Hypothalamic Peptides in the Control of Alcohol Intake

描述（由申请人提供）：下丘脑系统已知在食物摄入中起主要作用，在控制乙醇消耗中也很重要。我们之前的研究表明，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了这些肽的表达。最近，我们开始研究下丘脑皮层外侧周（PFLH），并发现该区域肽的功能与PVN有显著差异，因为它们与乙醇消耗有关。基于这些信息和由此产生的广泛的初步结果，我们计划在Sprague-Dawley大鼠身上测试PFLH中表达的下丘脑肽，特别是食欲素（OX）和黑色素浓缩激素（MCH），在促进乙醇饮用方面与PVN，脑啡肽（ENK）和丙氨酸（GAL）中的肽具有不同的功能。而PFLH肽启动乙醇摄入的发作，PVN肽延长乙醇消耗的时间。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入，在这一过程中相互作用，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。目的二是根据不同的行为和生物标记，确定这些多肽是否在预测有过量摄入乙醇风险的动物中受到干扰。我们将测试一个假设，即在动物学会喝乙醇之前或在预期的大量酒精消耗之前，处于危险中的动物下丘脑中肽的表达受到干扰。这一目的也将检查ENK在中脑边缘多巴胺（DA）系统，这是密切参与控制摄取奖励物质。目的3是确定由于产前暴露而有过量摄入乙醇风险的动物，是否在这些肽系统的子宫发育中表现出紊乱，从而导致肽表达增加和后代长期过量摄入。最后，目的4是研究一种假设，即与PVN相比，通过DA、-氨基丁酸（GABA）、谷氨酸（GLUT）和ENK输入的PFLH的神经化学反馈信号对局部肽系统有相反的影响，这决定了它们如何影响乙醇饮用行为。由于用于治疗酒精中毒的药物治疗部分是通过这些神经化学控制系统起作用的，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肽系统起作用；相比之下，那些治疗持续过度饮酒（类似于延长饮酒时间）更有效的疗法是通过PVN肽系统起作用的。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酒模式，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。

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.