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

• 批准号: 10032660
• 负责人: Remi Martin-Fardon
• 金额: $ 52.32万
• 依托单位: KAROLINSKA INSTITUTE
• 依托单位国家: 美国
• 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/10032660
• 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; 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

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，医学治疗进展甚微。我们正在采取转化方法并已 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。神经元目标是阿片类药物系统和对手假设。我们建议最初 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。事实上， MOP 拮抗剂纳曲酮是 FDA 批准的药物，可减少复发。 KOP 的拮抗剂是 进入不同神经精神疾病的临床试验。我们选择CERC-501作为指标药物， 在临床检查中是可逆的并且明显耐受性良好。行为记录后，大脑样本将 进行解剖并形成“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)，以及呈现 MOP 和/或 KOP 的电路。选定的样本将进行超分辨率处理 显微镜（定量单分子定位显微镜，qSMLM）。一项试点研究表明，已经 急性剂量的乙醇会破坏 MOP 和 KOP 的定位，而纳曲酮可阻断这种作用。乙醇如何影响 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。作为 qSMLM 分辨率可在单分子水平上实现。这两种技术都将用于研究合作 受体与信号级联相关蛋白的定位。我们假设 EtOH 会干扰 含有 MOP 和 KOP 的信号域的动态自组织， 控制 MOP 与 KOP 组织的机制是在长期接触 EtOH 期间形成的。与OP拮抗剂 固有的 MOP 和 KOP 信号复合物在纳米级水平上稳定。重点研究这些 机制将为乙醇诱导受体的分子机制提供重要的新见解 干扰是可以预防或逆转的。两种阿片类药物系统的相应重要性可能有所不同 个体之间的差异并影响 OP 拮抗剂个体化治疗的选择。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。