Circadian Rhythms and Cocaine Use Disorder

项目总结 尽管几十年来对其生物学机制和治疗方法进行了批判性研究，但物质使用 精神障碍(SUD)仍然是一个主要的世界卫生问题。在过去的几年里，大约有2100万人 需要SUD治疗。尽管如此，近年来因服药过量而死亡的人数急剧增加。 海洛因、处方类阿片和可卡因。有趣的是，有一些研究表明昼夜节律 以及特定受体和神经递质系统功能的强健的一天中的时间变化 与药物滥用、脆弱和复发有关。例如，日变化(即，明/暗)一直是 在中脑边缘多巴胺(DA)系统中观察到的，包括细胞外DA张力、DA转运体水平的节律。 功能和DA受体功能。此外，在人类和动物模型中的研究都观察到 吸毒和寻求毒品的程度在一天中可能会有所不同。虽然已发表的作品展示了监管机构 在DA音调和音调调节器的昼夜变化中，致力于了解 亚秒期DA释放的昼夜变化和昼夜节律的调节器。这是特别的 重要的是，阶段DA释放在强化学习、动机和目标导向行为中的作用 这在南德被改变了。此外，很少有人致力于了解内在的功能是如何 来自纹状体胆碱能中间神经元的DA时相释放的调节剂，如乙酰胆碱(ACh)，在不同的 一天的时间。因此，这项研究建议的总体目标是确定昼夜节律 快速DA和ACh信号的差异以及这些节律如何机械地与 动机行为，可卡因/奖赏寻求，以及线索-奖赏联系。我们的中心假设是 个体对与奖励和可卡因相关的线索表现出更高的敏感度的时间段是 可以导致寻找可卡因，这是由胆碱能中间神经元的一天中的时间变化所介导的 调制快速DA信号。特定目标1将使用大鼠模型来研究1)激励中的日变化 巴甫洛夫条件接近任务对奖赏相关线索的激励价值，2) 这些线索使用巴甫洛夫-工具迁移任务增加了工具反应，以及3)主观反应 可卡因的价值和相应的吸食可卡因的动机。我们还将检查这两个DA的大小 用体外快速扫描循环伏安法研究伏核(NAC)核内ACh信号 光明/黑暗的循环。特定目标2和3将利用伏安法、纤维光度学和光遗传学在自由- 行为大鼠测量24小时内DA和CIN活性的昼夜变化，并定义 刺激行为、寻求可卡因和相应大小差异的电路特定机制 NAC DA信号在光暗周期中的变化。

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.