Understanding endogenous opioid drive of alcohol consumption

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。

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.