Beta-arrestin Regulation of Ghrelin Signaling in Modulating Addictive Behavior

β-抑制素对 Ghrelin 信号传导在调节成瘾行为中的调节

• 批准号: 8811411
• 负责人: LAWRENCE S. BARAK
• 金额: $ 19.33万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8811411
• 关键词: Actins; Addictive Behavior; Adverse effects; Affect; Amphetamines; Animal Model; Antipsychotic Agents; Arr2; Arrestins; Basic Science; Behavior; Biochemical; Biological Assay; Biology; Brain; Cell model; Clinical; Cocaine; Cytoskeleton; Data; Disease; Dopamine; Dopamine Receptor; Drug Addiction; Drug Controls; Drug abuse; Drug usage; Eating; Event; Family; Feeding behaviors; Foundations; Future; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; GTP-Binding Proteins; Goals; Health; Healthcare Systems; Hormones; Illicit Drugs; Individual; Investigation; Knockout Mice; Laboratories; Ligands; Mediating; Medical; Modeling; Molecular; Mus; National Institute of Drug Abuse; Neuraxis; Neuronal Plasticity; Neurons; Obesity; Outcome; Pathology; Pathway interactions; Pharmaceutical Preparations; Play; Property; Protein Isoforms; Proteins; Regulation; Regulatory Pathway; Relative (related person); Reporting; Resources; Rewards; Rodent; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Societies; Surveys; System; Testing; Therapeutic Studies; United States; Work; addiction; arm; behavioral response; beta-arrestin; cell type; comparative; design; drug induced behavior; drug of abuse; drug seeking behavior; ghrelin; ghrelin receptor; interest; neuropsychiatry; novel; preference; programs; ranpirnase; receptor; response; small molecule; therapy development; tool; trafficking

DESCRIPTION (provided by applicant): The use of illicit drugs by over twenty millions individuals in the United States negatively impacts both the economy and allocation of medical resources. Drugs of abuse can interfere with the brain's dopamine reward system, leading to a model in which drug taking and drug seeking behaviors are considered pathologies of the central nervous system. When viewed in the perspective of a disease, drug abuse becomes treatable with pharmacological therapies that seek to restore dopamine signaling to normal. The endogenous hormone ghrelin, which regulates food intake, appears to be one of the strongest modulators of CNS dopamine signaling underlying reward, and thus ghrelin receptors may be prime targets for antagonizing addictive behaviors. The GHSR1a ghrelin receptor, like typical G protein coupled receptors (GPCRs), signals through two pathways, one regulated by G-proteins and the other by ¿-arrestin (¿arr) proteins. Each signaling arm is thus a potential target for pharmacological regulation by either classical ligands or the newly recognized class of functionally selective biased ligands. However, the signaling events by which GHSR1a mediates the response to drugs of abuse and the relative contribution of ¿arr, which may be important to the modulation of dopaminergic circuit plasticity, have not been well detailed. Our NIDA (National Institute on Drug Abuse) sponsored P30 Center has a program in place to identify and characterize small molecule GPCR ligands useful for understanding and treating drug abuse. We believe the GHSR1a presents an outstanding pharmacological target for treating addiction and that ¿arr signaling will play an important role in modulating dopaminergic signaling to this end. To test our hypotheses we have two specific aims: 1. Characterize GHSR1a signal transduction pathways using a model cell system. We will (a) determine the contribution ¿arr versus G protein to GHSR1a trafficking and signaling, (b) modify molecular determinants underlying the interaction between GHSR1a and ¿arrs, (c) evaluate ¿arr versus G protein signaling bias and (d) establish a high throughput and secondary screens to identify ¿arr/G protein biased ligands; 2. Determine the role of ¿arrs in GHSR1a-mediated behaviors using an animal model. We will establish in wild-type and ¿arr2 knockout (¿arr2KO) mice that pharmacological suppression and/or activation of GHSR1a produces a change in the behavioral responses to cocaine while determining the role of ¿arr2 in these responses. These studies from a basic research perspective will assess the importance of ¿arrs to ghrelin receptor regulation of reward seeking behavior; providing in cell and animal models a framework for investigating classical ghrelin receptor ligands as well as identifying and characterizing functionally selective ones. These studies will also provide a paradigm for future comparative investigations with ¿arr1KO mice and dopamine receptor subtype KO mice. Altogether, our studies from a clinical perspective lay crucial groundwork for the expeditious and safe pharmacological exploitation of ghrelin signaling to reduce drug use and drug-seeking behaviors.

描述（由申请人提供）：在美国，超过两千万人使用非法药物对经济和医疗资源的分配产生了负面影响。滥用药物会干扰大脑的多巴胺奖励系统，导致一种模型，其中吸毒和寻求药物的行为被认为是中枢神经系统的病理。当从疾病的角度来看时，药物滥用可以通过药物治疗来治疗，这些药物治疗旨在恢复多巴胺信号正常。调节食物摄入的内源性激素ghrelin似乎是中枢神经系统多巴胺信号传导的最强调节剂之一，因此ghrelin受体可能是拮抗成瘾行为的主要靶点。GHSR 1a ghrelin受体与典型的G蛋白偶联受体（GPCR）一样，通过两条途径发出信号，一条受G蛋白调节，另一条受抑制蛋白（抑制蛋白）调节。因此，每个信号传导臂都是经典配体或新识别的功能选择性偏置配体类的药理学调节的潜在靶标。然而，GHSR 1a介导对滥用药物的反应的信号事件和多巴胺的相对贡献，这可能对多巴胺能回路可塑性的调节很重要，还没有得到很好的详细说明。我们的NIDA（国家药物滥用研究所）赞助的P30中心有一个程序，以确定和表征小分子GPCR配体有用的理解和治疗药物滥用。我们相信GHSR 1a是治疗成瘾的一个突出的药理学靶点，并且GHSR 1a信号传导将在调节多巴胺能信号传导中发挥重要作用。为了验证我们的假设，我们有两个具体的目标：1。使用模型细胞系统表征GHSR 1a信号转导途径。我们将（a）确定GHSR 1a转运和信号传导中GHSR 1a和G蛋白的贡献，（B）修饰GHSR 1a和GHSR 1a之间相互作用的分子决定因素，（c）评估GHSR 1a和G蛋白信号传导的偏倚，（d）建立高通量和二次筛选以鉴定GHSR 1a/G蛋白偏倚配体; 2.使用动物模型确定GHSR 1a介导的行为中Arrs的作用。我们将在野生型和<$arr2基因敲除（<$arr2KO）小鼠中建立GHSR 1a的药理学抑制和/或激活，从而改变对可卡因的行为反应，同时确定<$arr2在这些反应中的作用。从基础研究的角度来看，这些研究将评估的重要性？arrs的胃饥饿素受体调节的奖励寻求行为;在细胞和动物模型中提供了一个框架，调查经典的胃饥饿素受体配体，以及识别和表征功能选择性的。这些研究也将为未来的比较研究提供一个范例，与<$arr1KO小鼠和多巴胺受体亚型KO小鼠。总之，我们从临床角度的研究奠定了快速和安全的药理学开发的ghrelin信号，以减少药物使用和药物寻求行为的关键基础。