Circadian Rhythms and Cocaine Use Disorder

项目摘要 尽管数十年来对其生物学机制和治疗方法进行了重要研究， 疾病（SUD）仍然是一个主要的世界健康问题。在过去的几年里，大约有2100万人 需要SUD治疗。尽管如此，近年来由于药物过量而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， 以及特定受体和神经递质系统功能的强烈时间变化， 与药物滥用脆弱性和复发有关。例如，昼夜（即，亮/暗）变化 在中脑边缘多巴胺（DA）系统中观察到，包括细胞外DA张力的节律，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。虽然已发表的工作表明， 在DA音调和音调调节剂的昼夜变化，有一个很大的差距，在研究致力于了解 亚秒，阶段性DA释放的昼夜变化和昼夜节律的调节剂。这是特别 考虑到阶段性DA释放在强化学习、动机和目标导向行为中的作用， 在SUD中改变。此外，很少有工作致力于了解内在的功能是如何发挥作用的。 多巴胺阶段性释放的调节剂，如来自纹状体胆碱能中间神经元的乙酰胆碱（ACh）， 一天的时间。因此，本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律如何与 动机行为，可卡因/奖励寻求，和线索奖励协会。我们的核心假设是， 是一天中的时间，个体将表现出对奖励和可卡因相关线索的敏感性增加， 可以导致可卡因寻求，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 对奖励相关线索的激励价值，2）使用巴甫洛夫条件接近任务， 使用巴甫洛夫工具转移任务，哪些线索增加工具反应，以及3）主观 可卡因的价值和相应的吸食动机。我们还将研究DA和 和乙酰胆碱信号在核延髓（NAc）核心使用离体快速扫描循环伏安法跨 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， 行为大鼠在24小时内测量阶段性DA和CIN活性的昼夜调节，并定义 动机行为、可卡因寻求和相应幅度差异的电路特异性机制 在光暗周期中NAc DA信号的变化。

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.