Testing a new strategy to reduce alcohol consumption by pH

测试通过 pH 值减少酒精消耗的新策略

• 批准号: 10303628
• 负责人: INYEONG CHOI
• 金额: $ 18.54万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10303628
• 关键词: Abdominal Pain; Acids; Affect; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Anion Gap; Astrocytes; Attenuated; Bicarbonates; Biological Factors; Blood; Brain; Cell membrane; Centers for Disease Control and Prevention (U.S.); Cerebrospinal Fluid; Cessation of life; Chronic; Complex; Consumption; DSM-IV; Development; Diagnosis; Diet; Down-Regulation; Fasting; Feeding Methods; Foundations; Frequencies; Goals; Grant; Habits; Human; Hyperglycemia; Individual; Industry; Intervention; Ion Channel; Knockout Mice; Lead; Measures; Mediating; Membrane; Mental disorders; Metabolic; Metabolic acidosis; Motivation; Movement; Mus; National Institute on Alcohol Abuse and Alcoholism; Nausea and Vomiting; Nervous system structure; Neuroglia; Neurons; Neurotransmitter Receptor; Nucleus Accumbens; Pattern; Pharmaceutical Preparations; Prevention strategy; Procedures; Property; Proteins; Regulation; Relapse; Reporting; Research; Research Personnel; Rewards; Risk; Role; Sedation procedure; Severities; Structure; Surveys; Synapses; Synaptic Cleft; Synaptic Transmission; Testing; Ventral Tegmental Area; World Health Organization; addiction; alcohol abuse therapy; alcohol reward; alcohol use disorder; base; binge drinker; clinically relevant; drinking; feeding; mesolimbic system; mouse model; novel strategies; overexpression; problem drinker; psychologic; restoration; risk minimization; sobriety

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.

概括 pH是神经系统中的重要生物学因素，它改变了许多人的结构和活动 蛋白质包括神经递质受体，离子通道和突触传递机制。它可能会影响 负责酒精奖励价值或酒精调节特性的电路中的神经元活动，从而 改变饮酒。该项目探讨了减少饮酒的可能性 改变脑pH。我们最近报道说，缺乏pH调节转运蛋白NBCN1失败的敲除小鼠 为了维持神经元的正常pH，导致细胞内pH值降低并减少脑脊液pH。 有趣的是，这些小鼠喝更多的酒精并增加酒精奖励价值的增加。 此外，在长期用酒精和人类饮酒的小鼠中，NBCN1被下调 障碍（AUD）。因此，NBCN1的异常功能不仅会影响饮酒，而且还会影响 由饮酒引起。基于我们以前和初步研究的中心假设是 酒精会导致NBCN1下调，这种下调会减少脑pH，随后增加 饮酒。该项目的目的是获取有关NBCN1介导的pH的作用的更多信息 饮酒中的监管，并为制定ph依赖性策略的基础 减少消耗。实现这一目标对于理解酒精性倾向至关重要 酮症酸中毒（又名）并制定预防策略。又名是暴饮后诱导的代谢性酸中毒 慢性酒精滥用，然后是禁食。它的特征是高酮血症和高阴离子间隙代谢 酸中毒没有明显的高血糖，会导致恶心，呕吐和腹痛。两个具体 目标将设定为实现目标。 AIM 1将检查pH恢复对饮酒增加的影响 NBCN1敲除小鼠的消耗。 pH在减少酒精消耗和NBCN1方面的功效 将研究参与此pH值。然后将通过注射NBCN1使用机械方法 到小鼠大脑，主要是在中左右系统中。 AIM 2将检查pH对小鼠的影响。 我们使用临床相关的酒精喂养程序开发了AKA的小鼠模型。我们将测试 调整系统性pH值是否会削弱AKA以及是否涉及NBCN1。碳酸氢盐将添加到 将测量饮食和又名诱导和严重程度。我们还将检查NBCN1表达和活动 在又名开发期间。此外，NBCN1过表达在中边系统中的影响将是 评估。结果将提供有关pH对酒精消耗的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 依赖p依赖的策略的新研究平台，以减少普通饮酒者的饮酒量 想要少喝酒，而慢性或暴饮暴食者可能会用又名代谢复杂。