New Medications to Treat Alcohol Dependence

描述（由申请人提供）：在过去的十年中，有一个新的知识爆炸的神经科学基础的酒精寻求行为。简而言之，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吡喃果糖衍生物）具有这些特征。为了支持这一观点，我们在一项II期药物临床试验中发现托吡酯在改善酒精依赖者（N = 150）的饮酒结果和减少饮酒渴望方面明显优于安慰剂（上级）。 使用人类实验室的仔细控制的环境，我们正在提交一份修订的申请，其中包含一组系统的研究，以直接评估与托吡酯的抗饮酒作用相关的机制神经药理学过程。 这将提供对酒精寻求行为的神经生物学的更全面的理解，并有助于开发更有效的治疗酒精依赖的化合物。 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相关的酒精效应。我们假设托吡酯会减少酒精诱导的渴求、奖赏和欣快; 2）确定使用急性有效剂量的托吡酯进行长期治疗是否会显著减少酒精相关线索诱导的渴求，从而降低治疗复发的可能性。我们假设，长期托吡酯管理将脱敏（减少）酒精相关的感官线索产生的酒精渴望;和3）确定是否托吡酯与酒精和不与神经认知障碍的相互作用。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，与治疗依从性降低无关。由于酒精的能力，产生神经认知障碍可能是通过类似的离子机制托吡酯介导的，拟议的人类实验室设置为我们提供了独特的机会，以更清楚地描绘托吡酯的神经认知作用，在存在和不存在酒精。 这项研究支持NIAAA的目标，即开发治疗酒精中毒的有效药物， 了解疾病的基本原理。

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.