Circadian Rhythms and Cocaine Use Disorder

昼夜节律和可卡因使用障碍

• 批准号: 10632122
• 负责人: Mark J Ferris
• 金额: $ 42.11万
• 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/10632122
• 关键词: Acetylcholine; Animal Model; Animals; Architecture; Association Learning; Behavior; Behavior assessment; Biological; Brain; Circadian Rhythms; Cocaine; Cocaine use disorder; Consumption; Corpus striatum structure; Cues; Darkness; Data; Dedications; Development; Diurnal Rhythm; Dopamine; Dopamine Receptor; Economics; Exhibits; Fiber; Frequencies; Goals; Heroin; Hour; Incentives; Individual; Interneurons; 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; brain based; cholinergic; circadian; cocaine related behaviors; cocaine reward; cocaine seeking; 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; neural; non-drug; optogenetics; overdose death; prescription opioid; receptor; receptor function; response; restoration; shift work; substance use treatment; therapeutic target; Acetylcholine; Animal Model; Animals; Architecture; Association Learning; Behavior; Behavior assessment; Biological; Brain; Circadian Rhythms; Cocaine; Cocaine use disorder; Consumption; Corpus striatum structure; Cues; Darkness; Data; Dedications; Development; Diurnal Rhythm; Dopamine; Dopamine Receptor; Economics; Exhibits; Fiber; Frequencies; Goals; Heroin; Hour; Incentives; Individual; Interneurons; 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; brain based; cholinergic; circadian; cocaine related behaviors; cocaine reward; cocaine seeking; 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; neural; non-drug; optogenetics; overdose death; prescription opioid; receptor; receptor function; 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.

项目摘要 尽管对其生物学机制和治疗方法进行了数十年的批判性研究，但使用物质 疾病（SUD）一直是世界重大健康问题。在过去的几年中，大约有2100万人 需要SUD治疗。尽管如此，近年来，到期的过量死亡人数急剧增加 致海洛因，处方阿片类药物和可卡因。有趣的是，有一些工作暗示了昼夜节律 以及定期定期的特定受体和神经递质系统功能的稳定时间变化 涉及滥用药物的脆弱性和复发。例如，昼夜（即光/黑暗）变化已经存在 在中脑脱离多巴胺（DA）系统中观察到，包括细胞外DA的节奏，DA转运蛋白水平/ 功能和DA受体功能。此外，人类和动物模型的研究都观察到 吸毒和寻求水平的水平在整天可能会有所不同。虽然已发表的作品展示了监管机构 DA音调和音调调节剂的昼夜变化，专门用于理解的研究差距很大 在阶段DA释放中，昼夜变化和昼夜节律的调节剂。尤其是 考虑到阶段性DA释放在强化学习，动机和目标指导行为中的作用很重要 这在SUD中发生了变化。此外，很少有工作专门用于理解内在的功能 阶段性DA释放的调节剂，例如纹状体胆碱能中间神经元的乙酰胆碱（ACH），跨越 一天的时间。因此，该研究建议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奏如何机械地与变化有关 动机行为，可卡因/奖励寻求和提示奖励关联。我们的中心假设是 是当日个人对奖励和可卡因相关线索的敏感性提高，这些线索的敏感性 可以导致可卡因寻求，这是由胆碱能中的日期变化介导的 调节快速DA信号传导。具体目标1将使用大鼠模型研究昼夜变化1）激励措施 使用Pavlovian条件方法任务朝着奖励相关提示的动机价值，2） 提示使用帕夫洛夫 - 乐器转移任务增加工具性响应，3）主观 可卡因的价值和采用可卡因的相应动机。我们还将检查两个DA的大小 使用离体快速扫描循环伏安法在伏隔核（NAC）核中的ACH信号传导跨整个 轻 /黑暗周期。特定目的2和3将在自由地使用伏安法，纤维光度法和光遗传学 行为大鼠在24小时的时间里测量阶段性DA和CIN活动的昼夜调制，并定义A 电路特定的机制，以动机行为，可卡因寻求和相应的幅度差异 NAC DA信号在光周期和黑暗周期上。