Neurobehavioral Regulation of Cigarette Cravings

描述（由申请人提供）： 这是NIDA K 08指导临床科学家奖的重新提交。我的职业目标是建立自己作为一个独立的研究者与强大的临床前研究计划，重点是尼古丁依赖和抑郁症的神经生物学。该申请提出了一个全面的，为期五年的监督培训和研究计划与雷蒙德Niaura，博士，和Lawrence H.普莱斯医学博士和玛丽娜·皮乔托博士和医学博士托尼·P·乔治耶鲁大学医学院这个多学科团队将在布朗脑科学计划和耶鲁大学神经科学系的培训计划中提供密切的指导，该计划包括结构化教学法，研讨会和课程。该研究计划的重点是描述神经行为机制，这些机制调节尼古丁依赖个体（有或无重度抑郁症易感性）的烟瘾和吸烟行为。在两项双盲、安慰剂对照激发研究中，将使用急性色氨酸耗竭（ATD）和α-甲基-对-酪氨酸（AMPT）分别检查5-羟色胺和多巴胺耗竭对烟瘾和吸烟地形图的影响。 具体目标是： (1)探讨5-羟色胺和多巴胺在调节抑郁易感吸烟者的烟瘾和吸烟地形图中的作用; (2)确定ATD和AMPT给药对（强迫渴望、奖励渴望）和吸烟地形的个体差异的相对影响; (3)确定ATD或AMPT给药后，提示诱导的渴望是否发生任何变化，与吸烟地形图的变化相对应;以及 (4)探讨是否与渴望相关的措施（例如，强迫和奖励渴望），吸烟（例如，地形，血液尼古丁水平），和诊断组的情绪变化介导的。 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的脆弱性之间的关联的理解，并可能对定制尼古丁渴望的药理学治疗产生影响。

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.