Hypothalamic Peptides in the Control of Alcohol Intake

描述(由申请人提供)：已知在食物摄取中起主要作用的下丘脑系统在控制乙醇消费方面也很重要。我们以前的研究表明，下丘脑室旁核(PVN)中的多肽系统参与刺激乙醇摄取，反过来反馈进一步增加这些相同的多肽的表达。最近，我们已经开始检查穹隆周围外侧下丘脑(PFLH)，并发现这一区域内与酒精消耗有关的肽的功能与室旁核有显著差异。基于这些信息和由此产生的广泛的初步结果，我们计划在Spraogue-Dawley大鼠身上测试这一新想法，即在PFLH中表达的下丘脑肽，特别是增食欲素(OX)和黑色素浓缩激素(MCH)，在促进酒精饮酒方面具有与PVN中的不同功能，脑啡肽(ENK)和甘丙素(GAL)。当PFLH多肽启动酒精摄入时，PVN多肽可延长酒精消耗期。目的1是研究这些肽在PFLH和PVN中的行为功能，因为它们触发或维持乙醇摄取，在这个过程中相互作用，并反过来对乙醇消耗和相应的血液乙醇浓度的变化做出反应。目标2是根据不同的行为和生物标志物，确定这些多肽在被预测为有过度饮酒风险的动物中是否受到干扰。我们将测试这一假设，即处于危险中的动物在学习喝乙醇之前或在预期的大量乙醇消费之前，已经扰乱了下丘脑中多肽的表达。这一目标还将检测中脑边缘多巴胺(DA)系统中的ENK，该系统与控制有益物质的摄入密切相关。目标3是确定由于产前暴露而有过度摄入乙醇风险的动物是否表现出这些肽系统在子宫内的发育障碍，从而导致这些肽的表达增加，并在后代中长期过度摄入。最后，目标4是调查假设，与PVN相比，通过DA、氨基丁酸(GABA)、谷氨酸(GLUT)和ENK输入到PFLH和PVN的神经化学反馈信号对决定它们如何影响酒精饮酒行为的局部肽系统具有相反的影响。由于用于治疗酒精中毒的药理疗法部分是通过这些神经化学控制系统发挥作用的，我们将测试在治疗人类复发方面更有效的药物(被视为类似于开始饮酒)是否通过PFLH肽系统发挥作用；相比之下，那些在治疗持续过度消费方面更有效的疗法，类似于延长饮酒时间，正在通过PVN肽系统发挥作用。总而言之，这4个目标将提供关于两个下丘脑区及其局部肽系统参与和调节的重要新信息，因为它们控制着酒精饮酒的模式，促进酒精滥用，并调解药物在治疗人类复发和持续饮酒方面的作用。 与公共健康相关：这个项目将调查正常开始和维持进食的大脑机制如何变得危险地频繁和长时间地饮酒。我们将识别开始饮酒和延长饮酒的神经肽；描述有过度饮酒风险的动物大脑的紊乱；调查产前酒精暴露如何使这些系统在以后的生活中增加酒精摄入量；并表征神经递质输入和控制这些肽的药物。这些对动物神经机制的研究将为如何预测和防止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.