Does Guanfacine, an alpha2 adrenergic agonist, attenuate stress-induced drinking?

胍法辛（一种 α2 肾上腺素能激动剂）是否可以减轻压力引起的饮酒？

基本信息

批准号：
8631313
负责人：
SHERRY ANN MCKEE
金额：
$ 37.46万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-02-01 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8631313
关键词：
Adrenergic Agonists Adult Adverse event Agonist Alcohol consumption Alcohols Anxiety Area Attention Attenuated Behavior Control Blood Pressure Cardiovascular system Catecholamines Cells Cognition Consumption Corticotropin DSM-IV Data Dependence Development Dizziness Dose Double-Blind Method Environment Frequencies Future Guanfacine Heart Rate Heavy Drinking Hour Human Hydrocortisone Imagery Investigation Laboratories Laboratory Study Mediating Mediator of activation protein Methods National Institute on Alcohol Abuse and Alcoholism Nausea Negative Reinforcements Outcome Pathway interactions Pharmaceutical Preparations Phase Phase II Clinical Trials Placebo Control Placebos Population Prefrontal Cortex Psychological reinforcement Public Health Randomized Research Research Priority Safety Sedation procedure Self Administration Short-Term Memory Smoking Smoking Behavior Stress Symptoms System Therapeutic Titrations Withdrawal Woman alcohol craving alcohol effect alcohol misuse alcohol relapse alcohol use disorder brief intervention cognitive function cost design drinking drinking behavior drug of abuse improved meetings men negative mood noradrenergic pre-clinical research preclinical study public health relevance receptor smoking cessation therapeutic target trait

项目摘要

DESCRIPTION (provided by applicant): Alcohol misuse continues to be a public health problem and identifying effective medications for the treatment of alcohol use disorders remains a high priority for NIAAA. One promising, yet relatively unexplored avenue for medication development for alcohol use are therapeutics that target stress-reactivity. Several lines of evidence suggest that stress is a primary mediator of alcohol use and relapse. Preclinical research demonstrates that noradrenergic pathways are involved in stress-induced consumption and reinstatement to alcohol, as well as alcohol-related reinforcement and withdrawal, and that their manipulation may be of potential therapeutic benefit for alcohol use. In a study evaluating guanfacine, an alpha2a noradrenergic agonist, for smoking cessation we demonstrated that 3mg/day guanfacine was well tolerated, attenuated the effects of stress on smoking, reduced smoking-related reinforcement, improved cognition, and significantly reduced smoking during a brief treatment phase. In a subsample of drinkers from our smoking study, guanfacine robustly reduced the quantity and frequency of alcohol consumption, reduced the frequency of binge consumption, and improved cognition. Medication effects on drinking were evident during the 3-week titration phase, and were independent of medication effects on smoking behavior. Our results suggest that guanfacine should be further evaluated as a potential treatment for alcohol use disorders. For this revised R01 application, we plan to build upon our promising pilot data and conduct the first Phase II human laboratory study evaluating the effect of guanfacine on alcohol consumption. Non-treatment seeking adults with alcohol use disorders will be randomized to guanfacine (3mg/day, 1.5mg/day, or placebo, n=50 per cell, n=150 total), titrated to steady state levels over a 3-week period, and will then complete two laboratory sessions consisting of a well validated method for inducing a stress or neutral/relaxing state (order counterbalanced), followed by a 2-hour alcohol self-administration paradigm known to be sensitive to medication effects. We hypothesize that guanfacine (1.5, or 3.0mg/day) compared to placebo (0 mg/day) will decrease the number of drinks consumed during the self-administration period, and that this effect will be more pronounced following stress. We also expect that guanfacine will be safe and well tolerated during the titration period and in combination with alcohol, and that adverse events will be dose-dependent. Results will provide important information concerning dose selection for future Phase II clinical trial investigations, evidence that targeting the noradrenergic system to reduce stress reactivity is a viable medication development strategy for alcohol use disorders, and elucidate potential mechanisms for these effects.

描述（由申请人提供）：滥用酒精仍然是一个公共卫生问题，确定治疗酒精使用障碍的有效药物仍然是NIAAA的重中之重。用于饮酒的药物开发的一种有希望但相对尚未开发的途径是针对应激反应性的治疗方法。几条证据表明，压力是酒精使用和复发的主要介体。临床前研究表明，去甲肾上腺素能途径参与压力引起的消费和恢复到酒精以及与酒精有关的增强和戒断，并且它们的操纵可能对酒精使用的潜在治疗益处。在一项评估鸟法汀（一种α2A去甲肾上腺素能激动剂）的研究，我们证明3mg/天鸟法碱的耐受性良好，减弱了压力对吸烟，减少吸烟相关的增强，改善认知，并在短暂治疗阶段减少吸烟的影响。在我们的吸烟研究中的饮酒者的子样本中，鸟法汀可稳健地降低饮酒的数量和频率，降低了暴饮暴食的频率和改善的认知。在3周的滴定阶段，对饮酒的药物影响很明显，并且与对吸烟行为的影响无关。我们的结果表明，应进一步评估鸟汀作为对酒精使用障碍的潜在治疗方法。对于此修订后的R01应用程序，我们计划基于我们有希望的飞行员数据，并进行第一阶段的人类实验室研究，以评估鸟量素对饮酒的影响。寻求非治疗饮酒障碍的成年人的非治疗将被随机分配给鸟宁（3mg/天，1.5毫克/天或安慰剂，或安慰剂，n = 50，总计n = 150个），在3周期间滴定至稳态水平，然后将在两次良好的压力或不足的方法中完成两种良好的实验室，以命令两次，以良好的状态进行反应，以纠正两种状态，以良好的状态（均为中性/中性），且中性/中性良好的方法，均为中性/中性良好的方法，并将已知对药物效应敏感的自我管理范式。我们假设与安慰剂（0 mg/day）相比，鸟法（1.5或3.0毫克/天）将减少自给自足期内消耗的饮料数量，并且在压力下，这种效果将更加明显。我们还期望鸟芬在滴定期间并与酒精结合使用，将是安全且耐受性的，并且不良事件将依赖于剂量。结果将为未来II期临床试验研究提供有关剂量选择的重要信息，这证明靶向去甲肾上腺素能降低压力反应性是一种可行的药物开发策略，用于饮酒障碍，并阐明了这些作用的潜在机制。