CHRONIC PCP--PRIMATE PFC DOPAMINE DEFICIT & SCHIZOPHRENI

描述(摘自申请者的摘要)：没有令人信服的动物模型 包括精神分裂症阳性症状和阴性症状的证据， 选择性药物逆转这些缺陷，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旧的 世界灵长类动物，这表明了这样一个模型的可能性以及 更有效和更有选择性的治疗策略。五氯苯酚已知 在人类身上反复使用可导致持久的精神分裂样综合症。 我们在大鼠和猴子身上的试验数据表明，亚慢性接触五氯苯酚 在前额叶引起DA缺乏，这一缺陷在 猴子的认知障碍和行为异常。此外， 这种认知障碍可以通过服用非典型药物来改善 抗精神病药物氯氮平--一种高效的治疗药物 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，这个项目将检查负责的机制 五氯苯酚反复给药引起的神经生物学改变 解剖完整性、神经递质调节和行为 与PFC关联的功能。 研究计划将调查以下假设：(1) 五氯苯酚亚慢性治疗引起PFC DA功能的持久变化 持续了一个多月，并证明了神经化学和 解剖学上的特异性。(2)MesoPFC DA系统对 应激和精神运动兴奋剂被钝化表明全球功能 对这些神经元的抑制。(3)特定AUTO-OR的调节异常 中脑DA神经元的传入调节控制负责或 与观察到的中皮质DA功能抑制有关 被PCP。(4)重复PCP所致的行为/认知功能障碍 暴露与PFC功能障碍直接相关。(5)非典型性将更多 在逆转认知方面比典型的抗精神病药物有效 这种差异依赖于DA D4受体机制。 猴子体内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 精神分裂症和帮助开发治疗精神分裂症的新策略 改善这一新的、潜在的神经化学和行为影响 这种疾病的动物模型。

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.