Neurobehavioral Regulation of Cigarette Cravings

描述(由申请人提供)： 这是NIDA K08指导临床科学家奖的重新提交。我的职业目标是通过一个强大的临床前研究项目，确立自己作为独立研究员的地位，专注于尼古丁依赖和严重抑郁症的神经生物学。该申请提出了一项为期五年的综合监督培训和研究计划，合作伙伴包括布朗医学院的雷蒙德·尼亚拉博士和劳伦斯·H·普莱斯医学博士，以及耶鲁医学院的玛丽娜·皮乔托博士和托尼·P·乔治医学博士。这个多学科团队将在培训计划中提供密切指导，该培训计划包括布朗脑科学项目和耶鲁大学神经科学系的结构化教学、研讨会和课程作业。该研究计划的重点是描述调节尼古丁依赖者吸烟渴望和吸烟行为的神经行为机制，这些人有或没有易患严重抑郁症。在两项双盲、安慰剂对照的挑战研究中，急性色氨酸耗竭(ATD)和α-甲基对酪氨酸(AMPT)将分别用于检测5-羟色胺和多巴胺耗竭对欲望和吸烟地形的影响。 具体目标是： (1)研究5-羟色胺和多巴胺在调节抑郁易感吸烟者吸烟欲望和吸烟地形图中的作用； (2)比较ATD和AMPT给药对强迫渴求、奖励渴求和吸烟地形个体差异的相对影响； (3)确定服用ATD或AMPT后线索诱导的渴求的任何变化是否与吸烟地形的变化相对应；以及 (4)探讨与渴求相关的措施(如强迫症和奖赏渴求)、吸烟(如地形、血液尼古丁水平)和诊断组之间的联系是否通过情绪变化来调节。 这项研究的结果将增加对5-羟色胺和多巴胺功能、线索诱导的渴望和严重抑郁症易感性之间的关系的理解，并可能对针对尼古丁渴望特征量身定做药物治疗具有指导意义。

DESCRIPTION (provided by applicant): This is a resubmission of a NIDA K08 Mentored Clinical Scientist Award. My career objective is to establish myself as independent investigator with a strong program of preclinical research focusing on the neurobiology of nicotine dependence and major depression. The application proposes a comprehensive, five-year program of supervised training and research with Raymond Niaura, Ph.D., and Lawrence H. Price, M.D., at Brown Medical School, and Marina Picciotto, Ph.D., and Tony P. George, M.D. at Yale School of Medicine. This multidisciplinary team will provide close guidance in a training plan comprised of structured didactics, seminars, and coursework in the Brown Brain Sciences Program and in the Department of Neuroscience at Yale University. The focus of the Research Plan is to characterize the neurobehavioral mechanisms that regulate cigarette cravings and smoking behavior among nicotine dependent individuals with and without vulnerability to major depression. In two double-blind, placebo-controlled challenge studies, acute tryptophan depletion (ATD) and alpha-methyl-para-tyrosine (AMPT) will be used to examine the effects of serotonin and dopamine depletion, respectively, on cravings and smoking topography. The specific aims are: (1) To examine the role of serotonin and dopamine in regulating cigarette cravings and smoking topography in depression vulnerable smokers; (2) To determine the relative effects of ATD and AMPT administration on individual differences in (obsessive craving, reward craving) and smoking topography; (3) To determine whether any changes in cue-induced cravings in response to ATD or AMPT administration correspond to changes in smoking topography; and (4) To explore whether associations among craving-related measures (e.g., obsessive and reward craving), smoking (e.g., topography, blood nicotine levels), and diagnostic group are mediated by changes in mood. Results of this research will increase understanding of the associations among serotonin and dopamine function, cue-induced cravings and vulnerability to major depression, and may have implications for tailoring pharmacological treatments to nicotine craving profiles.