Role of the kappa opioid receptor system in learning and substance use disorders

kappa阿片受体系统在学习和物质使用障碍中的作用

• 批准号: 10750800
• 负责人: Zahra Farahbakhsh
• 金额: $ 3.3万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10750800
• 关键词: Abstinence; Address; Agonist; Alcohol consumption; Automobile Driving; Behavior; Behavioral; Bilateral; Cells; Chronic; Cues; Data; Data Set; Dependence; Development; Dynorphins; Elements; Etiology; Event; Female; Fiber; Goals; High Prevalence; Intake; Internal Ribosome Entry Site; Investigation; Learning; Ligands; Measurement; Measures; Mediating; Modeling; Mus; Negative Reinforcements; Neurobiology; Neurosciences; Nucleus Accumbens; Operant Conditioning; Opioid Antagonist; Pattern; Pharmaceutical Preparations; Pharmacological Treatment; Phenotype; Photometry; Play; Positive Reinforcements; Process; Psychological reinforcement; Public Health; Receptor Signaling; Research; Resolution; Rewards; Role; Signal Transduction; Stimulus; Stress; Substance Use Disorder; System; Testing; Time; Training; Up-Regulation; Viral Vector; adaptive learning; addiction; antagonist; discrete time; drug reward; dysphoria; experimental study; in vivo; in vivo optical imaging; kappa opioid receptors; learned behavior; male; motivated behavior; negative affect; non-drug; norbinaltorphimine; novel; optogenetics; pharmacologic; predictive modeling; prevent; receptor function; receptor sensitivity; reinforcer; response; self-directed learning; sensor; substance use

Project Summary Despite their high prevalence, the underlying neurobiology of substance use disorders is still not understood, limiting effective pharmacological treatment options. Characterized by disruptions in learning processes, substance use disorders are thought to develop with the transition from being motivated by the positive reinforcing effects of the substance, to negative reinforcement where use occurs to avoid or alleviate an aversive state during abstinence. It is hypothesized that substance-induced upregulations in kappa opioid receptor (KOR) signaling play a causal role in the dysphoria that drives negative reinforcement. In support of this idea, KOR antagonists decrease drug intake in models of chronic use or dependence and the nucleus accumbens, a region critical to reinforcement learning and motivated behaviors, is one of the regions in which substance use has been shown to upregulate the KOR system. Despite this evidence of a causal role for KOR signaling in substance use disorders, this system’s function in adaptive reinforcement processes and the sufficiency of its upregulation in driving maladaptive learning remains unknown. Here, we aim to address these issues through direct investigation of the role of the KOR system in positive and negative reinforcement learning through pharmacological manipulation, sub-second measurement of in vivo dynorphin dynamics, and optogenetic activation of the KOR system. In aim 1, I will pair systemic antagonism of the KOR system with positive and negative reinforcement operant conditioning tasks to elucidate the role of KOR signaling in adaptive learning. In aim 2, I will conduct sub-second resolution, in vivo optical imaging of dynorphin release in the nucleus accumbens to uncover the role of endogenous KOR system activity in encoding information during reinforcement learning processes. Finally, in aim 3, I will optogenetically evoke accumbal dynorphin release to determine the sufficiency of augmentation of the KOR system in driving the maladaptive learning that underlies addiction. Through the completion of this proposal, I will receive well-rounded training in conducting independent research and contribute to the field of addiction neuroscience’s understanding of the mechanism by which the KOR system is involved in adaptive and maladaptive reinforcement learning processes.

项目摘要 尽管药物使用障碍的发病率很高，但其潜在的神经生物学仍不清楚， 限制有效的药物治疗选择。以学习过程的中断为特征， 物质使用障碍被认为是随着从积极动机的转变而发展起来的 物质的强化作用，当使用该物质来避免或减轻厌恶时，对负面强化的作用 禁欲期间的状态。据推测，物质诱导kappa阿片受体(KOR)表达上调 信号在导致负面强化的焦虑症中起着因果作用。为了支持这一想法，韩国 拮抗剂减少慢性使用或依赖模型的药物摄入量和伏隔核区 对强化学习和激励行为至关重要的，是物质使用的领域之一 被证明是对朝鲜半岛体系的升华。尽管有证据表明KOR信号在物质使用中具有因果作用 失调，该系统在自适应强化过程中的作用及其上调的充分性 驾驶适应不良学习仍不为人所知。在这里，我们旨在通过直接调查来解决这些问题 KOR系统在通过药理学进行积极和消极强化学习中的作用 操纵，体内强啡肽动力学的亚秒测量，以及KOR的光遗传激活 系统。在目标1中，我将把对朝鲜民主主义人民共和国制度的系统性对抗与积极和消极的强化结合起来 操作性条件反射任务，以阐明KOR信号在适应性学习中的作用。在《目标2》中，我将指挥 亚秒分辨率，体内光学成像在伏隔核内释放强啡肽以揭示 强化学习过程中内源性KOR系统活动在信息编码中的作用。 最后，在目标3中，我将通过光遗传学激发伏隔强啡肽的释放来确定 加强KOR系统，以推动导致成瘾的适应不良学习。通过 完成这项建议后，我将接受全面的培训，进行独立研究和 有助于成瘾神经科学领域理解KOR系统的机制 参与适应性和非适应性强化学习过程。