CLINICAL TRIAL: NEW MEDICATIONS TO TREAT ALCOHOL DEPENDENCE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 在过去的十年里，关于饮酒行为的神经科学基础的新知识呈爆炸式增长。通过促进γ-氨基丁酸功能和抑制兴奋性氨基酸的作用来调节中脑边缘多巴胺通路的药物应该可靠地减少酒精的奖励作用。托吡酯(一种氨基磺酸取代的果糖衍生物)具有这些特征。为了支持这一概念，我们在一项II型药物临床试验中表明，托吡酯在改善饮酒结果和减少(N=150)酒精依赖者的渴求方面明显优于安慰剂。利用精心控制的人体实验室环境，我们正在使用一套系统的研究，直接评估与托吡酯对酒精依赖者的戒酒作用有关的机械性神经药理学过程。这将有助于更全面地了解酒精行为的神经生物学，并有助于开发更有效的化合物来治疗酒精依赖。因此，该项目的具体目标是：1)确定托吡酯急性效应的剂量关系，以减少与其滥用和成瘾潜力有关的酒精效应；2)确定使用急性有效剂量的托吡酯进行慢性治疗是否能大幅减少与酒精相关的线索诱发的渴望，从而降低治疗复发的可能性；以及3)确定托吡酯与酒精的相互作用是否与神经认知障碍有关。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In the last decade, there has been an explosion of new knowledge of the neuroscientific basis of alcohol-seeking behavior. Medications that modulate mesolimbic dopamine pathways by facilitating gamma-aminobutyric function and inhibiting the action of excitatory amino acids should reliably diminish alcohol's rewarding effects. Topiramate (a sulfamate-substituted fructopyranose derivative) has these characteristics. In support of this concept, we have shown in a phase-II-type medications clinical trial that topiramate is significantly superior to placebo at improving drinking outcomes and decreasing craving among (N = 150) alcohol-dependent individuals. Using the carefully controlled environment of the human laboratory, we are using a set of systematic studies to assess directly the mechanistic neuropharmacological processes that are associated with topiramate's anti-drinking effects in alcohol-dependent individuals. This will provide a more comprehensive understanding of the neurobiology of alcohol-seeking behavior and aid in the development of even more effective compounds for the treatment of alcohol dependence. Thus, the specific aims of the project are to: 1) determine the dose relationship of acute effects of topiramate to reduce alcohol effects related to its abuse and addiction potential, 2) determine whether chronic treatment with an acutely effective dose of topiramate produces substantial reductions in alcohol-related cue-induced craving, thereby decreasing the potential for treatment relapse, and 3) determine whether topiramate interactions with and without alcohol are associated with neurocognitive impairment.