Neuroscience-informed Treatment Development for Adolescent Alcohol Use Disorders

项目概要/摘要 相关性：青少年饮酒是有问题的，并具有长期的负面认知和社会影响。 后果在这个早期阶段减少物质的使用可能会产生重大的长期效益， 心理社会结果，并阻止发展到习惯性使用;然而，努力预防或减少酒精 在青春期使用只有适度的效果，药物治疗研究集中在 青少年很少饮酒。评价替代和更有效的治疗方法， 青少年酗酒者是有理由的。 描述：N-乙酰半胱氨酸（NAC）是一种非处方抗氧化剂补充剂， 这些特性在治疗青少年大麻依赖方面显示出了希望。临床前研究结果 这表明NAC通过恢复被成瘾破坏的谷氨酸体内平衡起作用，这一发现被复制 滥用多种药物迄今为止，还没有发表的临床试验研究了NAC对 饮酒这是令人惊讶的，考虑到先前在大麻依赖青少年中有希望的NAC发现， 以及这种非处方补充剂的安全性、耐受性和可负担性。此K23应用程序建议 研究NAC对酒精提示反应、青少年神经系统和饮酒的影响。 在一项随机、双盲、安慰剂对照的受试者内交叉研究中观察行为。在 平衡顺序，40名参与者将接受为期10天的NAC 1200 mg，每日两次， 随后10天疗程的匹配安慰剂，每日两次，间隔洗脱期。人类实验室 将在基线时和每个疗程后进行影像学检查， NAC对多巴胺能系统和酒精提示反应性的影响。功能磁共振成像 功能性磁共振成像（fMRI）将检查酒精反应性，磁共振光谱将检查谷氨酸水平， 在相同的时间间隔内，NAC与安慰剂治疗后的前扣带回。 目的：本建议为申请人提供最佳培训，以获得物质使用障碍方面的专业知识 临床试验研究，青少年物质使用者的循证治疗，以及磁共振 进行独立的、以患者为导向的发展研究所需的光谱学方法和分析 与青少年药物使用和治疗相关的神经机制。这项研究的结果将 帮助确定NAC是否可以成为青少年药物使用者的有希望的治疗方法，这一研究领域 与美国国立卫生研究院为青少年确定和产生新物质使用治疗方法的倡议一致 (see PA-15-036和PA-15-256）。

PROJECT SUMMARY/ABSTRACT Relevance: Adolescent alcohol use is problematic and has long-term negative cognitive and social consequences. Decreasing substance use at this early stage could have significant long-term benefits to psychosocial outcomes and deter progression to habitual use; however, efforts to prevent or decrease alcohol use during adolescence have only been modestly effective, and pharmacotherapy research focused on adolescent alcohol use has been sparse. Evaluation of alternative and more efficacious treatments for adolescent alcohol users is warranted. Description: N-acetylcysteine (NAC) is an over-the-counter antioxidant supplement with glutamatergic properties that has shown promise in treating marijuana dependence in adolescents. Preclinical findings suggest NAC works through restoring glutamate homeostasis disrupted by addiction, a finding replicated across multiple substances of abuse. No published clinical trials to date have examined the efficacy of NAC on alcohol use. This is surprising, given previous promising NAC findings in marijuana-dependent adolescents and the safety, tolerability, and affordability of this over-the-counter supplement. This K23 application proposes to examine the effects of NAC on alcohol cue reactivity, adolescent glutamatergic systems, and drinking behaviors in a randomized, double-blind, placebo-controlled within-subjects crossover study. In counterbalanced order, 40 participants will receive a 10-day course of NAC 1200 mg twice daily and a subsequent 10-day course of matched placebo twice daily, separated by washout period. Human laboratory and imaging procedures will be conducted at baseline and after each course of medication treatment to clarify NAC's effect on glutamatergic systems and alcohol cue reactivity. Functional magnetic resonance imaging (fMRI) will examine alcohol reactivity and magnetic resonance spectroscopy will examine glutamate levels in the anterior cingulate after NAC versus placebo over the same interval. Aims: This proposal provides optimal training for the applicant to gain expertise in substance use disorder clinical trials research, evidence based treatments for adolescent substance users, and magnetic resonance spectroscopy methods and analysis needed to conduct independent, patient-oriented, developmental research on neural mechanisms associated with adolescent substance use and treatment. Findings from this study will help establish if NAC could be a promising treatment for adolescent substance users, an area of research that is consistent with trans-NIH initiative to identify and generate novel substance use treatments for adolescents (see PA-15-036 and PA-15-256).