Neuroimmune Interactions in High Alcohol Drinking

描述(申请人提供)：经常饮酒的欲望是酒精中毒的特征。许多研究已经观察到终生饮酒量与对身体的损害之间存在显著的相关性，包括大脑萎缩的程度和酗酒的风险。因此，控制高酒精饮酒是一个重要的问题，需要在所有科学层面上有更多的了解。此应用程序探索新的 增加我们对控制高酒精饮酒的理解的方法。初步数据表明，抗炎抗生素米诺环素(50 mg/kg)在两种已建立的饮酒模式下测试时，可有效减少成年C57BL/6J(B6)小鼠的酒精消耗量。然而，它在青春期B6小鼠中并不有效。这导致了我们的总体假设，即神经免疫细胞和通路在调节高酒精饮酒方面发挥着重要作用。我们设计了两个目标来检验我们的假设。具体目标1将检验功能性小胶质细胞在支持高酒精摄入量方面发挥作用的假设。特殊目的2本质上是翻译的，并将检验这一假设，即四环素饮酒效果的减少代表了基于分子结构特征的独特活动。我们的第一个目标是探索在调节高酒精时对脑小胶质细胞的需求。 使用已建立的动物模型B6小鼠饮酒。这些实验将提供关于小胶质细胞在大脑中的作用的新信息，假设这些小胶质细胞在高酒精摄入的非损伤水平和持续时间下所起的作用。这一结果不仅会影响酒精研究，还会影响奖赏机制和神经胶质生物学的研究。如果像我们预期的那样，这些研究证明了大脑小胶质细胞在酒精消费中的重要性，它们可能会改变关于高酒精饮酒表型背后的机制的教条。与更多地了解是什么控制了高酒精饮酒的需要相称，也需要减轻大量饮酒欲望的药物。第二个目标将探索米诺环素的其他剂量和剂量方案的禁酒特性，以及结构修饰的四环素在我们的黑暗中饮酒(DID)范例中的有效性。作为第一个测试四环素减少酒精消耗效果的研究，建议的后续研究是探索性的，应该会带来机械性质的、直接翻译的和对开发更好的药物重要的信息。总体而言，人们对这项提议的热情相当高。

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.