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令人虚弱的症状，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是为数不多的在治疗精神分裂症的阴性和认知症状方面取得成功的药物之一，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危险副作用的药物的开发。在人类中，重复使用苯环利定(PCP)经常会导致持久的精神分裂症样综合征。在猴子身上，我们发现亚慢性接触PCP会导致前额叶皮质(PFC)多巴胺功能下降，这种下降持续一个多月，并表现出神经化学和解剖学上的特异性。这种PCP诱导的PFC多巴胺缺乏症与猴子的认知障碍有关，这些障碍类似于精神分裂症。此外，服用氯氮平可部分改善这些认知缺陷。PCP还可使大鼠PFC第V层的突触数目减少，树突棘密度减少。利用大鼠和猴子的体内和体外技术，本项目将研究重复给予五氯苯酚对与PFC相关的解剖完整性、神经递质调节和行为功能的神经生物学改变的作用机制。此外，还将对亚慢性接触五氯苯酚所产生的认知缺陷的药理逆转机制进行评估。该研究计划将解决以下问题：多巴胺是否在PCP引起的啮齿类动物PFC中树突棘密度下降和脊突突触丢失中起关键作用？这些解剖学上的变化能被非典型APDS逆转吗？在大鼠中观察到的脊椎突触数量的丧失和脊椎密度的下降以及这种影响的多巴胺调制在猴子中是否保守？慢性应用非典型APDS能否逆转PCP和MPTP引起的前额叶皮质树突棘突触丢失和随后的认知缺陷？氯氮平能够使五氯苯酚治疗的猴子的前额叶细胞中的多巴胺代谢正常化，哪些受体是必不可少的？非典型APDS(或受体特异剂)逆转接受PCP治疗的猴子的PFC多巴胺缺乏是否可以减轻认知障碍？在这个PFC多巴胺缺乏和认知受损的猴子模型中产生关键的神经化学、解剖学和行为数据，将为了解与精神分裂症额叶皮质认知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，以改善这一潜在动物模型中的神经化学、解剖学和行为缺陷，并有望改善与精神分裂症和其他精神障碍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.