认知障碍？关键的神经化学，解剖和行为数据的产生在这个猴模型PFC多巴胺缺乏症和认知受损将提供重要的新的见解有关的神经系统额叶皮质认知功能障碍的精神分裂症。这些数据将有助于开发新的策略，以改善这种潜在的动物模型中的神经化学，解剖和行为缺陷，并希望在与精神分裂症和其他精神疾病相关的认知功能障碍。

DESCRIPTION (provided by applicant): 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 (APD), clozapine, is one of the few drugs with any success in treating the negative and cognitive symptoms of schizophrenia, it's 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 dopamine function in the prefrontal cortex (PFC) which persists for more than a month, and 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. PCP also causes a decrease in the number of spine synapses and density of dendritic spines in layer V of rat PFC. 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: Does dopamine play a critical role in the PCP induced decrease in dendritic spine density and spine synapse loss observed in the PFC of rodents? Can these anatomical changes be reversed by atypical APDs? Is the loss in the number of spine synapses and decrease in spine density and the dopamine modulation of this effect observed in the rat conserved in monkeys? Can the PCP and MPTP induced loss of dendritic spine synapses in the PFC and the ensuing cognitive deficits be reversed by chronic administration of atypical APDs? What receptors are essential for clozapine's ability to normalize dopamine turnover in the PFC of PCP treated monkeys? Do atypical APDs (or receptor specific agents) that reverse the PFC dopamine deficit in PCP-treated monkeys attenuate the cognitive impairments? The generation of critical neurochemical, anatomical and behavioral data in this monkey model of PFC dopamine deficiency and impaired cognition will provide important new insights concerning the neural systems relevant to the frontal cortical cognitive dysfunction in schizophrenia. These data will aid in the development of novel strategies for ameliorating the neurochemical, anatomical and behavioral deficits in this potential animal model, and hopefully in the cognitive dysfunctions associated with schizophrenia and other psychiatric disorders.