Lacosamide effects on alcohol self administration and craving in heavy drinkers

项目总结 美国有1600多万成年人患有酒精使用障碍(AUD)，据估计 澳元每年的经济负担为2490亿美元。大约88,000名美国人死于与酒精有关的疾病 每年的死因；未经治疗的澳门氏症是美国第四大可预防的死因。四种药物 到目前为止已经被FDA批准用于治疗AUD，但这些药物都没有被证明是 对患有这种疾病的不同人群有效。更有效地治疗成瘾有 成为国家优先事项，加速澳大利亚的药物开发是NIAAA的优先事项之一。这个 目前的提案旨在通过探索以下方面的潜力来响应加快药物开发的呼吁 一种新的抗惊厥药物，乳糖胺，作为治疗AUD的候选药物。这种药物，它是 FDA批准用于治疗癫痫障碍，具有独特的药理作用，包括 增强慢钠通道失活和抑制溃散素反应介质蛋白-2 (CRMP-2)。伏隔核内CRMP-2基因敲除的小鼠的酒精摄入量为 与对照组动物的水平相比有所下降。在啮齿动物研究中，乳糖胺给药产生了 减少过量饮酒，并在实验中诱导CRMP-2表达减少 蛋白。这些发现暗示CRMP-2在酒精消费的调节中发挥作用。没有一个 FDA批准的AUD药物或通常用于标签外治疗AUD的药物针对的是CRMP-2 途径，使乳糖胺成为AUD药物开发的一种有前途的化合物。这项研究的目的是： 1)测试乳糖胺对酒精自我给药和渴求的影响，2)评估乳糖胺的影响 关于酒精启动饮料的增强兴奋作用，3)测试5天的乳糖胺效果 给药对认知功能的影响，以及4)测试乳糖胺对饮酒和渴求的影响 在5天的暴露期间。5天的乳糖胺(300毫克)或安慰剂的效果将在 使用酒精自我给药方法的人体实验室。在这个受试者内部交叉设计中， 大量饮酒的人(N=24)在喝完之前将被随机分成不同的摄入顺序(乳糖胺或安慰剂 两次酒精自我给药试验。受试者将收到一杯酒精饮料，并将获得8 2小时以上的酒精饮料。我们预计受试者在饮酒期间会减少饮酒量 接受乳糖胺的自我给药试验与接受安慰剂的比较。意义重大 乳糖胺引起的自我给药量的减少将被认为是一种 这表明这种药物可能有作为AUD药物的价值。这项研究可能会为第二阶段提供理论依据。 在寻求治疗的AUD人群中测试乳糖胺的临床研究。这些结果也可能有助于 推动进一步的临床前研究CRMP-2在调节两种饮酒中的作用 和寻酒行为。

PROJECT SUMMARY More than 16 million adults suffer from Alcohol Use Disorder (AUD) in the United States and the estimated annual economic burden of AUD is $249 billion. Approximately 88,000 Americans die from alcohol-related causes each year; untreated AUD is the fourth most preventable cause of death in the US. Four medications have been approved by the FDA to date for treating AUD, but none of these medications have proven to be effective across the heterogeneous groups of people with this disorder. Treating addiction more effectively has become a national priority and accelerating drug development for AUD is one of the priorities for NIAAA. The present proposal is intended to answer this call for accelerating drug development by exploring the potential of a novel anticonvulsant, lacosamide, as a candidate medication for the treatment of AUD. This drug, which is FDA-approved for the treatment of seizure disorders, has unique pharmacological actions that include enhancement of slow sodium channel inactivation and inhibition of collapsin response mediator protein-2 (CRMP-2). Alcohol consumption in mice that had knockdown of CRMP-2 within the nucleus accumbens was decreased from levels seen in control animals. In rodent studies, lacosamide administration has produced reductions in `excessive' drinking and has experimentally-induced decreased expression of the CRMP-2 protein. These findings implicate CRMP-2 as playing a role in the regulation of alcohol consumption. None of the FDA-approved AUD medications or medications commonly used off-label to treat AUD target this CRMP-2 pathway, making lacosamide a promising compound for AUD drug development. The aims of this study are to: 1) test the effects of lacosamide on alcohol self-administration and craving, 2) assess the effects of lacosamide on the reinforcing stimulant effects of a priming drink of alcohol, 3) test the effects of 5 days of lacosamide administration on cognitive function, and 4) test the effects of lacosamide on alcohol consumption and craving during a 5-day period of exposure. The effects of 5-days of lacosamide (300mg) or placebo will be evaluated in a human laboratory using an alcohol self-administration methodology. In this within-subjects crossover design, heavy drinkers (N=24) will be randomized to the order of exposure (lacosamide or placebo) prior to completing two alcohol self-administration trials. Subjects will receive a priming drink of alcohol and will have access to 8 alcoholic drinks over a 2-hour period. We anticipate that subjects will consume less alcohol during an alcohol self-administration trial when receiving lacosamide compared to when they are receiving placebo. Significant lacosamide-induced reductions in the quantity of alcohol self-administered will be considered to be an indication that this drug may have value as an AUD medication. This study may provide a rationale for phase II clinical studies testing lacosamide with a treatment-seeking AUD population. These results may also help to spur further pre-clinical investigation into the role played by CRMP-2 in regulating both alcohol consumption and alcohol seeking behaviors.