Elucidating Mechanisms of Pharmacotherapy for Alcoholism

描述（由申请人提供）：这是一个以指导病人为导向的研究事业奖（K-23）的提案，旨在为候选人准备开展高质量的酒精中毒研究，并具有进行人体实验室研究的专业知识，以便：(a)确定治疗酒精使用障碍的潜在药物，(b)阐明有希望的药物发挥有益作用的生物行为机制，以及(c)描述与干预反应差异相关的患者特征。候选人还将培养进行转化研究的专业知识，将人类实验室的发现逻辑地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，以及(c)负责任的研究行为培训。指导将由Damaris Rohsenow博士和Robert Swift博士提供，并将由Peter Monti博士、Jennifer Tidey博士和Kent Hutchison博士组成的顾问团队提供支持。

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.