A Novel Pharmacotherapy for Alcoholism: Evaluation of Reward, Aversion, Compulsivity, Withdrawal & Reinstatement

一种治疗酒精中毒的新型药物疗法：奖励、厌恶、强迫、戒断的评估

基本信息

批准号：
10523383
负责人：
ABRAHAM A PALMER
金额：
$ 8.97万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-05 至 2023-04-30
项目状态：
已结题

项目摘要

Project summary Alcohol use disorder (AUD) is an extremely common and serious condition that is associated with numerous somatic diseases, early mortality, personal and interpersonal hardship, and direct and indirect economic costs to society. Although there are several effective pharmacological treatments for AUD, their limited effectiveness contributes to the ongoing burden of AUD on society. A major impediment to better treatments for AUD is the lack of understanding surrounding fundamental molecular mechanisms associated with alcohol’s acute and chronic effects on the brain. Ongoing work in our lab has demonstrated that genetic and pharmacological manipulation of the enzyme Glyoxalase 1 (GLO1) can reduce ethanol drinking in mice and rats. GLO1 is an evolutionarily conserved enzyme that metabolizes methylglyoxal (MG), which is a non- enzymatic side product of glycolysis and is thus present in all animal cells. Transgenic overexpression of GLO1 decreases MG (GLO1’s substrate) in the brain. Reciprocally, direct administration of MG, genetic knockdown of Glo1 or pharmacological inhibition of GLO1 increase MG concentrations in the brain. We showed that MG is a selective agonist at GABA-A receptors. More recently, we discovered that GLO1 and MG modulate ethanol drinking behavior, which we hypothesize is due to MG’s effects at GABA-A receptors. In this supplement request, we are extending on the studies funded by the parent R01 to pursue a new line of experimentation. Specifically, we are exploring the possibility that ethanol may be directly converted into MG on a timescale that is consistent with the acute effects of ethanol. This exciting possibility raises the tantalizing possibility that some of ethanol’s effects on GABA-A receptors could be due to MG (rather than ethanol), directly influencing GABA-A signaling. We will test this possibility by measuring MG levels at various time points following administration of ethanol. In subsequent experiments, we will explore the possibility that ethanol is directly converted into MG (as opposed to altering MG in an indirect manner) by administering stable-labeled ethanol in which the hydrogen atoms have been replaced with deuterium. We will use mass- spec to assess MG levels, which will allow us to distinguish unlabeled MG from MG labeled with one or more deuterium atoms. These studies have the potential to greatly enhance our mechanistic understanding of ethanol’s actions. The mentoring plan is also described; the primary goal is to prepare the trainee to enter a Ph.D. program.

项目摘要酒精使用障碍（AUD）是一种非常普遍且严重的疾病许多躯体疾病，早期死亡率，个人和人际交往困难以及直接和间接社会的经济成本。尽管AUD有几种有效的药物治疗有限的有效性有助于AUD对社会的持续燃烧。更好的障碍 AUD的治疗方法是缺乏围绕基本分子机制的理解酒精对大脑的急性和慢性影响。我们实验室正在进行的工作证明了遗传酶1（GLO1）的药物操纵可以减少小鼠的乙醇饮用和老鼠。 GLO1是一种进化保守的酶，代谢甲基甘氨酸（MG），这是一种非 - 糖酵解的酶促产物，因此存在于所有动物细胞中。 GLO1的转基因过表达减少大脑中的Mg（GLO1底物）。相互直接施用Mg，遗传敲低 GLO1或GLO1的药理抑制增加了大脑中的Mg浓度。我们表明MG是 GABA-A接收器的选择性激动剂。最近，我们发现GLO1和MG调节乙醇我们假设的饮酒行为是由于MG对GABA-A受体的影响。在此补充请求中，我们正在扩展父母R01资助的研究新的实验线。具体而言，我们正在探索乙醇可以直接转化的可能性在与乙醇的急性作用一致的时间尺度上进入MG。这种令人兴奋的可能性提高了诱人的可能性是，乙醇对GABA-A接收器的某些影响可能是由于MG造成的（而不是乙醇），直接影响GABA-A信号传导。我们将通过测量各种Mg水平来测试这种可能性给药乙醇后的时间点。在随后的实验中，我们将探讨通过施用乙醇直接转换为Mg（与间接方式更改MG相反）稳定标记的乙醇，其中氢原子已被氘代替。我们将使用质量 - 评估MG水平的规格，这将使我们能够区分一个或多个标记的MG未标记的MG 氘原子。这些研究有可能增强我们对乙醇的行为。还描述了心理计划；主要目标是准备学员进入博士程序。