Neurobiology of Dopamine in Schizophrenia

精神分裂症多巴胺的神经生物学

• 批准号: 7457818
• 负责人: JEFFREY A. LIEBERMAN
• 金额: $ 206.94万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-24 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7457818
• 关键词: Neurobiology; Dopamine; Schizophrenia

DESCRIPTION (provided by applicant): This is the second submission of this Conte Center for the Neuroscience of Mental Disorders (CCNMD) entitled "The Neurobiology of Dopamine in Schizophrenia. Schizophrenia might result from neurodevelopmental disruptions involving multiple cortico-subcortical and intracortical networks. While the precise mapping of these alterations remains unclear, multiple lines of evidence suggest that prefrontal cortex (PFC) is critically involved in the neurocircuitry underlying the pathophysiology of schizophrenia. Within these circuits, dysregulations of DA (DA) and glutamate (GLU) transmission have been strongly implicated. The unifying hypothesis of the Center is that schizophrenia is associated with an imbalance of DA (DA) systems, characterized by a persistent deficit in prefrontal cortical DA function (contributing to the cognitive impairment observed in these patients) and an intermittent excess of subcortical DA function (contributing to the emergence of psychotic states). This DA imbalance might stem from altered PFC connectivity involving GLU transmission and from a failure of PFC to appropriately modulate DA function. The overall goal of the Center is to combine clinical imaging with Positron Emission Tomography (PET) and epigenetic and transgenic animal models in mice and rhesus monkeys to test this hypothesis. A set of interrelated clinical and preclinical investigations are proposed to 1) better characterize the existence of such a DA imbalance in schizophrenia; 2) explore the underlying biological mechanisms that might account for such a DA phenotype; 3) understand the consequence of this imbalance for brain functions, clinical symptoms and treatment. Six highly integrated projects are proposed, including two clinical imaging projects in patients with schizophrenia (Projects by Abi-Dargham and Laruelle) four preclinical projects, performed in rhesus monkeys (Projects by Haber and Javitt) and mice (Projects by Kandel and Rayport). These projects will investigate this single hypothesis with state-of-the art methodologies. Six cores will provide shared resources and support for these projects (Administrative, Biostatistics and Data management, Clinical, Brain Imaging, Molecular and Cellular, and Neurochemistry Cores). Prominent investigators from three Institutions (Columbia University, University of Rochester and Nathan Kline Research Institute) will bring specific research skills and collaborate closely in this translational investigation. By integrating basic and clinical research in a unique way, this Center will provide a fundamental advance in understanding the neural substrates underlying schizophrenia, the developmental etiology of this phenotype, and the implications of these findings for the development of new treatment modalities.

描述（由申请人提供）：这是该孔戴神经科学中心的第二次提交（CCNMD）的标题为“精神分裂症中多巴胺的神经生物学。精神分裂症可能是由涉及多个皮质性和内型网络的神经发育中的神经产生造成的，同时涉及多个皮质性网络，同时这些精神分裂的途径。前额叶皮层（PFC）与精神分裂症的病理生理学的神经通律有关，在这些电路中，DA（DA）的失调（DA）和谷氨酸（GLU）的功能障碍与中心的统一假设有关。皮质DA功能（在这些患者中观察到的认知障碍），间歇性皮层DA功能过多（导致精神病态的出现）。这种DA失衡可能源于涉及GLU传输以及PFC失败以适当调节DA函数的PFC连接性的改变。该中心的总体目标是将临床成像与小鼠和恒河猴的正电子发射断层扫描（PET）以及表观遗传和转基因动物模型相结合，以检验该假设。提出了一组相互关联的临床和临床前研究，以更好地表征精神分裂症中这种DA失衡的特征； 2）探索可能解释这种DA表型的潜在生物学机制； 3）了解这种失衡对大脑功能，临床症状和治疗的结果。提出了六个高度综合的项目，包括精神分裂症患者（Abi-Dargham和Laruelle的项目）的两个临床成像项目，在恒河猴（Haber和Javitt的项目）和MICE（Kandel和Rayport的项目）中进行的四个临床前项目。这些项目将使用最先进的方法研究这一单一假设。六个核心将为这些项目提供共同的资源和支持（行政，生物统计学和数据管理，临床，脑成像，分子和细胞以及神经化学核心）。来自三个机构（哥伦比亚大学，罗切斯特大学和Nathan Kline研究所）的著名研究人员将带来特定的研究技能，并在这项翻译调查中紧密合作。通过以独特的方式整合基本和临床研究，该中心将提供基本的进步，以了解精神分裂症基础的神经底物，该表型的发展病因以及这些发现对发展新治疗方式的影响。

项目成果

Cholinergic agonists as novel treatments for schizophrenia: the promise of rational drug development for psychiatry.

胆碱能激动剂作为精神分裂症的新疗法：精神病学合理药物开发的前景。

• DOI: 10.1176/appi.ajp.2008.08050769
• 发表时间: 2008
• 期刊: The American journal of psychiatry
• 作者: Lieberman,JeffreyA;Javitch,JonathanA;Moore,Holly
• 通讯作者: Moore,Holly

Relating the effects of prenatal stress in rodents to the pathogenesis of schizophrenia.

• DOI: 10.1016/j.biopsych.2011.10.001
• 发表时间: 2011-11-15
• 期刊: BIOLOGICAL PSYCHIATRY
• 影响因子: 10.6
• 作者: Moore, Holly;Susser, Ezra
• 通讯作者: Susser, Ezra

Dopamine's role in social modulation of infant isolation-induced vocalization: II. Maternally modulated infant separation responses are regulated by D1- and D2-family dopamine receptors.

• DOI: 10.1002/dev.20355
• 发表时间: 2009-03
• 期刊: DEVELOPMENTAL PSYCHOBIOLOGY
• 影响因子: 2.2
• 作者: Muller, Jeff M.;Moore, Holly;Myers, Michael M.;Shair, Harry N.
• 通讯作者: Shair, Harry N.

Striatal and extrastriatal dopamine release measured with PET and [(18)F] fallypride.

• DOI: 10.1002/syn.20734
• 发表时间: 2010-05
• 期刊: SYNAPSE
• 影响因子: 2.3
• 作者: Slifstein, Mark;Kegeles, Lawrence S.;Xu, Xiaoyan;Thompson, Judy L.;Urban, Nina;Castrillon, John;Hackett, Elizabeth;Bae, S. -A.;Laruelle, Marc;Abi-Dargham, Anissa
• 通讯作者: Abi-Dargham, Anissa

Striatal and extrastriatal dopamine D2/D3 receptors in schizophrenia evaluated with [18F]fallypride positron emission tomography.

• DOI: 10.1016/j.biopsych.2010.05.027
• 发表时间: 2010-10-01
• 期刊: BIOLOGICAL PSYCHIATRY
• 影响因子: 10.6
• 作者: Kegeles, Lawrence S.;Slifstein, Mark;Xu, Xiaoyan;Urban, Nina;Thompson, Judy L.;Moadel, Tiffany;Harkavy-Friedman, Jill M.;Gil, Roberto;Laruelle, Marc;Abi-Dargham, Anissa
• 通讯作者: Abi-Dargham, Anissa