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Understanding endogenous opioid drive of alcohol consumption

了解饮酒的内源性阿片类药物驱动力

基本信息

批准号：
10190738
负责人：
Elyssa Margolis
金额：
$ 36.34万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-10 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10190738
关键词：
Affect Affinity Agonist Alcohol consumption Alcoholism Amygdaloid structure Animals Behavioral Brain region Cleaved cell Collaborations Complication Consumption Dependence Development Dynorphin A Electrophysiology (science)Elements Endorphins Ethanol Globus Pallidus Heavy Drinking Hypothalamic structure Injections Leucine Enkephalin Ligands Link Measures Mediating Messenger RNA Methionine Enkephalin Microdialysis Modeling Molecular Motivation Neuraxis Neurons Neurotransmitters Opioid Opioid Antagonist Opioid Peptide Opioid Receptor Opioid agonist Peptide Fragments Peptides Phenotype Population Pro-Opiomelanocortin Protein Precursors Rattus Receptor Activation Receptor Inhibition Receptor Signaling Signal Transduction Site Slice Source Stress Structure of nucleus infundibularis hypothalami Synapses Testing Therapeutic Agents Time Training Ventral Tegmental Area Withdrawal alcohol abuse therapy alcohol measurement base behavioral pharmacology delta opioid receptor design dopaminergic neuron drinking drinking behavior endogenous opioids experience experimental study gamma-Aminobutyric Acid improved in vivo kappa opioid receptors knock-down motivated behavior mu opioid receptors negative affect optogenetics postsynaptic pre-prodynorphin preproenkephalin receptor receptor expression receptor function relating to nervous system response synaptic function targeted treatment

项目摘要

PROJECT SUMMARY Endogenous opioids released in the Central Nervous System by drinking alcohol promote continued consumption. The endogenous opioid peptides are fragments of larger precursor peptides (preproenkephalin (PPENK), preprodynorphin (PPDYN) and pro-opiomelanocortin (POMC)) are implicated in regulating alcohol intake. The fragments that are actually released are unknown, however the known POMC and PPENK derived peptide fragments act both the mu and delta opioid receptors (MORs and DORs, respectively). We found that endogenous opioids acting at the DOR can protect against high levels of alcohol consumption, while opioids acting the MOR promote alcohol consumption. To better understand how endogenous opioids control ethanol consumption and to develop new opioid based therapeutic agents we need to determine how MORs and DORs are dynamically regulated and interact. Furthermore, a full understanding of how they regulate ethanol consumption will require identification of which opioid peptides fragments are released by drinking and then testing the action of these peptides at synaptic elements that express both receptors and are involved in regulating ethanol consumption. The ventral tegmental area (VTA) is a site where opioids act to control ethanol consumption. MOR selective antagonists injected into the VTA reduce while DOR antagonists increase ethanol consumption. Both MOR and DOR selective ligands have synaptic actions in the VTA that correlate with alcohol consumption. In this project we will study the interaction of MOR, DOR and kappa opioid receptor agonists on VTA synaptic function. We will collect and identify endogenous opioid peptides released in the VTA during voluntary ethanol drinking, then test the action of these peptides on opioid receptor expressing synaptic elements in the VTA. We will also use optogenetic approaches to activate and inhibit specific sources of opioid peptide input to the VTA to determine the critical circuit inputs that modify drinking behavior. This information will be used to better understand the molecular mechanisms that promote and inhibit alcohol consumption and to design new, more effective opioid ligands for the treatment of alcohol abuse.

项目摘要饮酒促进中枢神经系统释放内源性阿片类物质消费内源性阿片肽是较大的前体肽（前脑啡肽原）的片段前强啡肽原（PPENK）、前强啡肽原（PPDYN）和前阿黑皮素原（POMC））参与调节酒精摄入实际释放的片段是未知的，然而已知的POMC和PPENK衍生物肽片段作用于μ和δ阿片受体（分别为MORs和DORs）。我们发现作用于DOR的内源性阿片类药物可以防止高水平的酒精消耗，而阿片类药物莫尔促进酒精消费。为了更好地了解内源性阿片类物质如何控制乙醇消费和开发新的阿片类药物为基础的治疗药物，我们需要确定如何MORs和 DOR是动态调节和相互作用的。此外，充分了解他们如何调节乙醇消费将需要识别哪些阿片肽片段通过饮酒释放，然后测试这些肽在表达两种受体的突触元件上的作用，调节乙醇消耗。腹侧被盖区（VTA）是阿片类药物发挥作用的部位，乙醇消费VTA内注射的莫尔选择性拮抗剂减少，而DOR拮抗剂增加乙醇消费莫尔和DOR选择性配体在腹侧被盖区都有突触作用，酒精消费。本课题主要研究莫尔、DOR与κ阿片受体的相互作用 VTA突触功能的激动剂。我们将收集和鉴定内源性阿片肽释放在 VTA，检测这些肽对阿片受体表达的影响腹侧被盖区的突触成分我们还将使用光遗传学方法来激活和抑制特定的来源阿片肽输入到腹侧被盖区，以确定改变饮酒行为的关键回路输入。这这些信息将用于更好地了解促进和抑制酒精的分子机制消费和设计新的，更有效的阿片类药物配体用于治疗酒精滥用。