The role of nucleus accumbens dopamine in incubation of cocaine craving

伏隔核多巴胺在可卡因渴望孵化中的作用

• 批准号: 10676025
• 负责人: Sophia Jiahn Weber
• 金额: $ 4.77万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-08 至 2025-03-07
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10676025
• 关键词: AMPA Receptors; Abstinence; Animal Model; Behavior; Biosensor; Calcium; Clinical; Cocaine; Complex; Cue-induced relapse; Cues; Development; Dopamine; Dopamine Antagonists; Dopamine D1 Receptor; Dopamine D2 Receptor; Dopamine Receptor; Environment; Experimental Designs; Exposure to; Fellowship; Fiber; Fiber Optics; Fluorescence; Future; Glutamate Receptor; Glutamates; Goals; Home; Human; Implant; Incubated; Individual; Infusion procedures; Knowledge; Learning; Light; Literature; Manuscripts; Measures; Mentors; Modeling; Motivation; Neurosciences; Nose; Nucleus Accumbens; Permeability; Pharmaceutical Preparations; Phase; Photometry; Play; Postdoctoral Fellow; Pre-Clinical Model; Procedures; Rattus; Receptor Activation; Relapse; Reporting; Research Personnel; Rewards; Rodent Model; Role; Scientific Advances and Accomplishments; Scientist; Self Administration; Signal Transduction; Study models; Substance Use Disorder; Synapses; Synaptic Transmission; Technical Expertise; Techniques; Testing; Time; Training; Viral; Work; World Health Organization; Writing; cocaine craving; cocaine exposure; cocaine relapse; cocaine seeking; cocaine self-administration; craving; design; dopamine system; drug abstinence; drug of abuse; experience; experimental study; falls; improved; motivated behavior; mutant; neuromechanism; optical fiber; oral communication; pharmacologic; post-doctoral training; receptor; response; sensor; skills; symposium; transmission process

Project Summary Relapse represents a consistent clinical problem when treating individuals with Substance Use Disorder. To study this, I will use the incubation of craving model to investigate the role of dopamine in the nucleus accumbens (NAc) core subregion (NAcc) in the persistence of cue-induced cocaine craving in rats after protracted abstinence. The procedure begins with extended access cocaine self-administration during which the rat learns to associate a drug infusion with a light cue. This is followed by a period of forced abstinence during which the rat is returned to their home cage and has no exposure to the drug or drug-paired cues. At different time-points during this abstinence period, rats are returned to the operant boxes for cue-induced seeking tests, during which responding on the nose-poke hole that previously delivered drug and cue now delivers only the cue. As the duration of abstinence increases, responding under these conditions, our measure of cue-induced drug seeking or craving, progressively intensifies or ‘incubates’. This model is translationally relevant because incubation of craving also occurs in humans. The Wolf lab and others have demonstrated that incubation requires plasticity of excitatory synaptic transmission in the NAcc allowing for a strengthening of these synapses. However, despite the importance of dopaminergic signaling in the NAcc for motivated behavior, little is known about the role that dopamine plays in the incubation of cocaine craving. I hypothesize that dopamine transients in the NAcc associated with cue-induced drug seeking intensify during incubation and contribute to its expression. In Aim 1, I will use fiber photometry paired with the dopamine biosensor GRAB_DA to measure dopamine responses provoked by the drug paired cue during seeking tests in early abstinence, prior to incubation, and late abstinence, after incubation has plateaued. In Aim 2, I will determine the functional significance of NAcc dopaminergic transmission during incubation by injecting dopamine receptor antagonists into the NAcc before the drug seeking test. I predict that blockade of either D1 dopamine receptors or D2 dopamine receptors will reduce cue-induced cocaine seeking after incubation has occurred, and that this reduction will be less robust in early abstinence. This project will address a current gap in the literature regarding dopamine’s role in the incubation of craving. In addition to scientific advancement, this proposal offers me many opportunities to develop as a scientist. Learning fiber photometry and the other approaches required for this project, and applying these approaches to an established animal model of relapse, are key foundational technical skills that I can build upon during future postdoctoral training. Other goals of this fellowship training are to improve my written and oral communication skills by writing manuscripts and by attending conferences to present my work and network in the field of neuroscience, to improve my ability to design rigorous experiments, and to gain more experience with mentoring and supervising others. These skills will help me become a competitive post-doc candidate and will eventually allow me to become an independent researcher either at the PI level or the staff scientist level.

项目概要 在治疗药物滥用障碍患者时，复发是一个持续存在的临床问题。 研究这个，我将利用渴望模型的孵化来研究多巴胺在伏隔核中的作用 （NAc）核心亚区（NAcc）在大鼠长期持续的提示诱导可卡因渴望中的作用 该程序从延长可卡因自我给药开始，在此期间老鼠学习。 将药物输注与灯光提示联系起来 随后是一段强制禁欲期。 大鼠被送回其家中的笼子，并且在不同的时间点没有接触药物或药物配对线索。 在此禁欲期间，将大鼠放回操作盒进行提示诱导的寻找测试，在此期间 对之前提供药物和提示的鼻子戳孔做出反应，现在只提供提示。 禁欲的持续时间增加，在这些条件下做出反应，我们对线索诱导的药物寻求的测量 或渴望，逐渐加强或“孵化”，这种模式具有转化相关性，因为孵化。 沃尔夫实验室和其他实验室已经证明，孵化需要可塑性。 NAcc 中的兴奋性突触传递增强了这些突触的强度。 NAcc 中多巴胺能信号传导对于动机行为的重要性，但人们对它的作用知之甚少 多巴胺在可卡因渴望的孕育过程中发挥作用，我追踪了 NAcc 中的多巴胺瞬变。 与提示诱导的药物寻找相关，在孵化过程中会增强，并有助于其表达。 我将使用光纤光度法与多巴胺生物传感器 GRAB_DA 配合来测量多巴胺反应 在早期戒断、潜伏前和晚期戒断寻求测试期间由药物配对提示引起， 孵化稳定后，在目标 2 中，我将确定 NAcc 多巴胺能的功能意义。 在寻找药物之前，通过将多巴胺受体拮抗剂注射到 NAcc 中，在孵化期间进行传播 我预测阻断 D1 多巴胺受体或 D2 多巴胺受体将减少提示诱导。 可卡因在潜伏期后就开始寻求，并且这种减少在早期戒断中不会那么明显。 该项目将解决目前文献中有关多巴胺在渴望产生中的作用的空白。 除了科学进步之外，这个提案还为我提供了许多发展成为科学家的机会。 光纤光度测定法和该项目所需的其他方法，并将这些方法应用于 建立的复发动物模型，是我未来可以借鉴的关键基础技术技能 博士后培训的其他目标是提高我的书面和口头沟通能力。 通过撰写手稿和参加会议来展示我在该领域的工作和网络来提高技能 神经科学，提高我设计严格实验的能力，并获得更多指导经验 并监督他人。这些技能将帮助我成为一名有竞争力的博士后候选人，并最终将帮助我成为一名有竞争力的博士后候选人。 让我成为 PI 级别或科学家级别的独立研究员。