Elucidating Mechanisms of Pharmacotherapy for Alcoholism

描述（由申请人提供）：本提案为指导患者为导向的研究职业奖（K-23）的目的是准备候选人进行高质量的研究酗酒与专业知识进行人体实验室研究：（a）鉴定治疗酒精使用障碍的潜在药理学试剂，（B）阐明有希望的药物发挥其有益作用的生物行为机制，以及（c）描绘与对干预的不同响应相关联的患者特征。候选人还将发展进行转化研究的专业知识，这些研究在逻辑上将人类实验室的发现扩展到适当的临床试验研究，同时关注可能与结果相关的相关个体差异因素。为此，职业发展计划包括：（a）通过多学科导师-学徒培训模式进行一对一指导;（B）正式课程和指导阅读;（c）负责任地开展研究的培训。导师将由Damaris Rohsenow博士提供。和罗伯特·斯威夫特医学博士并将得到由彼得·蒙蒂博士组成的顾问团队的支持，Jennifer Tidey博士，和肯特哈奇森博士 为了帮助教学和指导工作，此应用程序包括一个混合随机 安慰剂对照研究，以检查纳洛酮（NAL）和昂丹司琼（OND）是否对降低响应于酒精与心理应激相关线索的饮酒冲动和生理反应性具有差异有效性。基于可分离的假定神经生物学机制参与压力与酒精线索相关的渴望，并基于每种药物的神经化学作用的不同部位，假设压力和酒精线索将与这些药物发生差异性相互作用。这项拟议的研究将招募132名接受药物滥用治疗的酒精依赖成年患者。患者将随机接受安慰剂， 仅NAL、仅OND或NAL + OND。在连续10天给药后，参与者将参加实验室会议，在此期间，将评估对涉及酒精和压力线索的个性化图像条件的主观和生理反应。NAL和OND在减少饮酒冲动和影响生理反应方面的效果不同，这一发现基于引发刺激是酒精线索还是压力相关，这将深入了解渴望的复杂潜在神经生物学，阐明药物发挥作用的机制，并为干预措施的发展提供信息。

DESCRIPTION (provided by applicant): This proposal for a Mentored Patient-Oriented Research Career Award (K-23) is designed to prepare the candidate to carryout high quality research on alcoholism with expertise in conducting human laboratory research to: (a) identify potential pharmacologic agents to treat alcohol use disorders, (b) elucidate biobehavioral mechanisms by which promising medications exert their beneficial effects, and (c) delineate patient characteristics that are associated with differential response to intervention. The candidate will also develop expertise in conducting translational studies which logically extend findings from the human laboratory to appropriate clinical trials research while attending to relevant individual difference factors that may relate to outcome. To this end, the career development plan includes: (a) one-on-one instruction through a multidisciplinary mentor-apprenticeship training model, (b) formal coursework and directed readings, and (c) training in responsible conduct of research. Mentorship will be provided by Damaris Rohsenow, Ph.D. and Robert Swift, MD, Ph.D., and will be supported by an advisory team comprised of Peter Monti, Ph.D., Jennifer Tidey, Ph.D., and Kent Hutchison, Ph.D. To assist didactic and mentorship efforts, this application includes a proposal for a mixed randomized placebo-controlled study to examine whether naltrexone (NAL) and ondansetron (OND) are differentially effective for reducing urge to drink and physiological reactivity in response to alcohol versus psychological stress-related cues. Based on the dissociable putative neurobiological mechanisms involved in stress vs. alcohol cue-related craving, and based on the distinct sites of neurochemical action of each medication, it is hypothesized that stress and alcohol cues will interact differentially with these medications. The proposed study will recruit 132 adult patients with alcohol dependence in substance abuse treatment. Patients will be randomized to receive placebo, NAL only, OND only, or NAL + OND. After ten consecutive days of dosing, participants will attend a laboratory session during which subjective and physiologic responses to personalized imagery conditions involving alcohol and stress cues will be assessed. A finding that NAL and OND are differentially effective at reducing urge to drink and affecting physiologic reactivity based on whether the eliciting stimuli are alcohol cues or are stress related would afford insight into the complex underlying neurobiology of craving, elucidate mechanisms by which agents exert effects, and inform intervention development.