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130万人符合可卡因标准 使用紊乱(CUD)。尽管需求不断增加，但目前还没有FDA批准的治疗CUD的方法。一个变量 在CUD研究中经常被忽视的是由此造成的昼夜节律(24小时)和昼夜(夜间/白天)的干扰。 节奏。研究表明，节奏紊乱会延长可卡因滥用的周期，并增加 旧病复发。使用三种不同的可卡因模式可以用可卡因自我给药(SA)来模拟CUD 摄取：短连续通路(SHA)、长持续通路(LGA)和间歇性通路(INTA)。虽然我们的 LAB已经确定了多巴胺(DA)动态节律的日变化，包括胆碱能中间神经元 (CIN)调制和幼稚动物的DA再摄取，目前尚不清楚如何适应可卡因的类型 SA摄取模式不同地影响这些节律和长期服用后涉及的机械途径 可卡因摄入量。伏核(NAC)内的中脑边缘DA系统是一种重要的中枢神经递质。 在CUD中不适应的动机和奖赏相关行为。CINS是关键的调节器 中脑边缘DA的释放是通过激活DA终末上的乙酰胆碱(ACh)受体实现的。而当 慢性可卡因对DA信号和CIN/ACh活性的影响已被广泛研究 该领域的一个主要障碍是可卡因诱导DA信号节律和电位的变化 节律紊乱的机制，例如CIN信号的改变，还没有被研究过。因此， 我的中心假设有两个：1)发现长期自愿吸食可卡因对时间的影响-- DA和ACh NAC信号的日节律，以及2)概述了ACh节律之间的机制联系 和DA信号。拟议的研究计划将检查节律在DA释放和CIN活性中的作用 在各种可卡因获取模式下，目标如下：(1)评估可卡因的历史和模式 摄入量对NAC DA释放的日变化的影响，(2)研究DA昼夜节律紊乱的机制 可卡因暴露动物的释放，以及(3)定义了CIN调节DA释放的时间结构 暴露在可卡因中的动物的数量。这些研究将突出内源性昼夜节律的重要性。 慢性可卡因摄入模式下NAC神经化学的节律提供更大的机械洞察力 节奏在CUD中的作用。了解CUD神经化学基础节律的影响将 提供新的治疗目标，并提出一天中最有效的目标时间。

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.