Chronic PCP Primate PFC Dopamine Deficit and Schizophrenia

描述（由申请人提供）：精神分裂症中出现的认知缺陷可以说是最使人衰弱的症状，也是对药物治疗最具抵抗力的。虽然非典型抗精神病药物氯氮平（APD）是少数成功治疗精神分裂症阴性症状和认知症状的药物之一，但其作用机制尚不完全清楚，这阻碍了其他比氯氮平更有效且没有其危险副作用的药物的开发。在男性中，反复使用苯环利定（PCP）往往会诱发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PCP会导致前额叶皮层（PFC）多巴胺功能的下降，这种下降持续一个多月，并表现出神经化学和解剖学的特异性。这种PCP诱导的PFC多巴胺缺乏与猴子的认知障碍有关，类似于精神分裂症。此外，这些认知缺陷可以通过氯氮平得到部分改善。PCP还会导致大鼠pfc第V层棘突触数量和树突棘密度的减少。本项目将通过在体和离体技术，研究PCP反复给药对pfc相关解剖完整性、神经递质调节和行为功能的神经生物学改变的机制。将评估亚慢性接触五氯苯酚所产生的认知缺陷的药理逆转机制。研究计划将解决以下问题：多巴胺是否在PCP诱导的啮齿动物PFC中树突棘密度下降和脊柱突触丢失中起关键作用？非典型apd能逆转这些解剖学改变吗？在大鼠中观察到的脊柱突触数量的减少和脊柱密度的降低以及多巴胺对这种效应的调节是否在猴子中保守？慢性非典型apd能否逆转PCP和MPTP诱导的PFC树突棘突触的丧失和随后的认知缺陷？哪些受体对氯氮平使PCP治疗的猴子PFC中多巴胺转换正常化的能力至关重要？在pcp治疗的猴子中，非典型apd（或受体特异性药物）逆转PFC多巴胺缺陷是否会减轻认知障碍？在这种PFC多巴胺缺乏和认知受损的猴子模型中产生的关键神经化学，解剖学和行为学数据将为精神分裂症额叶皮质认知功能障碍相关的神经系统提供重要的新见解。这些数据将有助于开发新的策略来改善这种潜在动物模型中的神经化学、解剖和行为缺陷，并有望改善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.