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A role for 5-lipoxyegenase in cocaine's actions

5-脂氧合酶在可卡因作用中的作用

基本信息

批准号：
7561691
负责人：
HARI MANEV
金额：
$ 15.7万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-02-01 至 2011-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7561691
关键词：
Affect Alzheimer&apos s Disease Anxiety Arachidonate 5-Lipoxygenase Arachidonic Acids Atherosclerosis Attention Award Basic Science Behavior Behavioral Biochemical Calcium Calmodulin Cell physiology Cocaine Complex Cyclic AMP-Dependent Protein Kinases Data Development Dose Drug abuse Enzymes Exploratory/Developmental Grant Exposure to Funding Future Genes Genetic Polymorphism Genotype Glutamate Receptor Inflammation Inflammatory Injection of therapeutic agent Isoxazoles Knock-out Knockout Mice LOX gene MK-886 Mediating Membrane Protein Traffic Molecular Mus Nerve Degeneration Neuronal Plasticity Neurons Nucleus Accumbens Pathway interactions Pharmaceutical Preparations Phase Phosphorylation Phosphotransferases Positioning Attribute Prefrontal Cortex Process Propionates Protein Kinase C Publishing Research Risk Factors Role Site Stroke Surface Testing Time Transgenic Mice Transgenic Organisms Variant Wolves Work addiction behavioral sensitization depression drug of abuse high risk innovation new therapeutic target novel programs receptor response therapeutic target translational study

项目摘要

DESCRIPTION (provided by applicant): Elucidating the role of processes that have not been investigated extensively in studies of cellular responses to exposure to drugs of abuse may uncover novel therapeutic targets for the treatment of addictions. We propose to test critical components of our innovative concept that an inflammatory enzyme, i.e., 5-lipoxygenase (5-LOX), influences biochemical and structural adaptations involved in behavioral sensitization to cocaine. Important for conceptualization of the proposed project was our accidental preliminary observation that cocaine responses (i.e., behavioral sensitization) differ between control and 5-LOX-deficient (knockout) mice. Neuroadaptive changes underlying behavioral sensitization have been related to those responsible for addicitive behaviors. Glutamate receptor-mediated neuroplasticity, which includes the phosphorylation and surface expression of the AMPA glutamate receptor subunit GluR1, is one of these changes. Recent published data and our preliminary results demonstrated that GluR1 phosphorylation can be increased by 5-LOX deficiency/inhibition. Hence, we hypothesize that 5-LOX inhibition/deficiency will facilitate cocaine-induced behavioral sensitization and that this will be accompanied by enhancement of the cocaine treatment- associated increase in GluR1 phosphorylation and surface expression. In AIM 1, we will use pharmacological 5-LOX inhibition (treatment with MK-886) and 5-LOX deficient transgenic (knockout) mice, to investigate the effects of 5-LOX inhibition/deficiency on cocaine-induced changes in GluR1 phosphorylation and GluR1 surface expression. Analyses will be performed in the nucleus accumbens (NAc) and prefrontal cortex (PFC) at different times after a single cocaine injection (time course studies). AIM 2 will test whether pharmacological 5- LOX inhibition and 5-LOX knockout alter the development phase of behavioral cocaine sensitization, whereas AIM 3 will test how pharmacological 5-LOX inhibition and 5-LOX knockout affect behavioral and molecular (i.e., GluR1 phosphorylation and surface expression) responses of cocaine-sensitized mice to a cocaine challenge administered after 7 days of wash-out. Demonstrating the involvement of 5-LOX in mechanisms of addiction would point to an unexplored putative therapeutic target (e.g., drugs that affect 5-LOX) and would bring attention to a possible role for 5-LOX gene polymorphisms in drug abuse in general. High-risk, conceptually creative and innovative projects are needed to significantly accelerate progress in drug abuse and addiction research. This proposal is aimed at testing critical components of the innovative concept that an inflammatory enzyme, i.e., 5-lipoxygenase (5-LOX), influences biochemical and structural adaptations involved in behavioral sensitization to cocaine. Demonstrating the involvement of 5-LOX in mechanisms of addiction would point to a novel and unexplored putative therapeutic target (e.g., drugs that affect 5-LOX) and also, if confirmed, elucidation of the role of 5-LOX in cocaine's effects would bring attention to a possible role for 5-LOX gene polymorphism in drug abuse in general. The concept we propose is highly innovative and no significant prior work is available to support it. We believe that with limited funding we will be in a position to verify the key components of our concept and to obtain the necessary data to initiate more complex future translational studies.

描述（由申请人提供）：阐明在暴露于滥用药物的细胞反应研究中尚未广泛研究的过程的作用，可能会发现治疗成瘾的新治疗靶点。我们建议测试我们的创新概念的关键组成部分，即炎症酶，即，5-脂氧合酶（5-LOX）影响可卡因行为敏化中涉及的生物化学和结构适应。对拟议项目的概念化很重要的是我们偶然的初步观察，可卡因的反应（即，行为敏化）在对照和5-LOX缺陷（敲除）小鼠之间存在差异。行为敏感化的神经适应性变化与成瘾行为有关。谷氨酸受体介导的神经可塑性，包括AMPA谷氨酸受体亚单位GluR 1的磷酸化和表面表达，是这些变化之一。最近发表的数据和我们的初步结果表明，GluR 1磷酸化可以增加5-LOX缺陷/抑制。因此，我们假设5-LOX抑制/缺乏将促进可卡因诱导的行为敏化，并且这将伴随着可卡因处理相关的GluR 1磷酸化和表面表达增加的增强。在AIM 1中，我们将使用药理学5-LOX抑制（MK-886处理）和5-LOX缺陷转基因（敲除）小鼠，研究5-LOX抑制/缺陷对可卡因诱导的GluR 1磷酸化和GluR 1表面表达变化的影响。将在单次可卡因注射后的不同时间在脑桥核（NAc）和前额叶皮层（PFC）中进行分析（时程研究）。AIM 2将测试药理学5- LOX抑制和5-LOX敲除是否改变行为可卡因致敏的发展阶段，而AIM 3将测试药理学5-LOX抑制和5-LOX敲除如何影响行为和分子（即，GluR 1磷酸化和表面表达）的反应。证明5-LOX参与成瘾机制将指向一个未探索的假定治疗靶点（例如，影响5-LOX的药物），并将引起人们对5-LOX基因多态性在药物滥用中的可能作用的关注。需要高风险、概念上有创意和创新的项目，以大大加快药物滥用和成瘾研究的进展。该提案旨在测试创新概念的关键组成部分，即炎症酶，即，5-脂氧合酶（5-LOX）影响可卡因行为敏化中涉及的生物化学和结构适应。证明5-LOX参与成瘾机制将指向一个新的和未探索的假定治疗靶点（例如，影响5-LOX的药物），而且，如果得到证实，5-LOX在可卡因作用中的作用的阐明将引起人们对5-LOX基因多态性在药物滥用中的可能作用的关注。我们提出的概念是高度创新的，没有重要的前期工作可以支持它。我们相信，有限的资金，我们将能够验证我们的概念的关键组成部分，并获得必要的数据，以启动更复杂的未来转化研究。