Drug targeting the dynamics of opioid systems in alcohol dependence

针对酒精依赖中阿片类药物系统动态的药物

基本信息

批准号：
10443881
负责人：
Remi Martin-Fardon
金额：
$ 51.92万
依托单位：
KAROLINSKA INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-20 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10443881
关键词：
Abstinence Acute Affect Alcohol abuse Alcohol consumption Alcohol dependence Amygdaloid structure Animal Behavior Animal Model Animals Attenuated Autopsy Behavioral Binding Binding Sites Brain Cell Culture Techniques Cell Nucleus Cell membrane Cells Chronic Clinical Clinical Trials Complex Country Data Dependence Dose Drug Targeting Dynorphins Elements Enkephalins Ethanol Ethanol dependence FDA approved Fluorescence Fluorescence Spectroscopy Future Gene Expression Genes Genetic Polymorphism Genotype Global Change Homo Image Imaging Techniques Immunohistochemistry In Situ Individual Investigation Lateral Length Life Lipids Longevity Medical Membrane Membrane Microdomains Mental Depression Microscopy Modeling Molecular Naltrexone Negative Reinforcements Neurons Opioid Opioid Antagonist Opioid Receptor Pharmaceutical Preparations Pilot Projects Proteins Publishing Rattus Reaction Receptor Signaling Recording of previous events Relapse Resolution Savings Scandinavian Signal Transduction Societies Specimen Spectrum Analysis System Techniques Technology Testing Time Transcript alcohol effect alcohol exposure alcohol use disorder antagonist behavioral phenotyping brain tissue clinical effect clinical examination craving dimer disorder later incidence prevention epidemiology study fluorescence imaging hedonic indexing insight interest kappa opioid receptors mu opioid receptors nanoscale neuropsychiatry novel overtreatment personalized medicine prevent receptor single molecule social tissue preparation trafficking translational approach

项目摘要

PROJECT SUMMARY Alcohol use disorder (AUD) is a serious condition with severe medical and societal consequences.There has been little progress in medical treatment over the past decades. We are taking a translational approach and have established an animal model, where alcohol-dependent rats in various stages of abstinence are subjects of investigation. The neuronal target is the opioid systems and the opponent hypothesis. We propose that the initial euphoric effects are channeled through the enkephalin/mu-opioid receptor (MOP) and the later developing negative reinforcement (craving) is related to activity at the dynorphin/kappa-opioid receptor (KOP). In fact, the MOP antagonist, naltrexone is a FDA-approved agent with indication to reduce relapse. KOP antagonists are entering clinical trials in different neuropsychiatric conditions. We have chosen CERC-501 as index drug, being reversible and apparently well tolerated in clinical examination. After behavioral recordings, brain specimens will be dissected and form a “brain bank” for further analysis. A focus of interest is the central nucleus of the amygdala (CeA), and the circuitry presenting MOP and/or KOP. Selected specimens will undergo superresolution microscopy (quantitative Single Molecule Localization Microscopy, qSMLM). A pilot study showed that already an acute dose of EtOH disrupts localization of MOP and KOP, an effect blocked by naltrexone. How EtOH affects receptor mobility in the plasma membrane, receptor clustering (homo- and hetero-dimers) and association with protein- and lipid-rich membrane domains will be studied by fluorescence correlation spectroscopy (FCS). As with qSMLM resolution is achieved at the single-molecule level. Both technologies will be used to study co- localization of receptors with proteins of relevance for the signaling cascade. We hypothesize that EtOH perturbs the dynamic selforganization of signaling domains harboring MOPs and KOPs, that distinct alterations in mechanisms controlling MOP vs KOP organization develop during chronic EtOH exposure. With OP antagonists innate MOP and KOP signaling complexes are stabilized at the nanoscale level. Focused studies of these mechanisms will provide critical new insight into molecular mechanisms through which EtOH-induced receptor disruptions may be prevented or reversed. The commensurate importance of the two opioid systems may vary between individuals and influence the choice of personalized therapy with OP antagonists. Studies will include the N40D MOP genotype known to affect the behavioral phenotype and sensitivity to naltrexone.

项目概要酒精使用障碍 (AUD) 是一种严重疾病，会造成严重的医疗和社会后果。过去几十年来，我们在医学治疗方面进展甚微。建立了一种动物模型，以处于不同戒酒阶段的酒精依赖大鼠为实验对象调查的神经目标是阿片类药物系统和对手假设。欣快效应通过脑啡肽/μ阿片受体（MOP）和后来发展的负强化（渴望）与强啡肽/κ-阿片受体（KOP）的活性有关。 MOP 拮抗剂纳曲酮是 FDA 批准的药物，可减少 KOP 拮抗剂的复发。我们选择CERC-501作为指标药物，进入不同神经精神疾病的临床试验。在临床检查中是可逆的并且明显具有良好的耐受性。被解剖并形成“大脑库”以供进一步分析感兴趣的焦点是杏仁核的中央核。 (CeA)，并且呈现 MOP 和/或 KOP 的电路将进行超分辨率。显微镜（定量单分子定位显微镜，qSMLM）的初步研究表明这一点。急性剂量的乙醇会破坏 MOP 和 KOP 的定位，而纳曲酮会阻断这种作用。质膜中的受体迁移率、受体聚类（同源和异源二聚体）以及与富含蛋白质和脂质的膜域将通过荧光相关光谱（FCS）进行研究。 qSMLM 分辨率是在单分子水平上实现的，这两种技术都将用于研究协同。我们发现乙醇会扰乱信号级联相关的受体的定位。含有 MOP 和 KOP 的信号域的动态自组织，长期接触 EtOH 时，控制 MOP 与 KOP 组织的机制会发展。固有的 MOP 和 KOP 信号复合物在纳米级水平上稳定。机制将为乙醇诱导受体的分子机制提供重要的新见解两种阿片类药物系统的相应重要性可能有所不同。个体之间的差异以及影响 OP 拮抗剂个体化治疗选择的研究将包括。 N40D MOP 基因型已知会影响行为表型和对纳曲酮的敏感性。