Elucidating Mechanisms of Pharmacotherapy for Alcoholism

描述(由申请人提供)：这项以患者为导向的研究职业奖(K-23)的建议旨在为候选人进行高质量的酒精中毒研究做准备，该研究具有进行人体实验室研究的专业知识，以：(A)确定治疗酒精使用障碍的潜在药理学药物，(B)阐明有希望的药物发挥其有益效果的生物行为机制，以及(C)描述与干预的不同反应相关的患者特征。候选人还将发展进行转化性研究的专业知识，这些转化性研究将人类实验室的研究结果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)通过多学科师徒培训模式进行一对一指导；(B)正式课程和指导阅读；(C)负责任地开展研究工作的培训。导师将由Damaris Rohsenow博士和Robert Swift博士提供，并由Peter Monti博士、Jennifer Tidey博士和Kent Hutchison博士组成的顾问小组提供支持。 为了帮助教学和辅导的努力，这项申请包括一个混合随机的建议 一项安慰剂对照研究，考察纳曲酮(NAL)和恩丹西酮(OND)在减少饮酒冲动和对酒精反应的生理反应方面是否与心理应激相关的线索有不同的有效性。基于与压力和酒精线索相关的渴求相关的可分离的神经生物学机制，以及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有不同的相互作用。这项拟议的研究将招募132名酒精依赖的成年患者进行药物滥用治疗。患者将被随机接受安慰剂治疗， 仅NAL、仅OND或NAL+OND。在连续给药10天后，参与者将参加一个实验室会议，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。根据诱发刺激是酒精暗示还是与压力相关的，NAL和OND在缓解饮酒冲动和影响生理反应方面的有效性不同，这一发现将使我们深入了解渴望的复杂神经生物学基础，阐明代理人发挥作用的机制，并为干预发展提供信息。

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.