CHRONIC PCP--PRIMATE PFC DOPAMINE DEFICIT & SCHIZOPHRENI

描述（改编自申请人摘要）：无令人信服的动物模型 包括精神分裂症阴性和阳性症状的证据， 选择性药理逆转这些缺陷，或提供证据， 它的病理生理回路。 我们有令人兴奋的新数据在一个旧的 世界灵长类动物，这表明这种模型的可能性，以及 更有效和更有选择性的治疗策略。 五氯苯酚已知 在人类中反复使用会诱发持久的精神分裂样综合征。 我们在大鼠和猴子身上的试验数据表明， 在PFC中诱导DA缺乏，并且这种缺乏表现在 认知障碍和行为异常。 此外，本发明还 这种认知损害通过给予非典型的 抗精神病药物氯氮平，一种对治疗精神分裂症 精神分裂症患者的阴性症状 使用体内和体外技术 在老鼠和猴子身上，这个项目将研究 对于重复PCP给药引起的神经生物学变化， 解剖结构的完整性，神经递质的调节和行为 与PFC相关的功能。 本研究计划将探讨以下假设：（1） PCP亚慢性治疗诱导PFC DA功能的持久变化 持续一个多月，并显示神经化学和 解剖特异性 (2)中尺度PFC DA系统对 压力和精神刺激剂的作用减弱， 抑制这些神经元。 (3)特异性自动或 中脑DA神经元的传入调节控制负责或 与所观察到的抑制中皮层DA功能诱导 关于PCP (4)重复PCP引起的行为/认知缺陷 暴露与PFC功能障碍直接相关。 (5)非典型性将更多 比典型的抗精神病药物更有效地逆转， 缺陷，并且这种差异依赖于DA D4受体机制。 猴子关键神经化学和行为数据的产生 将提供有关神经系统的重要新见解， 精神分裂症和援助的新战略的发展， 改善这种新的，潜在的， 疾病的动物模型。

DESCRIPTION (Adapted from applicant's abstract): No convincing animal-model includes evidence of both negative and positive symptoms of schizophrenia, selective pharmacological reversal of these deficits, or provides evidence of its pathophysiological circuits. We have exciting new data in an Old World primate which suggests the possibility of such a model as well as strategies for more effective and selective treatments. PCP is known to induce an enduring schizophrenic-like syndrome with repeated use in humans. Our pilot data in rats and monkeys indicate that subchronic PCP exposure induces a DA deficiency in the PFC and that this deficiency is manifest in cognitive impairment and behavioral abnormalities in the monkey. Further, this cognitive impairment is ameliorated by administration of the atypical antipsychotic drug clozapine, an agent with high efficacy in treating negative symptoms in schizophrenics. 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. The research plan will investigate the following, hypotheses: (1) Subchronic treatment with PCP induces enduring changes in PFC DA function that persist for more than a month and demonstrates neurochemical and anatomical specificity. (2) The responsivity of the mesoPFC DA system to stress and psychomotor stimulants is blunted suggesting a global functional inhibition of these neurons. (3) Dysregulation of specific auto- or afferent-regulatory control of midbrain DA neurons is responsible for or associated with the observed inhibition of meso-cortical DA function induced by PCP. (4) The behavioral/cognitive deficits induced by repeated PCP exposure are directly related to PFC dysfunction. (5) Atypical will be more effective than typical antipsychotic drugs in reversing,the cognitive deficits, and this difference is dependent on a DA D4 receptor mechanism. The generation of critical neurochemical and behavioral data in the monkey will provide important new insight concerning the neural systems relevant to schizophrenia and aid in the development of novel strategies for ameliorating the neurochemical and behavioral effects in this new, potential animal model of the disorder.