Understanding endogenous opioid drive of alcohol consumption

项目总结 饮酒促进中枢神经系统释放内源性阿片 消费。内源性阿片肽是较大的前体多肽(前脑啡肽原)的片段 前强啡肽(PPENK)、前强啡肽原(PPDYN)和前阿片黑素皮质素(POMC)与酒精调节有关 入口处。实际释放的片段是未知的，但已知的POMC和PPENK是从 多肽片段既作用于MU受体，也作用于Delta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费，而阿片类药物 代理农业部促进了酒精消费。为了更好地了解内源性阿片类药物如何控制乙醇 为了开发新的基于阿片类药物的治疗药物，我们需要确定MORS和 DORS受到动态监管并相互作用。此外，对他们如何监管乙醇的充分理解 消费将需要识别哪些阿片肽片段是通过饮酒释放的，然后 测试这些多肽对表达这两种受体并参与其中的突触元件的作用 规范乙醇消费。腹侧被盖区(VTA)是阿片类药物起控制作用的部位 乙醇消耗量。注射到VTA的MOR选择性拮抗剂减少而DOR拮抗剂增加 乙醇消耗量。MOR和DOR选择性配体在VTA中都有突触作用 与饮酒有关。在本项目中，我们将研究MOR、DOR和kappa阿片受体的相互作用 VTA突触功能的激动剂。我们将收集和鉴定体内释放的阿片肽 自愿饮酒时的VTA，然后检测这些多肽对阿片受体表达的作用 室旁核内的突触成分。我们还将使用光遗传方法来激活和抑制特定来源 阿片肽输入到VTA，以确定改变饮酒行为的关键电路输入。这 信息将被用来更好地理解促进和抑制酒精的分子机制 为治疗酗酒而设计新的、更有效的阿片类药物配体。

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.