CHRONIC PCP--PRIMATE PFC DOPAMINE DEFICIT & SCHIZOPHRENI

慢性 PCP--灵长类 PFC 多巴胺缺乏症

• 批准号: 2675682
• 负责人: ROBERT Henry ROTH
• 金额: $ 32.11万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-25 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2675682
• 关键词: Cercopithecidae; amphetamines; clozapine; cognition; disease /disorder model; dopamine; dopamine receptor; ethology; frontal lobe /cortex; haloperidol; laboratory rat; neurochemistry; neuropharmacology; neurotransmitter metabolism; pharmacokinetics; phencyclidine; psychopharmacology; pyridoindole; schizophrenia; tyrosine 3 monooxygenase

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.

描述（改编自申请人的摘要）：没有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， 选择性药理学逆转这些缺陷，或提供证据 其病理生理回路。 我们在旧的数据中拥有令人兴奋的新数据 世界灵长类动物表明了这种模型的可能性以及 更有效和选择性治疗的策略。 PCP 众所周知 在人类中重复使用会诱发持久的精神分裂症样综合症。 我们在大鼠和猴子中的试验数据表明，亚慢性五氯苯酚暴露 导致 PFC 中 DA 缺乏，这种缺乏表现在 猴子的认知障碍和行为异常。 更远， 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。 使用体内和离体技术 在大鼠和猴子中，该项目将研究负责的机制 重复使用 PCP 引起的神经生物学变化 解剖学完整性、神经递质调节和行为 与 PFC 相关的功能。 研究计划将调查以下假设：（1） PCP 亚慢性治疗可引起 PFC DA 功能的持久变化 持续一个多月并显示出神经化学和 解剖学特异性。 (2) mesoPFC DA系统的响应度 压力和精神运动兴奋剂减弱，表明整体功能 抑制这些神经元。 (3) 特定自体或功能失调 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 功能抑制相关 由PCP。 (4) 反复PCP引起的行为/认知缺陷 暴露与 PFC 功能障碍直接相关。 (5)非典型会较多 在逆转认知障碍方面比典型的抗精神病药物更有效 缺陷，这种差异取决于 DA D4 受体机制。 猴子关键神经化学和行为数据的生成 将提供有关神经系统的重要新见解 精神分裂症并协助制定新策略 改善这种新的、潜在的神经化学和行为效应 该疾病的动物模型。