CLINICAL TRIAL: NEW MEDICATIONS TO TREAT ALCOHOL DEPENDENCE

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 在过去的十年里，关于酒精寻求行为的神经科学基础的新知识激增。 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）。 利用人类实验室精心控制的环境，我们正在使用一系列系统研究来直接评估与托吡酯对酒精依赖个体的抗饮酒作用相关的神经药理学机制过程。 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）确定托吡酯的急性作用的剂量关系，以减少与其滥用和成瘾潜力相关的酒精作用，2）确定用急性有效剂量的托吡酯进行慢性治疗是否产生与酒精相关的线索诱导的渴望的显著减少，从而降低治疗复发的潜力，和3）确定托吡酯与酒精或不与酒精的相互作用是否与神经认知损害相关。

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.