The role of neuroactive steroids in stress, drug craving and drug use in cocaine use disorders

项目总结/摘要 本指导研究科学家发展（K 01）奖中描述的研究和培训 申请将为候选人提供成为独立调查员所需的技能。 开发成瘾新治疗靶点。一个多学科的培训和指导计划， 在耶鲁大学医学院提出，这将有助于过渡到独立的 通过提供结构化的指导、监督和教学技巧进行研究，以解决以下问题 培训目标：a）成瘾治疗的开发和临床结果，B）药物治疗的高级培训 开发药理学，和c）与实验相关的数据分析技术 重复时间点和纵向多层次药物使用结果的精神药理学研究。 为了实现这些职业培训目标，设计了一项创新的研究提案， 使用双烯醇酮（PREG）作为机制探针，以增加有效的GABA增强水平， 神经活性类固醇allopregnanolone（ALLO），并检查（a）其对激发应激和药物提示的影响 诱导的渴望，以及对压力和药物线索渴望状态的生理、认知、情绪反应，B） 不同剂量的PREG的安全性和药代动力学（PK）/药效学（PD）特征及其 向下游神经活性类固醇的转化概况，以及（c）探索其对每日可卡因渴望的影响， 情绪症状和可卡因使用结果8周;并探讨这些中的性别差异 目标。从MRSDA项目中获得的知识将使我们了解PREG和ALLO在以下方面的作用： 情绪，生理和神经内分泌唤醒反应的压力和药物线索暴露， 复发的重要预测因素;其安全性和PK/PD，及其代谢为下游神经活性类固醇 以前没有在CUD中进行过测试;它对个体可卡因渴望和药物使用的影响， 可卡因使用者的生态有效环境;以及这些结果中可能存在的性别差异。所有 这些都是新的，以前从未解决过的问题，可卡因成瘾。 动手设计和执行拟议的研究，结合结构化的指导， 监督和教学培训，将使候选人满足急需的培训目标，并产生 作为新的和潜在的治疗靶点的双烯醇酮和其他神经类固醇类似物的初步数据， 可卡因成瘾的设计和提交的R 01建议在04年的MRSDA培训。所以这 MRSDA将是候选人走向科学独立的关键垫脚石。

Project Summary/Abstract The research and training described in this Mentored Research Scientist Development (K01) Award application will provide the candidate with the skills necessary to become an independent investigator in the development of novel treatment targets in addictions. A multidisciplinary training and mentoring program is proposed at the Yale University School of Medicine that will help assist in the transition to independent research by providing structured mentoring, supervision and didactic techniques to address the following training goals: a) treatment development and clinical outcomes in addictions, b) advanced training in drug development pharmacology, and c) data analytical techniques relevant to experimental psychopharmacological studies with repeated time-points and longitudinal multilevel drug use outcomes. In order to achieve these career training goals, an innovative research proposal has been designed to use pregnenolone (PREG) as a mechanistic probe to increase levels of the potent GABA potentiating neuroactive steroid allopregnanolone (ALLO) and examine (a) its effects on provoked stress and drug-cue induced craving, and physiological, cognitive, emotional responses to stress and drug cue craving states, b) the safety and pharmacokinetic (PK) / pharmacodynamic (PD) profile of various doses of PREG and its conversion profile to downstream neuroactive steroids, and (c) explore its effects on daily cocaine craving, mood symptoms and cocaine use outcomes for 8 weeks; and also explore gender differences in each of these aims. The knowledge obtained from this MRSDA project would inform us on the role of PREG and ALLO in emotional, physiological and neuroendocrine arousal in response to stress and drug-cue exposure which are important predictors of relapse; its safety and PK/PD, and its metabolism into downstream neuroactive steroids which have not been previously tested in CUD; its effects on individual cocaine craving and drug use in ecologically valid environments of cocaine users; and gender differences that may exist in these outcomes. All of these are novel and never before addressed questions in cocaine addiction. The hands-on design and execution of the proposed research, combined with the structured mentoring, supervision and didactic training, will allow the candidate to meet much needed training goals, and generate preliminary data on pregnenolone and other neurosteroid analogs as novel and potential treatment targets in cocaine addiction for the design and submission of an R01 proposal in Year 04 of MRSDA training. Hence, this MRSDA will be a crucial stepping stone in the candidate's progression toward scientific independence.