The Role of the Neurokinin-1 Receptor and NF kappa B in alcohol-induced behavior

酒精中毒是一种严重的疾病，影响着数百万美国人的生活，但成功的治疗 难以捉摸一些药物目前已被批准用于治疗，但它们缺乏广泛的疗效， 这在某些情况下是由于药物遗传学相互作用。未来的研究必须继续确定 药物开发的潜在目标，并解决影响对 药物治疗.大脑压力系统可以影响酒精消费和酒精寻求在这两个 人类和动物模型。在啮齿动物中，暴露于压力导致P物质（SP）的释放， 激活其神经激肽1受体（NK 1 R），NK 1 R阻断抑制酒精寻求， 消费NK 1 R拮抗剂的功效在酒精偏好大鼠中增强，我们已经证明了这一点。 有一个上调的NK 1 R系统一个悬而未决的问题是，这种NK 1 R系统超敏反应是否 是酒精中毒的诱发因素，由长期酒精暴露引起，或两者兼而有之。这项建议会 通过确定长期饮酒后NK 1 R表达是否增加来直接解决这个问题 暴露，和rf这与增加的酒精寻求行为，是敏感的NK 1 R拮抗作用。 这些实验的结果将对临床治疗产生重大影响，因为它们将确定， NK 1 R拮抗剂对大多数有长期滥用史的酗酒者是有益的，或者如果NK 1 R拮抗剂的疗效不佳， 该药物将仅限于表现出NK 1 R超敏反应的部分人群。 虽然NK 1 R在酒精寻求和消费中的作用有很好的记录，但对NK 1 R的了解较少。 潜在的细胞内信号机制。NK 1 R诱导核转录因子的活性 因子κ B（NF κ B），作为多种基因的转录调节因子。这 转录因子在啮齿动物中被应激源和酒精激活，因此是一个有趣的靶点， 影响NK 1 R介导的应激-酒精相互作用。在这里概述的研究中，我将首先描述 酒精暴露后NK 1 R和NFkB激活之间的关系，并确定下游 这种相互作用导致的行为效应，如戒断焦虑和酒精奖励。NK 1 R和 NFkB也调节吗啡诱导的行为，这表明靶向这些系统的药物可能是 对酒精、鸦片和多种物质滥用的有效治疗。这具有重要的治疗意义， 因为多种物质滥用在药物依赖者中非常普遍。 作为过渡补助金，培训是K99阶段的主要组成部分。除了研究 为了实现上述目标，这项建议旨在促进我从指导博士后的过渡， 研究员到独立的，终身制的研究人员在一个学术机构。在指导期间， 第一阶段，我学习了分子生物学的新技术，包括电迁移率变化分析，这将提高 我在多个层面上回答科学问题的能力在这一重要的科学训练之外， 在项目管理、学生指导、资助写作和科学交流方面的经验。的 该赠款的指导阶段非常成功，导致出版了几份同行评审的 手稿，提供有益的培训，并帮助我建立-为未来的成功。的主要目标 导师的一年是获得终身助理教授的位置，这是完成。在 2014年1月，1将开始在生理学系担任助理教授， 格鲁吉亚大学的药理学。

Alcoholism is a serious condition that affects the lives of millions of Americans, but successful treatment has been elusive. Some medications are currently approved for treatment, but they lack widespread efficacy, which in some cases is due to pharmacogenetic interactions. Future research must continue to identify potential targets for medications development, and address factors that influence response to pharmacotherapy. Brain stress systems can influence alcohol consumption and alcohol seeking in both humans and animal models. In rodents, exposure to stress results in the release of substance P (SP) and activation of its neurokinin 1 receptor {NK1R), and NK1R blockade suppresses alcohol seeking and consumption. The efficacy of NK1R antagonists is enhanced in alcohol preferring rats, which we have shown to have an upregulated NK1R system. One outstanding question is whether this NK1R system hypersensitivity is a predisposing factor for alcoholism, results from chronic alcohol exposure, or both. This proposal will directly address this question by determining if NK1R expression is increased following chronic alcohol exposure, and rf this associates with increased alcohol seeking behavior that is sensitive to NK1R antagonism. The findings of these experiments will have a significant impact on clinical treatment, as they will identify if NK1R antagonism would be beneficial for most alcoholics with long term history of abuse, or if the efficacy of this drug would be confined to a portion of the population that exhibits NK1R hypersensitivity. While the role of NK1R in alcohol seeking and consumption is well documented, less is known about underlying intracellular signaling mechanisms. The NK1R induces the activity of the transcription factor Nuclear Factor kappa B (NFkB), which serves as a transcriptional modulator for a wide range of genes. This transcription factor is activated in rodents both by stressors and alcohol, and therefore is an intriguing target for influencing NK1 R-mediated stress-alcohol interactions. In the studies outlined here, I will first describe the relationship between NK1R and NFkB activation following alcohol exposure, and determine the downstream behavioral effects that result from this interaction, such as withdrawal anxiety and alcohol reward. NK1R and NFkB also regulate morphine-induced behaviors, suggesting that agents targeting these systems could be useful treatments for alcohol, opiate, and polysubstance abuse. This has important therapeutic implications, since polysubstance abuse is very common in drug dependent individuals. As a transition grant, training was a major component of the K99 phase. In addition to the research aims described above, this proposal was designed to facilitate my transition from mentored post-doctoral research fellow to independent, tenure track research faculty at an academic institution. During the mentored phase, 1 learned new techniques in molecular biology including electromobility shift assays, which will enhance my ability to answer scientific questions on multiple levels. Outside of this important scientific training, I gained experience in project management, student mentorship, grant writing, and scientific communication. The mentored phase of this grant was highly successful, resulting in the publication of several peer-reviewed manuscripts, providing beneficial training, and helping to set me up -for future success. A primary goal of the mentored year was to obtain a tenure track assistant professor position, and this was accomplished. In January 2014,1 will begin a position as an Assistant Professor in the Department of Physiology and Pharmacology at the University of Georgia.