Diurnal Variation in Acetylcholine Modulation of Dopamine Dynamics Following Chronic Cocaine Intake

项目摘要 2020年，估计有520万美国人报告使用可卡因，其中130万人符合可卡因的标准 使用障碍。尽管需求不断增加，但没有FDA批准的CUD治疗方法。一个变量 在CUD研究中经常被忽视的是昼夜节律（24小时）和昼夜节律（夜间/白天）的破坏 节奏节律紊乱已被证明会延长可卡因滥用的周期，并增加 复发CUD可以用可卡因自我给药（SA）建模，使用三种不同的可卡因模式 摄入量：短连续接入（ShA）、长连续接入（LgA）和间歇接入（IntA）。虽然我们的 实验室已经建立了多巴胺（DA）动力学节律的昼夜变化，包括胆碱能中间神经元 (CIN)调节和DA再摄取的幼稚动物，目前还不清楚如何适应可卡因的类型 SA摄入模式差异影响这些节奏和机制途径涉及以下长期 可卡因摄入量中脑边缘多巴胺系统位于中脑核核心区（NAc），是多巴胺受体的重要介导者。 动机和奖励相关的行为，是不适应的CUD。CINs是一种重要的调节剂， 中脑边缘DA在NAc中的释放通过它们激活DA末端上的乙酰胆碱（ACh）受体。而 长期可卡因对DA信号和CIN/ACh活性的影响已被广泛研究 点，该领域的一个主要障碍是可卡因诱导的DA信号节律和电位的变化， 尚未研究节律中断的机制，例如CIN信号传导的改变。因此，在本发明中， 我的中心假设是双重的：1）发现长期自愿摄入可卡因对时间的影响- DA和ACh NAc信号传导中的日节律，以及2）概述了ACh节律之间的机械联系 和DA信号拟议的研究计划将检查节律在DA释放和CIN活动中的作用 （1）评估可卡因的使用历史和使用模式， 摄入对NAc DA释放日变化的影响;（2）研究DA昼夜节律被破坏的机制 可卡因暴露的动物中的DA释放，以及（3）定义CIN调节DA释放的时间结构 可卡因暴露的动物中的剂量。这些研究将突出内源性昼夜变化的重要性， 慢性可卡因摄入模式后NAc神经化学的节律，以提供更好的机制见解 节奏在CUD中的作用。了解CUD神经化学基础节律的影响， 提供新的治疗目标，并提出一天中最有效的治疗时间。

Project Summary In 2020, an estimated 5.2 million Americans reported using cocaine, with 1.3 million meeting criteria for Cocaine Use Disorder (CUD). Despite the increasing need, there are no FDA-approved treatments for CUD. One variable that is often overlooked in CUD research is the resulting disruption of circadian (24-hour) and diurnal (night/day) rhythms. Disrupted rhythms have been shown to prolong the cycle of cocaine abuse and increase the risk of relapse. CUD can be modeled with cocaine self-administration (SA) using three different patterns of cocaine intake: short continuous access (ShA), long continuous access (LgA), and intermittent access (IntA). Though our lab has established diurnal variation in rhythms of dopamine (DA) dynamics, including cholinergic interneuron (CIN) modulation and DA reuptake in naïve animals, it is not yet understood how adapting the type of cocaine SA intake pattern differentially affects these rhythms and the mechanistic pathways involved following long-term cocaine intake. The mesolimbic DA system in the nucleus accumbens core (NAc) is an important mediator of motivated and reward-associated behaviors that are maladapted in CUD. CINs are critical modulators of mesolimbic DA release in the NAc via their activation of acetylcholine (ACh) receptors on DA terminals. While the effects of chronic cocaine on DA signals and CIN/ACh activity have been studied extensively at single time points, a major obstacle in the field is that cocaine-induced changes in DA signaling rhythms and potential mechanisms for rhythmic disruptions, such as alterations in CIN signaling, have not been investigated. Thus, my central hypothesis is twofold: 1) to discover the effect of long-term, voluntary cocaine intake on time- of-day rhythms in DA and ACh NAc signaling, and 2) outline a mechanistic link between rhythms of ACh and DA signaling. The proposed research plan will examine the role of rhythms in DA release and CIN activity under various patterns of cocaine access with the following aims: (1) Assess the cocaine history and pattern of intake on diurnal variation in NAc DA release, (2) Examine a mechanism for disrupted diurnal rhythms in DA release in cocaine-exposed animals, and (3) Define the temporal architecture of CIN modulation of DA release magnitude in cocaine-exposed animals. These studies will highlight the importance of endogenous diurnal rhythms in NAc neurochemistry following chronic cocaine intake patterns to provide greater mechanistic insight into the role of rhythms in CUD. Understanding the influence of rhythms underlying CUD neurochemistry will provide novel treatment targets and propose times throughout the day in which to target them most effectively.