Mechanisms underlying neuropeptide release in the extended amygdala

尽管内源性神经肽递质在增强作用中起着关键作用 在乙醇消费和酒精戒除的负面影响方面，我们有一个很差的 中枢性神经肽释放机制的理解(S)。这一差距 在我们的知识中严重削弱了我们阐明乙醇生物效应的能力 (乙醇)，AS 1)多项研究表明，急性和慢性乙醇可诱导释放 与乙醇强化和戒断相关的脑区神经肽的研究 厌恶，以及2)极少数常用的治疗酒精过敏症的药物之一(纳曲酮 渴求被认为是通过对抗内源性阿片肽的作用而起作用的。 多项行为学研究证明内源性神经肽参与了对 压力、药物和其他行为状态，但我们仍然对生理上的 神经肽释放的潜在机制。然而，这种知识可能会显著地 增强我们为酒精依赖创造新的药物疗法的能力。 我们实验室和其他实验室之前的研究表明，神经肽的释放增加 急性乙醇暴露所致的杏仁中央核(CEA)。此外，还有几项研究 在慢性间歇性戒断后表现出持续释放特定的多肽 这些多肽可能介导了“焦虑样”的戒断行为。然而，我们目前 初步数据表明，许多传统的肽释放概念可能是不准确的或 不完全的；具体地说，对于多肽来说，高频活动既不充分也不必要 放手。我们最近开始探索潜在的细胞现象，这种现象可能会调节 肽的释放和我们的初步数据表明，我们可以相对选择性地诱导 用光遗传方法释放神经肽促肾上腺皮质激素释放因子(CRF)。在……里面 此外，我们还鉴定了BK钾通道在调节乙醇中的潜在作用。 效果。蛋白质组学分析表明，BK通道与胞内酶相连 Dynamin-1，一种介导肽释放所必需的蛋白质。我们假设与之相反的是 轴突终末的快速突触传递，中枢神经肽的释放是由 机制依赖于BK通道和Dynamin-1。 因为大量的临床前数据表明内源性神经肽有影响 酒精消耗量和纳曲酮(通过阻断效应起作用)的临床经验 内源性阿片肽)，我们认为生理和 乙醇诱导的杏仁核延长区释放的多肽可能促进了大鼠脑梗塞的发生。 治疗酒精中毒的新药物疗法。

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.