Testing a new strategy to reduce alcohol consumption by pH

总结 pH值是神经系统中的重要生物因素，在神经系统中，它改变了许多神经元的结构和活性。 蛋白质包括神经递质受体、离子通道和突触传递机制。可能会影响 负责酒精奖励值或酒精调节特性的回路中的神经元活动， 改变酒精消费。该项目探讨了减少酒精消费的可能性， 我们最近报道，缺乏pH调节转运蛋白NBCn1的基因敲除小鼠， 维持神经元内的正常pH值，导致细胞内pH值降低和脑脊液pH值降低。 有趣的是，这些小鼠喝更多的酒，并增加了酒精的奖励价值。 此外，NBCn1在长期饮酒的小鼠和饮酒的人类中下调 疾病（AUD）。因此，NBCn1的功能异常不仅影响酒精摄入，而且还 由酒精消费引起的。基于我们先前和初步研究的中心假设是， 酒精导致NBCn1下调，这种下调降低了脑pH值， 酒精消费。该项目的目标是获得更多关于NBCn1介导的pH作用的信息。 调节酒精消费，并为制定pH依赖性策略提供基础， 减少消费。实现这一目标对于理解酗酒倾向将是重要的 酮症酸中毒（AKA）和制定预防策略。AKA是一种代谢性酸中毒， 长期酗酒然后禁食其特征是高酮血症和高阴离子间隙代谢 无明显高血糖的酸中毒，并引起恶心、呕吐和腹痛。两个具体 目标是为了实现目标而设定的。目的1将检查pH恢复对酒精增加的影响 NBCn1基因敲除小鼠的消耗量。pH值在减少酒精消耗和NBCn1方面的功效 将研究这种pH效应的参与。然后将使用一种机械方法， 主要是在中脑边缘系统。目的2研究pH对小鼠AKA的影响。 我们使用临床相关的酒精喂养程序开发了AKA小鼠模型。我们将测试 调节全身pH是否减弱AKA以及NBCn1是否参与。将添加Bicycle， 将测量饮食和AKA诱导和严重程度。我们还将研究NBCn1的表达和活性， 在AKA开发过程中。此外，NBCn1过表达在中脑边缘系统中的作用将被证实。 评估。结果将提供有关pH值对酒精消费影响的前所未有的信息， NBCn1参与产生这些影响。我们预计，该项目将导致建立一个 一个新的研究平台，用于pH依赖性策略，以减少普通饮酒者的酒精消费， 想要少喝酒的人，以及慢性或酗酒的人，他们可能患有AKA代谢并发症。

Summary pH is an important biological factor in the nervous system, where it alters the structure and activity of numerous proteins including neurotransmitter receptors, ion channels, and synaptic transmission machinery. It may affect neuronal activities in the circuits responsible for alcohol reward value or alcohol modulatory properties, thereby changing alcohol consumption. This project explores the possibility of reducing alcohol consumption by changing brain pH. We recently reported that knockout mice lacking the pH-regulating transporter NBCn1 fail to maintain normal pH in neurons, causing decreased intracellular pH and decreased cerebrospinal fluid pH. Interestingly, these mice drink more alcohol and develop an increase in the reward value of alcohol. Furthermore, NBCn1 is downregulated in mice chronically fed with alcohol and humans with alcohol use disorder (AUD). Thus, abnormal function in NBCn1 not only influences alcohol consumption, but is also induced by alcohol consumption. The central hypothesis based on our previous and preliminary studies is that alcohol causes NBCn1 downregulation and this downregulation reduces brain pH and subsequently increases alcohol consumption. The goal of the project is to obtain more information on the role of NBCn1-mediated pH regulation in alcohol consumption and to provide a foundation for development of pH-dependent strategies to reduce consumption. Achieving this goal will be important for understanding propensity toward alcoholic ketoacidosis (AKA) and developing a prevention strategy. AKA is a metabolic acidosis induced after binge or chronic alcohol abuse followed by fasting. It is characterized by hyperketonemia and high anion gap metabolic acidosis without significant hyperglycemia, and causes nausea, vomiting, and abdominal pain. Two specific aims are set to achieve the goal. Aim 1 will examine the effects of pH restoration on increased alcohol consumption in NBCn1 knockout mice. The efficacy of pH in reducing alcohol consumption and NBCn1 involvement in this pH effect will be investigated. A mechanistic approach will then be used by injecting NBCn1 to the mouse brain, primarily in the mesolimbic system. Aim 2 will examine the effects of pH on AKA in mice. We developed a mouse model of AKA using a clinically relevant alcohol feeding procedure. We will test whether adjusting systemic pH attenuates AKA and whether NBCn1 is involved. Bicarbonate will be added to the diet and AKA induction and severity will be measured. We will also examine NBCn1 expression and activity during AKA development. In addition, the effects of NBCn1 overexpression in the mesolimbic system will be assessed. The results will provide unprecedented information about the pH effects on alcohol consumption and NBCn1 involvement in producing these effects. We anticipate that the project will lead to the establishment of a new research platform for pH-dependent strategies to reduce alcohol consumption for ordinary drinkers who want to drink less, and chronic or binge drinkers who could be metabolically complicated with AKA.