Medication Development for Protracted Abstinence in Alcoholism

描述（由申请人提供）：酒精依赖（AD）是一个主要的公共卫生问题，缺乏可用的治疗方法。开发具有更大效应的新型药物来治疗AD是NIAAA的优先事项。这一竞争延续的目的是确定新的药物来治疗阿尔茨海默病的长期禁欲，同时开发和验证一种筛选潜在药物的转化方法，这将推动该领域的发展。长期戒酒涉及急性酒精戒断后易复发的状态，这是由中枢神经系统的压力和奖励系统失调所驱动的。在之前的资助期内，在开发对药物效应敏感的动物和人类长期戒断模型方面取得了重大进展，并通过阿坎普罗酸、度洛西汀、加巴喷丁、纳曲酮和普瑞巴林的II期和III期临床试验的疗效结果得到了验证。在持续戒断模型开发的下一步（Specific Aim 1-临床前，Specific Aim 3-人类），我们的人类线索反应模型将进一步发展，包括压力诱导的渴望，以更全面地评估药物对持续戒断的疗效。线索和应激诱导恢复的动物模型将在依赖和酗酒动物中得到完善，以更接近于AD的人类状况。作为药物开发的下一步（Specific Aim 2-临床前，Specific Aim 4-人类），我们已经确定了5种药物（阿瑞吡坦，左乙拉西坦，唑尼沙胺，奥卡西平，吡唑嗪），假设它们能使与长期戒断相关的消极情绪状态和渴望相关的失调大脑系统正常化，这些药物将在我们的转化模型中评估潜在的药物功效。为临床前研究选择的其他药物代表了可能用于人体研究的理想靶点的管道。总的假设是，所选择的动物和人类模型将为减少长期戒断复发风险的特定药物的治疗潜力提供有效、可靠和差异化的筛选。来自动物和人体成分的动态反馈，以及临床试验数据的可用性，将促进这些模型的进一步发展。本提案的一个关键方面是提出的来自动物成分和临床成分的动态反馈，这两者都旨在简化信息并为最终的临床使用提供聚合证据。目前的建议提供了一个高级的筛选层，将允许识别治疗阿尔茨海默病和终点可能在临床试验中成功。

DESCRIPTION (provided by applicant): Alcohol dependence (AD) is a major public health problem with a paucity of available treatments. The development of novel drugs with larger effect sizes to treat AD is a NIAAA priority. The purpose of this competing continuation is to identify new medications to treat protracted abstinence in AD while at the same time developing and validating a translational approach to screening potential medications that will move the field forward. Protracted abstinence involves a state of heightened relapse vulnerability following acute alcohol withdrawal that is driven by dysregulation in stress and reward systems in the CNS. In the previous funding period, significant progress was made in developing animal and human models of protracted abstinence with sensitivity to drug effects that were validated by efficacy outcomes in Phase II and III clinical trials of acamprosate, duloxetine, gabapentin, naltrexone and pregabalin. As next steps in model development for protracted abstinence (Specific Aim 1-preclinical, Specific Aim 3-human), our human cue reactivity model will be further developed to include stress-induced craving to more comprehensively assess medication efficacy for protracted abstinence. Animal models of cue- and stress- induced reinstatement will be refined in dependent and binge-drinking animals, to more closely parallel the human condition of AD. As next steps in medication development (Specific Aim 2-preclinical, Specific Aim 4-human) we have identified 5 drugs (aprepitant, levetiracetam, zonisamide, oxcarbazepine, prazosin) hypothesized to normalize the dysregulated brain systems related to the negative emotional states and craving associated with protracted abstinence that will be assessed for potential drug efficacy in our translational models. Additional drugs selected for preclinical studies represent a pipeline of desirable targets that may become available for human studies. The overall hypothesis under test is that animal and human models chosen will provide efficient, reliable and differential screens for the treatment potential of specific drugs for reducing relapse risk in protracted abstinence. Dynamic feedback from the animal and human components, and clinical trial data as it becomes available, will facilitate further development of these models. A critical aspect of the present proposal is the proposed dynamic feedback from the animal component and the clinical component, both of which are designed to streamline information and provide converging evidence for ultimate clinical use. The present proposal provides an advanced tier of screening that will allow identification of treatments for AD and endpoints likely to succeed in clinical trials.