Opioidergic mechanisms underlying cocaine conditioned reinforcement

可卡因条件强化背后的阿片样物质机制

• 批准号: 10229240
• 负责人: Lauren Grace Rysztak
• 金额: $ 3.82万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10229240
• 关键词: Affect; Affinity; American; Attenuated; Behavior; Behavioral; Binding; Brain; Cocaine; Cocaine Abuse; Collection; Complex; Cues; Data; Disease; Dopamine; Enkephalin Receptors; Enkephalins; Exposure to; Extinction (Psychology); Feeling; Female; Glutamates; Human; Knowledge; Lead; Measures; Mediating; Microdialysis; Neurobiology; Neuropeptides; Nucleus Accumbens; Opioid; Opioid Antagonist; Opioid Peptide; Opioid Receptor; Pathway interactions; Peptide Receptor; Pharmaceutical Preparations; Pharmacology; Phase; Procedures; Property; Psychological reinforcement; Rattus; Receptor Activation; Relapse; Reporting; Research; Rewards; Role; Scientist; Sex Differences; Stimulus; Substance Use Disorder; System; Testing; Training; Work; addiction; behavioral response; classical conditioning; cocaine relapse; cocaine use; conditioning; craving; delta opioid receptor; drug development; drug of abuse; drug relapse; drug seeking behavior; effective therapy; endogenous opioids; experimental study; in vivo; insight; male; naltrindole; nervous system disorder; neurobiological mechanism; neurochemistry; novel; novel therapeutics; paired stimuli; prevent; reinforcer; relapse risk; relating to nervous system; response; reward circuitry; skills training; therapeutic target; therapeutically effective; training opportunity

Project summary/abstract: Cocaine use disorder affects nearly one million Americans, yet there are no current approved therapeutics for effective treatment or to prevent relapse. Major contributors to relapse are drug paired cues that can elicit feelings of craving in humans and lead to drug seeking. The ability of cues to maintain drug seeking behavior after sufficient number of cue and cocaine pairings is termed the conditioned reinforcing effects of cocaine. Previous work suggests that dopaminergic and glutamatergic systems in reward circuitry are involved, and other studies have implicated the endogenous opioid system, particularly in the nucleus accumbens, in mediating behavior elicited by cocaine-paired cues. Specifically, blocking opioid receptor activation attenuates drug seeking behavior. Similarly, increases in levels of enkephalin, an endogenous opioid peptide, in the nucleus accumbens have been shown with some primary reinforcers and can lead to reinstatement of drug seeking. Little is known about the role of endogenous opioids in conditioned reinforcement nor the opioidergic mechanisms contributing to this complex behavior. To gain insights into the contribution of the endogenous opioid system in addiction and specifically in cocaine-paired cues, I will explore the enkephalinergic response to cues and opioid receptor activation modulating these effects. The current proposal is supported by our preliminary studies that activation of the delta opioid receptor (DOR) potentiates operant responding for drug-paired cues, indicating an increase in conditioned reinforcement. Here I will test the central hypothesis that presentation of cues that have acquired conditioned reinforcing properties lead to an increase of enkephalin in the nucleus accumbens shell that acts on DORs to drive operant responding for cocaine-paired cues. This work will 1) measure and potentiate enkephalin levels and 2) manipulate opioid receptor activation pharmacologically in the nucleus accumbens during a stringent test of cocaine conditioned reinforcement. This work will lead to better understanding of and insight into the underlying mechanisms behind the conditioned reinforcing properties of cocaine cues. This proposal will provide me essential training in 1) in vivo neuropeptide collection, 2) pharmacological manipulation of the endogenous opioid system, and 3) rigorous behavioral experiments in addiction research. The skills and training opportunities described in this proposal will enable me to be a successful professional scientist working in drug development to identify novel therapeutics for neurological disorders.

项目总结/摘要： 可卡因使用障碍影响近100万美国人，但目前还没有批准的治疗方法 有效治疗或预防复发。复发的主要原因是药物配对的线索，可以引起的感觉 并导致人们寻求毒品。线索维持药物寻求行为的能力， 足够数量的线索和可卡因配对被称为可卡因的条件强化效应。先前 一项研究表明，多巴胺能和多巴胺能系统参与了奖赏回路， 暗示内源性阿片系统，特别是在延髓核，在介导的行为 由可卡因配对线索引起的具体地说，阻断阿片受体激活会减弱药物寻求 行为类似地，脑啡肽（一种内源性阿片肽）水平的增加， 已被证明与一些主要的药物，并可能导致恢复药物寻求。知之甚少 关于内源性阿片类物质在条件强化中的作用，也不是阿片类物质的机制， 这种复杂的行为。深入了解内源性阿片系统在成瘾和 特别是在可卡因配对线索，我将探讨脑啡肽反应的线索和阿片受体 激活调节这些效应。目前的建议得到了我们初步研究的支持， δ阿片受体（DOR）的增强对药物配对线索的操作性反应，表明增加 在条件强化中。在这里，我将测试的核心假设，提出的线索，已获得 条件强化特性导致中脑核壳中脑啡肽的增加， DOR驱动可卡因配对线索的操作性反应。这项工作将1）测量和增强脑啡肽 水平和2）操纵阿片受体激活在丘脑核中， 可卡因条件强化的严格测试。这项工作将有助于更好地理解和了解 可卡因线索的条件强化特性背后的潜在机制。这项建议会 为我提供以下方面的基本培训：1）体内神经肽收集，2） 内源性阿片系统; 3）成瘾研究中严格的行为实验。的技能和培训 本计划书中描述的机会将使我成为一名成功的专业科学家， 开发，以确定新的治疗神经系统疾病。