New Medications to Treat Alcohol Dependence

描述(由申请者提供)：在过去的十年里，关于寻求酒精行为的神经科学基础的新知识呈爆炸式增长。简而言之，通过促进伽马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-吡喃糖衍生物)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，我们提交了一份修订后的申请，其中包含一系列系统研究，以直接评估与托吡酯的戒酒效果相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。我们假设托吡酯将减少酒精诱导的渴望、奖励和欣快感；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导的渴望，从而降低治疗复发的可能性。我们假设，长期服用托吡酯将使酒精相关的感觉线索产生的酒精渴望脱敏(减少)；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。包括我们在内的临床研究表明，使用托吡酯可能与神经认知效应有关，如注意力丧失和记忆障碍。在我们自己的研究中，这些影响是轻微的，与治疗依从性的降低无关。由于酒精产生神经认知障碍的能力可能是通过与托吡酯相似的离子机制来调节的，拟议的人体实验室环境为我们提供了一个独特的机会，让我们能够更清楚地描述托吡酯在酒精存在和不存在时的神经认知影响。 这项研究支持NIAAA的目标，即开发治疗酒精中毒的有效药物，并 了解这种疾病的基本基础。

DESCRIPTION (provided by applicant): In the last decade, there has been an explosion of new knowledge of the neuroscientific basis of alcohol-seeking behavior. Briefly, medications that modulate mesolimbic dopamine pathways by facilitating gamma amino butyric function and inhibiting the action of excitatory amino acids should reliably diminish alcohol's rewarding effects. Topiramate (a sulfamate-substituted fructo-pyranose 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 submitting a revised application containing a set of systematic studies to assess directly the mechanistic neuropharmacological processes that are associated with topiramate's anti-drinking effects. 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. We hypothesize that topiramate will reduce alcohol-induced craving, reward, and euphoria; 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. We hypothesize that chronic topiramate administration will desensitize (reduce) alcohol craving produced by alcohol-related sensory cues; and 3) determine whether topiramate interactions with and without alcohol are associated with neurocognitive impairment. Clinical studies including ours have suggested that topiramate use may be associated with neurocognitive effects such as loss of concentration and memory impairment. In our own study, these effects were mild and not associated with reduced treatment compliance. Since alcohol's ability to produce neurocognitive impairment may be mediated through similar ionic mechanisms to that of topiramate, the proposed human laboratory setting affords us the unique opportunity to more clearly delineate topiramate's neurocognitive effects in both the presence and absence of alcohol. This study supports NIAAA's goal to develop effective medications for treating alcoholism and to understand the basic underpinnings of the disease.