Neuroimmune Interactions in High Alcohol Drinking

大量饮酒时的神经免疫相互作用

• 批准号: 8728700
• 负责人: SUSAN E. BERGESON
• 金额: $ 21.06万
• 依托单位: TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8728700
• 关键词: Adolescent; Adult; Affect; Alcohol consumption; Alcoholism; Alcohols; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antibiotics; Antibodies; Apoptosis; Applications Grants; Behavioral; Biology; Blood; Blood - brain barrier anatomy; Brain; Build-it; CD11b Antigens; Cells; Chemicals; Consumption; Data; Development; Dose; Ethanol; FDA approved; Future; Generations; Goals; ITGAM gene; Injection of therapeutic agent; Intoxication; Lead; Life; Macrophage-1 Antigen; Measures; Mediating; Microglia; Minocycline; Modification; Monoclonal Antibodies; Mus; Nature; Pathway interactions; Peripheral; Pharmaceutical Preparations; Phenotype; Play; Population; Property; Proteins; Publishing; Rattus; Reagent; Regimen; Rewards; Ribosomes; Risk; Role; Signal Pathway; Signaling Molecule; Small Business Innovation Research Grant; Structure; System; Testing; Tetracyclines; Translational Research; alcohol research; alcohol testing; base; cerebral atrophy; chemical conjugate; drinking; efficacy testing; follow-up; improved; innovation; insight; intraperitoneal; macrophage; monocyte; novel; public health relevance; research study; Adolescent; Adult; Affect; Alcohol consumption; Alcoholism; Alcohols; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antibiotics; Antibodies; Apoptosis; Applications Grants; Behavioral; Biology; Blood; Blood - brain barrier anatomy; Brain; Build-it; CD11b Antigens; Cells; Chemicals; Consumption; Data; Development; Dose; Ethanol; FDA approved; Future; Generations; Goals; ITGAM gene; Injection of therapeutic agent; Intoxication; Lead; Life; Macrophage-1 Antigen; Measures; Mediating; Microglia; Minocycline; Modification; Monoclonal Antibodies; Mus; Nature; Pathway interactions; Peripheral; Pharmaceutical Preparations; Phenotype; Play; Population; Property; Proteins; Publishing; Rattus; Reagent; Regimen; Rewards; Ribosomes; Risk; Role; Signal Pathway; Signaling Molecule; Small Business Innovation Research Grant; Structure; System; Testing; Tetracyclines; Translational Research; alcohol research; alcohol testing; base; cerebral atrophy; chemical conjugate; drinking; efficacy testing; follow-up; improved; innovation; insight; intraperitoneal; macrophage; monocyte; novel; public health relevance; research study

DESCRIPTION (provided by applicant): The desire to frequently drink large quantities of alcohol is a hallmark of alcoholism. Numerous studies have observed a significant correlation between life-long quantity of alcohol consumed and detriment to the body, including the degree of brain atrophy and risk for alcoholism. Thus, control of high alcohol drinking is an important problem that requires greater understanding at all scientific levels. This application explores new ways to increase our understanding of what controls high alcohol drinking. Preliminary data indicates that the anti-inflammatory antibiotic minocycline (50 mg/kg) is effective in reducing alcohol consumption in adult C57BL/6J (B6) mice when tested in two established drinking paradigms. However, it was not effective in adolescent B6 mice. This has led to our overarching hypothesis that neuroimmune cells and pathways have a significant role in mediating high alcohol drinking. We have devised 2 aims to test our hypothesis. Specific Aim 1 will test the hypothesis that functional microglia play a role in supporting high alcohol consumption. Specific Aim 2 is translational in nature and will test the hypothesis that the diminution of drinking effec of tetracyclines represents a unique activity based on specific structural features of the molecule. Our first aim will explore the requirement for brain microglial in mediating high alcohol drinking using an established animal model, the B6 mouse. These experiments will provide new information on the role of microglia in the brain under presumably non-injurious levels and durations of high alcohol intake. The results will impact not only alcohol research, but the study of reward mechanisms and glial biology. If, as we expect, these studies demonstrate the significance of brain microglia in alcohol consumption, they will potentially change the dogma regarding mechanisms that underlie a high alcohol drinking phenotype. Commensurate with the need for a greater understanding of what controls high alcohol drinking, medications that mitigate the desire to drink large quantities of alcohol are also needed. The second aim will explore the anti-drinking properties of other doses and dosing regimens of minocycline, as well as the efficacy of structurally-modified tetracyclines in our drinking-in-the-dark (DID) paradigm. As the first to test the efficacy of tetracyclines for the reduction of alcohol consumption, the follow-up studies proposed are exploratory and should lead to information that is mechanistic in nature, directly translational and important for the development of better medications. Overall, enthusiasm for the proposal was fairly high.

描述（由申请人提供）：经常喝大量酒精的愿望是酒精中毒的标志。大量研究观察到终生消耗的酒精和损害人体之间存在显着相关性，包括脑部萎缩程度和酗酒的风险。因此，控制大量饮酒是一个重要的问题，需要在所有科学水平上有更多的了解。此应用程序探讨了新的 增加我们对控制高酒精饮酒的理解的方法。初步数据表明，在两种既定的饮酒范式中测试时，抗炎抗生素米诺环素（50 mg/kg）可有效减少成人C57BL/6J（B6）小鼠的饮酒量。但是，它在青春期B6小鼠中无效。这导致了我们的总体假设，即神经免疫细胞和途径在介导高饮酒中具有重要作用。我们已经设计了2个旨在检验我们的假设的旨在。具体目标1将检验以下假设：功能性小胶质细胞在支持高酒精消耗中起作用。特定目标2本质上是翻译的，将检验以下假设：四环素饮用效率的减少代表基于分子的特定结构特征的独特活动。我们的第一个目标将探讨介导高酒精的脑小胶质细胞的需求 使用已建立的动物模型B6小鼠喝酒。这些实验将提供有关小胶质细胞在大脑中的作用的新信息。结果不仅会影响酒精研究，而且会影响奖励机制和神经胶质生物学的研究。如果正如我们所期望的那样，这些研究表明了脑小胶质细胞在饮酒中的重要性，它们将有可能改变有关高饮酒表型基础机制的教条。还需要更多地了解控制高酒精的方法，还需要减轻喝大量酒精的渴望的药物。第二个目标将探索其他剂量和米诺环素的剂量方案的抗饮科，以及在我们的黑暗中饮酒（DID）范式中结构改性的四环素的疗效。作为第一个测试四环素减少酒精消耗功效的疗效的人，提出的后续研究是探索性的，应该导致信息本质上是机械性的，直接转化，对于开发更好的药物。 总体而言，对该提案的热情相当高。