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DEFINING DYNORPHIN-CRF CIRCUITS IN STRESS AND NICOTINE BEHAVIORS

定义压力和尼古丁行为中的强啡肽-CRF 回路

基本信息

批准号：
9766228
负责人：
Ream Al-Hasani
金额：
$ 24.9万
依托单位：
ST. LOUIS COLLEGE OF PHARMACY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9766228
关键词：
Amygdaloid structure Anatomy Anxiety Anxiety Disorders Attention Award Behavior Behavior Control Behavioral Paradigm Brain region CRF receptor type 1 Cell Nucleus Cells Cessation of life Characteristics Chronic Chronic stress Corticotropin-Releasing Hormone Data Development Drug Addiction Drug abuse Dynorphins Exposure to Goals Incidence Intake Internal Ribosome Entry Site Knockout Mice Lead Learning Link Measures Mediating Mediation Mediator of activation protein Mental Depression Mentors Microdialysis Modeling Mus Negative Reinforcements Neurons Neuropeptides Neurosciences Nicotine Nicotine Dependence Nicotine Withdrawal Nucleus Accumbens Pathway interactions Pharmaceutical Preparations Pharmacology Phase Population Property Receptor Activation Regulation Relapse Research Role Serotonergic System Signal Transduction Site Source Stress Substance Withdrawal Syndrome System Technical Expertise Technology Testing Therapeutic Tobacco use Training Wireless Technology Withdrawal Work acute stress anxiety-like behavior behavioral pharmacology behavioral response biological adaptation to stress cell type cigarette smoking drug abuse vulnerability drug withdrawal dysphoria in vivo insight kappa opioid receptors liquid chromatography mass spectrometry multidisciplinary negative affect negative emotional state neural circuit neurochemistry nicotine exposure nicotine seeking behavior nicotine use novel optical fiber optogenetics public health relevance side effect small molecule smoking cessation success transmission process

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this research is to better understand role of dynorphin and CRF in negative affective behaviors that are associated with nicotine withdrawal. Both dynorphin and CRF systems have been shown to drive stress and aversive behaviors but few studies have determined how these systems modulate one another to drive these behaviors through the extended amygdala. Dynorphin/Kappa Opioid Receptor (KOR) activity has been known to mediate negative emotional states inducing, dysphoria, aversions, and depression. CRF also produces dysphoria, aversion and anxiety-like behavior via dynorphinergic interactions, and it has been hypothesized that the increased release of CRF may be a primary contributor in the development of anxiety disorders. Therefore, we propose to examine the role and interactions of CRF and dynorphin in the mediation of aversive behaviors and whether this in turn modulates nicotine withdrawal. This five-year project has three specific aims. In the first aim (during the K99 phase) we will determine whether dynorphin regulates aversion in the ventral NAc. The second aim (during the K99 phase) is to examine the mechanisms in which nicotine interacts with the dynorphin/kappa opioid system to regulate negative affective behaviors. Here we will determine whether stimulation of dynorphin containing neurons in the NAc mediates aversion and withdrawal behavior and whether this is KOR-dependent. In these aims we will quantify dynorphin release in the NAc following optogenetic stimulation. During the R00 independent phase (Aim 3) we will quantify dynorphin release in the NAc before and following chronic nicotine exposure. We will also optogenetically stimulate CeA- CRF containing neurons and measure dynorphin release in the NAc, to examine whether CRF regulates dynorphin release and behavior characteristic of withdrawal. Since, both CRF and dynorphin are involved in the stress response and preliminary data has shown that chronic stress can block KOR-induced drug seeking, we will also determine the role of CRF1-R/KOR interactions in reinstatement of nicotine seeking, following exposure to stress. Together this work has important therapeutic implications as it will enhance our understanding of dynorphin/CRF cell-types, neural circuits that modulate negative affective behaviors.

描述(申请人提供)：这项研究的总体目标是更好地了解强啡肽和CRF在与尼古丁戒断相关的负面情感行为中的作用。强啡肽和CRF系统都被证明可以驱动应激和厌恶行为，但很少有研究确定这些系统如何相互调节，通过延伸的杏仁核来驱动这些行为。强啡肽/Kappa阿片受体(KOR)的活性被认为是介导负性情绪诱导、烦躁不安、厌恶和抑郁的媒介。CRF还通过强啡肽能相互作用产生烦躁、厌恶和焦虑样行为，推测CRF释放的增加可能是焦虑症发生的主要因素。因此，我们建议研究CRF和强啡肽在调节厌恶行为中的作用和相互作用，以及这是否反过来调节尼古丁戒断。这个五年计划有三个具体目标。在第一个目标中(在K99阶段)，我们将确定强啡肽是否调节腹侧NAc中的厌恶。第二个目标(在K99阶段)是研究尼古丁与强啡肽/kappa阿片系统相互作用以调节负面情感行为的机制。在这里，我们将确定刺激NAC中含有强啡肽的神经元是否介导厌恶和戒断行为，以及这是否依赖于KOR。在这些目标中，我们将量化光遗传刺激后NAC中强啡肽的释放。在R00非依赖阶段(目标3)，我们将量化慢性尼古丁暴露前后NAC中强啡肽的释放。我们还将光基因刺激含有CEA-CRF的神经元，并测量NAC中强啡肽的释放，以检测CRF是否调节强啡肽的释放和戒断的行为特征。由于CRF和强啡肽都参与了应激反应，并且初步数据表明慢性应激可以阻止KOR诱导的药物寻找，我们还将确定CRF1-R/KOR相互作用在应激后恢复尼古丁寻找中的作用。总之，这项工作具有重要的治疗意义，因为它将加强我们对强啡肽/CRF细胞类型的理解，这些细胞类型是调节负面情感行为的神经回路。