Probenecid as pharmacotherapy for alcohol use disorder

项目总结 在受控人类酒精实验室范例中测试药物疗法对于识别和 开发预防酒精使用障碍(AUD)的治疗干预措施。因此，对于这项提议，一个 对于未寻求治疗的AUD患者，将采用酒精管理程序，以建立 新药丙磺舒的安全性和耐受性。 这是一项发展/探索性临床试验，旨在测试提出潜在可能性的假设 PAnnexin 1通道与酒精的关系。这项建议的目标是评估安全和 AUD潜在治疗新靶点的耐受性。 促使这项人体实验室研究的前提是基于我们前期工作的直接证据 在AUD的临床前模型中使用丙磺舒。这项工作证明了丙磺舒能够减少酒精含量。 酒精依赖大鼠的饮酒量。在AUD中测试丙磺舒的科学原理是由 丙磺舒作为PAnnexin 1通道抑制剂的已知作用机制及其在酒精诱导中的作用 细胞外腺苷的释放，这一过程是由过量酒精暴露的历史促进的。 在受控的人类酒精实验室环境中，我们将使用行为和神经精神药理学 确定丙磺舒酒精给药安全性和耐受性的方法(目标1)。在我们的 次要目标，我们将检验丙磺舒治疗将减弱酒精的刺激作用的假设 (目标2)和酒精耐受性(目标3)。 在这些目标中，丙磺舒与酒精的有针对性的药理操作将被用来评估 丙磺舒与酒精同时给药的安全性和耐受性。我们包括渴望和主观 作为探索性的偏好措施，目的是为未来更大规模的试验提供信息。这项拟议的研究具有重要意义 因为，使用药理学探针，它将提供对基础知识的迫切需要的洞察 酒精生物行为效应的神经生物学机制及其改善治疗的目标 AUD患者的结果。

PROJECT SUMMARY Testing pharmacotherapies in controlled human alcohol laboratory paradigms is critical for the identification and development of therapeutic interventions to prevent alcohol use disorder (AUD). Thus, for this proposal, an alcohol administration procedure will be adopted in non-treatment-seeking individuals with AUD to establish the safety and tolerability of probenecid as a novel pharmacotherapy. This is a developmental/exploratory clinical trial that aims to test the hypothesis that proposes a potential relationship between the pannexin 1 channel and alcohol. The goal of this proposal is to evaluate the safety and tolerability of potential new therapeutic targets for the treatment of AUD. The premise prompting this human laboratory study is based on the direct evidence from our preliminary work with probenecid in a preclinical model of AUD. This work demonstrated that probenecid is able to reduce alcohol consumption in alcohol-dependent rats. The scientific rationale for testing probenecid in AUD was derived by the well-known mechanism of action of probenecid as a pannexin 1 channel inhibitor, its role in alcohol-induced extracellular adenosine release, and that this process is promoted by a history of exposure to excessive alcohol. In a controlled human alcohol laboratory setting, we will use behavioral and neuropsychopharmacological approaches to establish the safety and tolerability of probenecid administered with alcohol (Aim 1). In our secondary aims, we will test the hypotheses that treatment with probenecid will diminish alcohol's stimulant effect (Aim 2) and alcohol tolerance (Aim 3). In these aims, targeted pharmacological manipulation of probenecid with alcohol will be employed to evaluate the safety and tolerability of probenecid when administered with alcohol. We included craving and subjective preference measures as exploratory aims to inform a future larger trial. The proposed research is significant because, using pharmacological probes, it will provide a much-needed insight into the fundamental neurobiological mechanisms underlying alcohol biobehavioral effects with the goal of improving the therapeutic outcomes for individuals with AUD.