Mechanisms underlying neuropeptide release in the extended amygdala

扩展杏仁核中神经肽释放的机制

• 批准号: 9898253
• 负责人: Scott D. Moore
• 金额: --
• 依托单位: DURHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898253
• 关键词: Accounting; Acute; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcohol-Related Disorders; Alcoholism; Amygdaloid structure; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Behavior; Behavioral; Biological; Brain; Brain region; Cell Nucleus; Chronic; Clinical; Corticotropin-Releasing Hormone; Data; Development; Diagnosis; Dynamin; Dynamin I; Electrophysiology (science); Enzymes; Ethanol; Frequencies; Individual; Intervention; Knowledge; Link; Measures; Mediating; Medical; Methods; Naltrexone; Neurons; Neuropeptides; Operative Surgical Procedures; Opioid Peptide; Peptides; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Physiological; Play; Potassium Channel; Presynaptic Terminals; Proteins; Proteomics; Role; Services; Stimulus; Stress; Synaptic Transmission; Techniques; Testing; Therapeutic; Therapeutic Studies; United States Department of Veterans Affairs; Veterans; Withdrawal; alcohol craving; alcohol effect; alcohol exposure; alcohol reinforcement; alcoholism therapy; anxious; behavioral study; channel blockers; comorbidity; endogenous opioids; experience; inhibitor/antagonist; large-conductance calcium-activated potassium channels; novel; optogenetics; pre-clinical; release factor; response

Although endogenous neuropeptide transmitters play critical roles in the reinforcing effects of ethanol consumption and the aversive effects of ethanol withdrawal, we have a poor understanding of mechanism(s) underlying central neuronal release of neuropeptides. This gap in our knowledge critically undermines our abilities to elucidate the biological effects of ethanol (EtOH), as 1) multiple studies have demonstrated that acute and chronic EtOH induces release of neuropeptides in brain regions associated with EtOH reinforcement and withdrawal-induced aversion, and 2) one of the very few medications (naltrexone) commonly used to treat EtOH craving is assumed to act by antagonizing effects of endogenously-released opioid peptides. Multiple behavioral studies document involvement of endogenous neuropeptides in response to stress, drugs and other behavioral states, but we still know very little about the physiological mechanisms underlying neuropeptide release. Howevever, this knowledge could significantly enhance our ability to create novel pharmacotherapies for alcohol dependence. Previous studies from our lab and others have shown enhanced release of neuropeptides in the central nucleus of the amygdala (CeA) by acute EtOH exposure. In addition, several studies have shown persistent release of specific peptides following withdrawal from chronic intermittent EtOH; these peptides may mediate the “anxious-like” withdrawal behaviors. However, our current preliminary data suggest that many conventional notions of peptide release may be inaccurate or incomplete; specifically, high-frequency activity is neither sufficient nor necessary for peptide release. We have recently begun exploring potential cellular phenomena that could regulate peptide release and our preliminary data demonstrate that we can relatively selectively induce release of the neuropeptide corticotropin-releasing factor (CRF) using optogenetic methods. In addition, we have characterized the potential role of the BK potassium channel in mediating EtOH effects. Proteomic analysis has shown that the BK channel is linked to the intracellular enzyme dynamin-1, a protein essential for mediating peptide release. We hypothesize that in contrast to fast synaptic transmission at axonal terminals, central neuropeptide release is mediated by a mechanism dependent on both the BK channel and dynamin-1. Because of the wealth of preclinical data implicating endogenous neuropeptides in effects of ethanol consumption and the clinical experience with naltrexone (which acts by blocking effects of endogenous opioid peptides), we believe that mechanistic studies of the physiological and ethanol-induced release of peptides in the extended amygdala may facilitate development of novel pharmacotherapies for the treatment of alcoholism.

虽然内源性神经肽递质在增强效应中起着关键作用， 乙醇消费和乙醇戒断的不良影响，我们有一个穷人 理解中枢神经元释放神经肽的潜在机制。这一差距 严重削弱了我们阐明乙醇生物效应的能力 （EtOH），因为1）多项研究表明，急性和慢性EtOH诱导释放 与EtOH强化和戒断诱导相关的脑区中神经肽的变化 厌恶，和2）常用治疗EtOH的极少数药物之一（纳曲酮） 据推测，渴望通过拮抗内源性释放的阿片肽的作用而起作用。 多项行为研究记录了内源性神经肽对 压力，药物和其他行为状态，但我们仍然对生理 神经肽释放的潜在机制。然而，这些知识可以大大 增强我们创造治疗酒精依赖的新药物的能力。 我们实验室和其他人以前的研究表明， 杏仁核中央核（CeA）急性乙醇暴露。此外，一些研究 已经显示出在从慢性间歇性 EtOH;这些肽可以介导“焦虑样”戒断行为。然而，我们目前 初步数据表明肽释放的许多常规概念可能是不准确的 不完全;具体地，高频活性对于肽来说既不充分也不必要。 release.我们最近开始探索潜在的细胞现象， 肽释放和我们的初步数据表明，我们可以相对选择性地诱导， 使用光遗传学方法释放神经肽促肾上腺皮质激素释放因子（CRF）。在 此外，我们已经表征了BK钾通道在介导EtOH中的潜在作用， 方面的影响.蛋白质组学分析表明，BK通道与细胞内酶 发动蛋白-1，一种介导肽释放所必需的蛋白质。我们假设， 在轴突末端的快速突触传递中，中枢神经肽的释放是由 这一机制依赖于BK通道和发动蛋白-1。 由于丰富的临床前数据暗示内源性神经肽的影响， 酒精消耗和纳洛酮的临床经验（通过阻断作用起作用） 内源性阿片肽），我们认为，机制的研究，生理和 乙醇诱导的延伸杏仁核中肽的释放可能促进 用于治疗酒精中毒的新药物疗法。