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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要 2020 年，估计有 520 万美国人报告使用可卡因，其中 130 万符合可卡因标准尽管需求不断增加，但目前还没有 FDA 批准的针对 CUD 的治疗方法。 CUD 研究中经常被忽视的是由此造成的昼夜节律（24 小时）和昼夜节律（夜间/白天）的扰乱节律紊乱已被证明会延长可卡因滥用的周期并增加吸食可卡因的风险。 CUD 可以使用三种不同的可卡因模式通过可卡因自我给药 (SA) 进行建模。摄入量：短时间连续访问（ShA）、长时间连续访问（LgA）和间歇访问（IntA）。实验室已确定多巴胺 (DA) 动态节律的昼夜变化，包括胆碱能中间神经元 (CIN) 在幼稚动物中的调节和 DA 重摄取，目前尚不清楚如何适应可卡因的类型 SA 摄入模式对这些节律和长期运动后涉及的机制途径有不同的影响伏隔核 (NAc) 中的中脑边缘 DA 系统是可卡因摄入的重要介质。 CIN 中不适应的动机和奖励相关行为是 CIN 的关键调节因素。中脑边缘 DA 通过激活 DA 末端的乙酰胆碱 (ACh) 受体在 NAc 中释放。慢性可卡因对 DA 信号和 CIN/ACh 活性的影响已被一次性广泛研究点，该领域的一个主要障碍是可卡因引起的 DA 信号节奏和电位的变化节律破坏的机制，例如 CIN 信号传导的改变，尚未得到研究。我的中心假设有两个：1）发现长期自愿摄入可卡因对时间的影响- DA 和 ACh NAc 信号传导中的日间节律，2) 概述了 ACh 节律之间的机制联系拟议的研究计划将研究节律在 DA 释放和 CIN 活动中的作用。不同的可卡因获取模式，其目的如下： (1) 评估可卡因的历史和模式摄入量对 NAc DA 释放的昼夜变化的影响，(2) 检查 DA 昼夜节律被破坏的机制暴露于可卡因的动物中的释放，以及 (3) 定义 CIN 调节 DA 释放的时间结构这些研究将强调内源性昼夜节律的重要性。慢性可卡因摄入模式后的 NAc 神经化学节律，以提供更深入的机制洞察了解节律在 CUD 中的作用将有助于了解节律对 CUD 神经化学的影响。提供新的治疗目标，并建议一天中最有效地针对这些目标的时间。