Hypothalamic Peptides in the Control of Alcohol Intake

描述（由申请人提供）：已知在食物摄入中起主要作用的下丘脑系统在控制乙醇消耗方面也很重要。我们以前的研究表明，下丘脑室旁核（PVN）中的肽系统参与刺激乙醇摄入，这反过来又反馈进一步增加这些相同肽的表达。最近，我们已经开始检查穹窿周围外侧下丘脑（PFLH），并确定了显着差异的PVN在这方面的肽的功能，因为它们涉及到乙醇的消耗。基于这些信息和广泛的初步结果，我们计划在Sprague-Dawley大鼠中测试新的想法，即在PFLH中表达的下丘脑肽，特别是食欲素（OX）和黑色素浓集激素（MCH），具有与PVN中的脑啡肽（ENK）和甘丙肽（GAL）不同的功能，以增强乙醇饮用。而PFLH肽启动乙醇摄入事件，PVN肽延长乙醇消耗的时间。目的1是研究这些肽在PFLH和PVN的行为功能，因为它们触发或维持乙醇摄入，在这个过程中相互作用，并反过来响应乙醇消耗和相应的血液乙醇浓度的变化。目的2是确定这些肽是否在基于不同的行为和生物标志物预测有过度消耗乙醇风险的动物中受到干扰。我们将检验这样一个假设，即处于危险中的动物在学习饮用乙醇之前或在预期的大量乙醇消耗之前，下丘脑中的肽表达受到干扰。这一目标也将检查ENK在中脑边缘多巴胺（DA）系统，这是密切参与控制奖励物质的摄入。目的3是确定是否动物在过度消费乙醇的风险，由于产前暴露，表现出这些肽系统的子宫内发育的干扰，导致增加的表达的肽和长期过度消费的后代。最后，目的4是调查的假设，神经化学反馈信号的PFLH相比，PVN，通过DA，-氨基丁酸（GABA），谷氨酸（GLUT）和ENK的输入，有相反的影响，当地的肽系统，确定他们如何影响乙醇饮用行为。由于用于治疗酒精中毒的药物疗法部分通过这些神经化学控制系统起作用，我们将测试是否药物更有效地治疗人类复发，类似于开始饮酒，通过PFLH肽系统起作用;相反，那些治疗持续过度消费更有效，类似于延长饮酒，通过PVN肽系统起作用。总的来说，这4个目标将提供有关两个下丘脑区域及其局部肽系统的参与和调节的重要新信息，因为它们控制乙醇饮用模式，促进酒精滥用，并介导药物治疗人类复发和持续饮酒的作用。 公共卫生相关性：这个项目将调查大脑机制，通常开始和维持饮食变得危险地参与频繁和长期的饮酒。我们将确定神经肽，开始饮酒回合和那些延长它;表征干扰的动物大脑中的风险过度饮酒;调查如何产前暴露于酒精程序这些系统，以增加酒精摄入量以后的生活;和表征神经递质输入和药物控制这些肽。这些对动物神经机制的研究将为如何预测和预防过度饮酒提供有用的信息，并可能有助于设计可用于治疗酒精使用障碍的药物。

DESCRIPTION (provided by applicant): Hypothalamic systems known to have a primary role in food intake are also important in controlling the consumption of ethanol. Our previous studies have shown that peptide systems in the hypothalamic paraventricular nucleus (PVN) become engaged in stimulating ethanol intake, which in turn feeds back to further increase the expression of these same peptides. More recently, we have begun to examine the perifornical lateral hypothalamus (PFLH) and have identified marked differences from the PVN in the functioning of the peptides in this area as they relate to ethanol consumption. Building on this information and the extensive preliminary results developed from it, we plan to test in Sprague-Dawley rats the novel idea that hypothalamic peptides expressed in the PFLH, specifically orexin (OX) and melanin-concentrating hormone (MCH), have different functions from those in the PVN, enkephalin (ENK) and galanin (GAL), in enhancing ethanol drinking. Whereas PFLH peptides initiate episodes of ethanol intake, PVN peptides prolong periods of ethanol consumption. Aim 1 is to examine the behavioral functions of these peptides in the PFLH and PVN, as they trigger or sustain ethanol intake, interact in this process, and respond in turn to the changes in ethanol consumption and corresponding blood ethanol concentrations. Aim 2 is to determine whether these peptides are disturbed in animals predicted to be at risk for overconsuming ethanol based on different behavioral- and bio-markers. We will test the hypothesis that animals at risk have disturbed expression of peptides in the hypothalamus prior to learning to drink ethanol or before an anticipated, large bout of ethanol consumption. This aim will also examine ENK in the mesolimbic dopamine (DA) system, which is intimately involved in controlling the ingestion of rewarding substances. Aim 3 is to determine whether animals at risk for overconsuming ethanol, due to prenatal exposure, exhibit disturbances in in utero development of these peptide systems that cause increased expression of the peptides and long-term overconsumption in the offspring. Lastly, Aim 4 is to investigate the hypothesis that neurochemical feedback signals to the PFLH compared to the PVN, via DA, -aminobutyric acid (GABA), glutamate (GLUT) and ENK inputs, have opposite effects on the local peptide systems that determine how they influence ethanol drinking behavior. As pharmacological therapies used to treat alcoholism act in part through these neurochemical control systems, we will test whether medications more effective in treating relapse in humans, seen as analogous to initiation of drinking, are working through the PFLH peptide systems; in contrast, those therapies more effective in treating ongoing excessive consumption, analogous to prolongation of drinking, are working through the PVN peptide systems. Collectively, these 4 Aims will provide significant, new information regarding the involvement and regulation of two hypothalamic areas and their local peptide systems, as they control patterns of ethanol drinking, contribute to alcohol abuse, and mediate the actions of medications in treating relapse and ongoing drinking in humans. PUBLIC HEALTH RELEVANCE: This project will investigate how brain mechanisms that normally start and maintain eating become dangerously engaged in frequent and prolonged bouts of drinking alcohol. We will identify neuropeptides that start a drinking bout and those that prolong it; characterize disturbances in the brains of animals at risk for excessive alcohol consumption; investigate how prenatal exposure to alcohol programs these systems to increase alcohol intake later in life; and characterize neurotransmitter inputs and medicines that control these peptides. These studies of neural mechanisms in animals will provide useful information on how to predict and prevent overconsumption of alcohol and may help in designing drugs that can be used in the treatment of alcohol-use disorder.