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.

项目摘要 当治疗患有药物使用障碍的个体时，复发代表了一个一致的临床问题。到 研究这一点，我将使用渴望模型的孵化来研究多巴胺在伏隔核中的作用 （NAC）核心子区域（NACC）在持久的大鼠中持续的可卡因渴望的持续性 节制。该过程始于扩展访问可卡因自我管理，在此期间 将药物输注与光提示相关联。接下来是一个强迫禁欲的时期 大鼠被送回他们的家笼，没有接触药物或药物的提示。在不同的时间点 在此禁欲期间，将大鼠返回操作箱，以进行提示引起的寻求测试，在此期间 现在在先前输送药物并提示的鼻脚孔上做出反应，现在仅提供提示。作为 禁欲的持续时间增加，在这些条件下做出响应，我们测量提示诱导的药物寻求药物 或渴望，逐步加强或“孵化”。该模型是相关的，因为 渴望也发生在人类中。狼实验室和其他实验室已经证明，孵化需要可塑性 NACC中的兴奋性合成传递允许增强这些突触。但是，需求 多巴胺能信号在NACC中对动机行为的重要性，对 多巴胺在可卡因渴望的孵化中发挥作用。我假设NACC中的多巴胺瞬变 与提示诱导的药物寻求在孵育过程中加剧并有助于其表达相关。在AIM 1中， 我将使用与多巴胺生物传感器grab_da配对的纤维光度法测量多巴胺反应 在寻求早期戒酒，孵化和晚期戒酒期间寻求测试期间，该药物配对的提示引起 孵育后平稳。在AIM 2中，我将确定NACC多巴胺能的功能意义 通过在寻求药物之前将多巴胺受体拮抗剂注入NACC，在孵育过程中传播 测试。我预测D1多巴胺受体或D2多巴胺受体的阻塞将减少提示诱导的 孵化后寻求可卡因，并且这种减少在早期戒酒中的稳定性较低。 该项目将解决有关多巴胺在渴望孵化中的作用的当前差距。在 除科​​学进步外，该提案为我提供了许多发展的机会。学习 纤维光度法和该项目所需的其他方法，并将这些方法应用于 已建立的接力动物模型是我将来可以基于的关键基础技术技能 博士后培训。该奖学金培训的其他目标是改善我的书面和口头交流 通过编写手稿和参加会议来介绍我的工作和网络的技能 神经科学，以提高我设计严格实验的能力，并获得更多的心理经验 并监督他人。这些技能将有助于我成为竞争性的候选人，并最终将 允许我在PI级别或工作人员科学家级别成为独立研究人员。