CHRONIC PCP--PRIMATE PFC DOPAMINE DEFICIT & SCHIZOPHRENI

慢性 PCP--灵长类 PFC 多巴胺缺乏症

• 批准号: 2891004
• 负责人: ROBERT Henry ROTH
• 金额: $ 33.04万
• 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 2000-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2891004
• 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）：无说服力的动物模型 包括精神分裂症的负症状和阳性症状的证据， 这些缺陷的选择性药理逆转或提供证据 它的病理生理回路。 我们有一个旧的新数据令人兴奋 世界灵长类动物表明这种模型以及 更有效和选择性治疗的策略。 PCP已知 诱导一种持久的精神分裂症综合征，并在人类中反复使用。 我们在大鼠和猴子中的试验数据表明，亚基pcp暴露 诱发PFC的DA不足，并且这种缺陷在 猴子的认知障碍和行为异常。 更远， 通过非典型的给药来改善这种认知障碍 抗精神病药氯氮平，一种在治疗方面具有高疗效的药物 精神分裂症患者的负面症状。 使用体内和前体技术 在老鼠和猴子中，该项目将检查负责的机制 对于反复给药引起的神经生物学变化 解剖完整性，神经递质调节和行为 与PFC相关的功能。 研究计划将研究以下假设：（1） PCP的亚慢性治疗可诱导PFC DA功能的持久变化 这持续了一个多月，并展示了神经化学和 解剖学特异性。 （2）中间FC DA系统对 压力和精神运动刺激剂被钝化，暗示了全球功能 抑制这些神经元。 （3）特定自动或 中脑DA神经元的传入调节控制负责或 与观察到的中质DA功能抑制有关的抑制 由PCP。 （4）重复的PCP引起的行为/认知缺陷 暴露与PFC功能障碍直接相关。 （5）非典型会更多 比典型的抗精神病药在逆转中有效，认知能力 缺陷，这种差异取决于DA D4受体机制。 猴子中关键的神经化学和行为数据的产生 将提供有关与神经系统有关的重要新见解 精神分裂症和帮助制定新的策略 在这种新的潜力中改善神经化学和行为效应 该疾病的动物模型。