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

慢性可卡因摄入后乙酰胆碱对多巴胺动力学调节的昼夜变化

• 批准号: 10679573
• 负责人: MELODY Courtney-Lynn IACINO
• 金额: $ 4.77万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-15 至 2025-03-14
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10679573
• 关键词: Acetylcholine; Affect; American; Animals; Architecture; Behavior; Biological Rhythm; Cells; Cholinergic Receptors; Chronic; Circadian Dysregulation; Cocaine; Cocaine Abuse; Cocaine use disorder; Consumption; Corpus striatum structure; Cues; Darkness; Data; Development; Disease; Diurnal Rhythm; Dopamine; Drug usage; Electrophysiology (science); Exhibits; FDA approved; Fiber; Hour; Intake; Interneurons; Intravenous; Light; Link; Long-Term Effects; Mediator; Modeling; Neurons; Nicotinic Receptors; Nucleus Accumbens; Pathway interactions; Pattern; Periodicity; Persons; Phase; Photometry; Rattus; Recording of previous events; Relapse; Reporting; Research; Rewards; Risk Factors; Rodent; Role; Self Administration; Signal Transduction; Time; United States; Variant; cholinergic; cocaine exposure; cocaine seeking; cocaine self-administration; cocaine use; fluorescence imaging; insight; meetings; mesolimbic system; motivated behavior; neural; neural circuit; neurochemistry; novel; patch clamp; relapse risk; response; reuptake

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.

项目摘要 2020年，估计有520万美国人报告使用可卡因，有130万人满足可卡因的标准 使用障碍（CUD）。尽管需求越来越大，但没有FDA批准的CUD治疗方法。一个变量 在CUD研究中通常会忽略这是昼夜节律的破坏（24小时）和昼夜的中断 节奏。已证明有破坏的节奏可以延长可卡因滥用的周期，并增加 复发。 CUD可以使用可卡因的三种不同模式以可卡因自我管理（SA）建模 进气：短连续访问（SHA），长连续访问（LGA）和间歇访问（INTA）。虽然我们的 实验室已经建立了多巴胺（DA）动力学节奏的昼夜变化，包括胆碱能中间神经元 （CIN）幼稚动物的调制和DA重新摄取，尚不了解可卡因类型 SA摄入模式对这些节奏和长期后涉及的机械途径有所不同 可卡因摄入量。伏隔核（NAC）中的中脑纤维DA系统是 在CUD中不良的动机和奖励相关行为。 CIN是关键调节器 中脑纤维DA通过在DA末端的乙酰胆碱（ACH）受体的激活在NAC中释放。尽管 慢性可卡因对DA信号和CIN/ACH活性的影响已在一次广泛研究 要点，该领域的主要障碍是可卡因诱导的DA信号节奏的变化和潜力的变化 尚未研究有节奏破坏的机制，例如CIN信号的改变，尚未研究。那， 我的中心假设是双重的：1）发现长期，自愿可卡因摄入对时间的影响 - DA和ACH NAC信号的日期节奏，以及2）概述ACH节奏之间的机械联系 和DA信令。拟议的研究计划将检查节奏在DA和CIN活动中的作用 在可卡因访问的各种模式下，以下目的：（1）评估可卡因的历史和模式 NAC DA释放中昼夜变化的摄入量，（2）检查DA中破坏昼夜节奏的机制 在可卡因暴露的动物中释放，（3）定义DA释放的CIN调制的临时结构 可卡因暴露动物的大小。这些研究将突出内源性昼夜的重要性 慢性可卡因摄入模式后，NAC神经化学的节奏可提供更大的机械洞察力 进入节奏在cud中的作用。了解基本的CUD神经化学的影响 全天提供新颖的治疗目标和建议时间，以最有效地针对它们。