DOPAMINE DEFICIT AND SCHIZOPHRENIA

多巴胺缺乏和精神分裂症

基本信息

批准号：
6490813
负责人：
ROBERT Henry ROTH
金额：
$ 37.55万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-09-25 至 2005-12-31
项目状态：
已结题

项目摘要

DESCRIPTION: (Adapted from applicant's abstract) 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, clozapine, is the one of the few drugs with any success in treating the negative and cognitive symptoms of schizophrenia, its 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 doparnine function in the prefrontal cortex (PFC), which persists for more than a month. 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 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 four specific aims: (1) What neurobiological changes; responsible for the reduction in dopamine function in the PFC following repeated PCP administration, (2) clozapine's ability to reverse the PCP-induced cognitive impairment mediated by a preferential increase dopamine turnover in the PFC, and what receptors are essential for this action? (3) Determine if atypical antipsychotic drugs (or receptor specific agents) that reverse the PFC dopamine deficit in PCP-treated monkey attenuate the cognitive impairments, and (4) Determine whether there are regionally specific adaptive changes the parvalbumin GABAergic interneurons of the PFC in the monkey repeatedly treated with PCP. The generation of critical neurochemical and behavioral data in this monkey model of PFC dopamine deficiency and impaired cognition will provide important new insights concerning the neural systems relevant the frontal cortical cognitive dysfunction in schizophrenia. These data will aid in the development of novel strategies for ameliorating the neurochemical and behavioral deficits in this potential animal model, and in the cognitive dysfunctions associated with schizophrenia and other psychiatric disorders.

描述：（改编自申请人的摘要）认知缺陷发生在精神分裂症中的症状可以说是最使人衰弱的症状，并且对药物治疗最有抵抗力。虽然非典型抗精神病药物氯氮平是少数在治疗抑郁症方面取得成功的药物之一治疗精神分裂症的阴性和认知症状，其机制行动尚未得到充分理解，这阻碍了其他行动的发展比氯氮平更有效且没有危险副作用的药物影响。在人类中，重复使用苯环己哌啶 (PCP) 通常会诱发持久的精神分裂症样综合症。在猴子身上我们发现亚慢性接触五氯苯酚会导致多巴胺功能下降前额皮质（PFC），持续一个多月。表明，神经化学和解剖学特异性。这种 PCP 诱导的 PFC 多巴胺缺乏与猴子的认知障碍相关，这类似于此外，这些认知缺陷是在精神分裂症中发生的通过施用氯氮平可部分改善体内和离体使用在大鼠和猴子身上进行技术，该项目将研究其机制是反复 PCP 引起的神经生物学变化的原因管理对解剖完整性、神经递质调节和与 PFC 相关的行为功能。此外，机制参与药理逆转认知缺陷将评估亚慢性接触五氯苯酚的情况。研究计划将解决以下四个具体目标：（1）什么神经生物学变化；导致多巴胺功能降低重复使用 PCP 后的 PFC，(2) 氯氮平的能力逆转PCP引起的认知障碍，该障碍是由优先介导的增加 PFC 中的多巴胺周转，以及哪些受体对于这个动作？ (3) 确定是否使用非典型抗精神病药物（或受体）逆转 PCP 治疗猴子 PFC 多巴胺缺陷的特定药物减轻认知障碍，以及 (4) 确定是否存在区域特异性适应性改变小白蛋白 GABA 能中间神经元反复接受五氯苯酚（PCP）治疗的猴子的前额皮质（PFC）。这只猴子的关键神经化学和行为数据的生成 PFC 多巴胺缺乏和认知受损模型将提供重要的关于与额叶皮质相关的神经系统的新见解精神分裂症的认知功能障碍。这些数据将有助于开发改善神经化学和行为缺陷的新策略在这种潜在的动物模型中，以及相关的认知功能障碍中患有精神分裂症和其他精神疾病。