Circadian Rhythms and Cocaine Use Disorder

昼夜节律和可卡因使用障碍

• 批准号: 10456216
• 负责人: Mark J Ferris
• 金额: $ 45.39万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 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 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10456216
• 关键词: Acetylcholine; Animal Model; Animals; Architecture; Base of the Brain; Behavior; Behavioral; Biological; Brain; Circadian Rhythms; Cocaine; Cocaine use disorder; Consumption; Corpus striatum structure; Cues; Data; Development; Diurnal Rhythm; Dopamine; Dopamine Receptor; Economics; Exhibits; Fiber; Frequencies; Goals; Heroin; Hour; Incentives; Individual; Interneurons; Lead; Learning; Light; Link; Measures; Mediating; Modeling; Motivation; Muscarinic Acetylcholine Receptor; Neurobiology; Neurophysiology - biologic function; Neurotransmitters; Nicotinic Receptors; Nucleus Accumbens; Outcome; Periodicity; Persons; Pharmaceutical Preparations; Phase; Photometry; Play; Psychological reinforcement; Public Health; Publishing; Rattus; Relapse; Replacement Therapy; Research; Research Proposals; Rewards; Role; Scanning; Signal Transduction; Sleep Wake Cycle; Stimulant; Substance Use Disorder; System; Testing; Time; United States; Variant; Work; World Health; behavioral economics; cholinergic; circadian; classical conditioning; cocaine self-administration; cost; craving; dopamine transporter; drug abuse vulnerability; drug craving; drug of abuse; drug relapse; effective therapy; extracellular; fluorescence imaging; human model; mesolimbic system; motivated behavior; non-drug; optogenetics; overdose death; prescription opioid; receptor; receptor function; relating to nervous system; response; restoration; shift work; substance use treatment; therapeutic target

PROJECT SUMMARY Despite decades of critical research into its biological mechanisms and treatment approaches, Substance Use Disorder (SUD) persists as a major world health problem. In the last few years, approximately 21 million people required SUD treatment. Still, recent years have seen dramatic increases in the number of overdose deaths due to heroin, prescription opioids, and cocaine. Interestingly, there is some work that suggests a circadian rhythm and robust time-of-day shifts in the function of specific receptors and neurotransmitter systems that are routinely implicated in drug abuse vulnerability and relapse. For example, diurnal (i.e., light/dark) variation has been observed in mesolimbic dopamine (DA) system, including rhythms in extracellular DA tone, DA transporter levels/ function, and DA receptor function. Moreover, research in both humans and animal models has observed that level of drug taking and seeking can vary throughout the day. While published work demonstrates regulators of diurnal variation in DA tone and tone regulators, there is a large gap in research dedicated to understanding regulators of diurnal variation and circadian rhythms in subsecond, phasic DA release. This is particularly important given the role of phasic DA release in reinforcement learning, motivation, and goal-directed behavior that is altered in SUD. Moreover, little work has been dedicated to understanding how the function of intrinsic modulators of phasic DA release, such as acetylcholine (ACh) from striatal cholinergic interneurons, vary across time-of-day. Therefore, the overall objective of this research proposal is to determine the circadian diurnal differences in rapid DA and ACh signaling and how these rhythms are mechanistically linked to changes in motivated behavior, cocaine/reward seeking, and cue-reward associations. Our central hypothesis is that there are times-of-day that individuals will exhibit increased sensitivity to reward- and cocaine-associated cues that can lead to cocaine seeking, which are mediated by time-of-day variations in the cholinergic interneuron modulation of rapid DA signaling. Specific Aim 1 will use rat models to investigate diurnal variation in 1) incentive motivational value towards reward-associated cues using pavlovian conditioned approach task, 2) the degree to which cues increase instrumental responding using a pavlovian-instrumental transfer task, and 3) the subjective value of cocaine and corresponding motivation to take cocaine. We will also examine the magnitude of both DA and ACh signaling in the nucleus accumbens (NAc) core using ex vivo fast scan cyclic voltammetry across the light / dark cycles. Specific Aims 2 and 3 will utilize voltammetry, fiber photometry, and optogenetics in freely- behaving rats to measure diurnal modulation of phasic DA and CIN activity across a 24-hour day and define a circuit specific mechanism for differences in motivated behavior, cocaine seeking, and corresponding magnitude of NAc DA signals across the light and dark cycle.

项目概要 尽管对其生物机制和治疗方法进行了数十年的批判性研究，但药物使用 疾病（SUD）仍然是一个主要的世界健康问题。在过去几年中，大约 2100 万人 需要SUD治疗。尽管如此，近年来因服药过量死亡的人数急剧增加 海洛因、处方阿片类药物和可卡因。有趣的是，有一些研究表明昼夜节律 特定受体和神经递质系统的功能在一天中的时间发生强烈的变化，这些变化是常规的 与药物滥用脆弱性和复发有关。例如，昼夜（即明/暗）变化已被 在中脑边缘多巴胺 (DA) 系统中观察到，包括细胞外 DA 音调的节律、DA 转运蛋白水平/ 功能和 DA 受体功能。此外，对人类和动物模型的研究发现 一天中吸毒和寻求毒品的程度可能有所不同。虽然已发表的研究表明监管机构 DA 音调和音调调节剂的昼夜变化，致力于理解的研究存在很大差距 亚秒、阶段性 DA 释放中昼夜变化和昼夜节律的调节因子。这一点特别 鉴于阶段性 DA 释放在强化学习、动机和目标导向行为中的作用，这一点很重要 这在 SUD 中被改变。此外，很少有人致力于理解内在功能如何发挥作用。 阶段性 DA 释放的调节剂，例如来自纹状体胆碱能中间神经元的乙酰胆碱 (ACh)，在不同的阶段有所不同 一天中的某个时间。因此，本研究提案的总体目标是确定昼夜节律 快速 DA 和 ACh 信号传导的差异以及这些节律如何与 动机行为、可卡因/奖励寻求以及提示奖励关联。我们的中心假设是 是一天中个体对奖励和可卡因相关线索表现出更高敏感性的时间 可能导致可卡因寻求，这是由胆碱能中间神经元的时间变化介导的 快速 DA 信号传导的调节。具体目标 1 将使用大鼠模型来研究 1) 激励的昼夜变化 使用巴甫洛夫条件方法任务对奖励相关线索的动机价值，2） 使用巴甫洛夫工具转移任务来增加工具响应，3）主观 可卡因的价值以及服用可卡因的相应动机。我们还将检查 DA 的大小 使用离体快速扫描循环伏安法检测伏隔核（NAc）核心中的ACh和ACh信号传导 光/暗循环。具体目标 2 和 3 将利用伏安法、光纤光度法和光遗传学来自由地 行为大鼠测量 24 小时内阶段性 DA 和 CIN 活动的昼夜调节，并定义 动机行为、可卡因寻求和相应程度差异的电路特定机制 NAc DA 信号在光和暗周期中的分布。