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

神经活性类固醇在可卡因使用障碍中的压力、药物渴望和药物使用中的作用

• 批准号: 10548880
• 负责人: VERICA MILIVOJEVIC
• 金额: $ 18.26万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10548880
• 关键词: Addictive Behavior; Address; Admission activity; Alcohol abuse; Allopregnanolone; Animals; Anxiety; Area; Arousal; Award; Cardiovascular system; Clinical; Cocaine Abuse; Cocaine Dependence; Cocaine Users; Cocaine use disorder; Cognitive; Complex; Corticotropin; Cues; Data; Data Analytics; Development; Disease; Dose; Double-Blind Method; Drug Kinetics; Drug usage; Ecological momentary assessment; Emotional; Emotions; Enrollment; Environment; Exposure to; Female; Functional disorder; Goals; Guided imagery; Hour; Human; Hydrocortisone; Imagery; Individual; Inpatients; Intake; Investigation; Knowledge; Laboratories; Mentors; Metabolism; Neurosciences Research; Neurosecretory Systems; Outcome; Outpatients; Participant; Patients; Persons; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Physiological; Physiology; Pilot Projects; Placebos; Pregnenolone; Progesterone; Public Health; Randomized; Recovery; Relapse; Research; Research Personnel; Research Proposals; Research Training; Role; Safety; Scientist; Societies; Steroids; Stress; Structure; Supervision; Techniques; Testing; Time; Training; Universities; Woman; addiction; analog; arm; biological adaptation to stress; career; cocaine craving; cocaine related behaviors; cocaine use; craving; cue reactivity; design; drug craving; drug development; flexibility; gamma-Aminobutyric Acid; gender difference; hands on research; hypothalamic-pituitary-adrenal axis; improved; innovation; laboratory experiment; male; medical schools; men; mood symptom; multidisciplinary; negative mood; neuropsychiatry; neurosteroids; novel; pharmacokinetics and pharmacodynamics; pharmacologic; positive emotional state; primary outcome; programs; psychopharmacologic; relapse prediction; relapse risk; response; sex; skills; steroid hormone; stress reduction; therapy development; training opportunity

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.

项目概要/摘要 本指导研究科学家发展 (K01) 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 开发成瘾的新治疗靶点。多学科培训和指导计划是 耶鲁大学医学院提出的建议，将有助于协助过渡到独立 通过提供结构化指导、监督和教学技术来解决以下问题的研究 培训目标：a) 成瘾治疗的开发和临床结果，b) 药物高级培训 开发药理学，以及 c) 与实验相关的数据分析技术 具有重复时间点和纵向多水平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 使用孕烯醇酮 (PREG) 作为机制探针来提高有效 GABA 增强剂的水平 神经活性类固醇四氢孕酮 (ALLO) 并检查 (a) 它对诱发压力和药物提示的影响 诱发的渴望，以及对压力和药物提示渴望状态的生理、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 下游神经活性类固醇的转化概况，以及（c）探索其对日常可卡因渴望的影响， 情绪症状和可卡因使用结果 8 周；并探讨这些方面的性别差异 目标。从这个 MRSDA 项目中获得的知识将使我们了解 PREG 和 ALLO 在 对压力和药物提示暴露的反应的情绪、生理和神经内分泌唤醒 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 之前未在 CUD 中进行过测试；它对个人可卡因渴望和吸毒的影响 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。全部 其中一些是新奇的、以前从未解决过的可卡因成瘾问题。 拟议研究的实际设计和执行，结合结构化指导， 监督和教学培训，将使候选人能够满足急需的培训目标，并产生 关于孕烯醇酮和其他神经类固醇类似物作为新的和潜在的治疗靶点的初步数据 可卡因成瘾在 MRSDA 培训的第 04 年设计和提交 R01 提案。因此，这个 MRSDA 将成为候选人迈向科学独立的重要垫脚石。