Melanocortin Neuropeptides & Ethanol Intake

黑皮质素神经肽

• 批准号: 8448326
• 负责人: TODD E. THIELE
• 金额: $ 28.03万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8448326
• 关键词: ART protein; Abstinence; Address; Agonist; Alcohol abuse; Alcohol consumption; Alcoholism; Alcohols; Amygdaloid structure; Attenuated; Behavior; Brain region; Chronic; Cues; Cyclic AMP-Dependent Protein Kinases; Dependence; Endorphins; Ethanol; Exhibits; Exposure to; Hypothalamic structure; Individual; Infusion procedures; Injection of therapeutic agent; Left; Ligands; Melanocortin 3 Receptor; Melanocortin 4 Receptor; Melanocyte stimulating hormone; Mus; Mutant Strains Mice; Neurobiology; Neuropeptides; Nucleus Accumbens; Opioid Peptide; PKA inhibitor; Pathway interactions; Peptides; Pro-Opiomelanocortin; Property; Protein Kinase A Inhibitor; Proteins; Rattus; Receptor Signaling; Recording of previous events; Recruitment Activity; Relapse; Research; Risk; Rodent; Role; Self Administration; Site; Structure of nucleus infundibularis hypothalami; Testing; Training; Ventral Tegmental Area; Work; alcohol reinforcement; alcohol relapse; alcohol response; alcohol seeking behavior; base; deprivation; endogenous opioids; immunoreactivity; insight; melanocortin receptor; paraventricular nucleus; public health relevance; receptor

DESCRIPTION (provided by applicant): There is a growing body of evidence that endogenous opioid peptides, including proopiomelanocortin (POMC)- derived b-endorphin, can modulate the neurobiological responses to ethanol and that administration of ethanol alters the expression of POMC and b-endorphin. Given that ethanol has direct effects on POMC activity, it is possible that the other POMC-derived peptides, namely the melanocortins (MCs), are also involved with neurobiological responses to ethanol. MC peptides include a-melanocyte stimulating hormone (a-MSH), which is synthesized in the arcuate nucleus of the hypothalamus and projects to many brain regions of known relevance to alcoholism. Agouti-related protein, synthesized in the arcuate nucleus and secreted in the same terminals as a-MSH, is a natural MC receptor (MCR) antagonist. Consistent with a role in modulating neurobiological responses to ethanol, recent work has shown that MCR agonists reduce, and MCR antagonists increase, ethanol consumption in rodents, and that the MC-4 receptor (MC4R) modulates the effects of MCR compounds on ethanol drinking. Additionally, exposure to ethanol significantly reduces central a-MSH immunoreactivity (IR), and increases central AgRP IR, indicating that these endogenous MCR ligands modulate neurobiological responses to ethanol. The specific aims proposed below will extend our recent findings by testing the guiding hypothesis that MC4R signaling modulates the reinforcing properties of ethanol and ethanol relapse-like behaviors, in a brain-region-specific and protein kinase A (PKA)- dependent fashion. Specifically, we will determine if operant self-administration of ethanol alters a-MSH, AgRP, MC3R and/or MC4R IR in specific brain regions (Specific Aim 1), if a MC4R agonist modulates ethanol self-administration in brain regions implicated in ethanol reinforcement (Specific Aim 2), if MC4R signaling requires normal PKA activity to modulate operant self-administration of ethanol (Specific Aim 3), and if MC4R signaling modulates relapse-like behaviors (Specific Aim 4). These studies will provide important insight into the mechanisms by which MC4R signaling modulates the reinforcing properties of ethanol and relapse of ethanol-seeking behaviors.

描述（由申请人提供）：越来越多的证据表明，内源性阿片类肽，包括促蛋白酶类皮质素（POMC） - 衍生的B-内啡肽，可以调节对乙醇的神经生物学反应，并使乙醇的施用改变POMC和B- C和B- C和B- B-和B- b-和内啡肽。鉴于乙醇对POMC活性有直接影响，因此其他POMC衍生的肽（即黑色皮质蛋白（MC））也可能与对乙醇的神经生物学反应有关。 MC肽包括刺激激素（A-MSH）的A-甲状腺细胞，该激素是在下丘脑的弧形核中合成的，并投射到许多已知与酒精中毒相关的大脑区域。在弧形核中合成的Agouti相关蛋白质是天然MC受体（MCR）拮抗剂，并在弓形核中合成，并在同一末端分泌。与调节神经生物学对乙醇的作用一致，最近的工作表明，MCR激动剂减少，MCR拮抗剂增加，啮齿动物的乙醇消耗，MC-4受体（MC4R）调节MCR化合物对乙醇饮用的影响。此外，暴露于乙醇可显着降低中央A-MSH免疫反应性（IR），并增加中央AGRP IR，表明这些内源性MCR配体调节对乙醇的神经生物学反应。下面提出的具体目的将通过测试指导假设来扩展我们的最新发现，即MC4R信号传导调节乙醇和乙醇复发样行为的增强特性，在大脑区域特异性和蛋白质激酶A（PKA）中 - 依赖性。具体而言，我们将确定特定脑部区域中乙醇的操作术自我给药是否会改变A-MSH，AGRP，MC3R和/或MC4R IR（特定目标1），如果MC4R激动剂会调节乙醇在乙醇中涉及乙醇区域的乙醇自我加热强化（特定目标2），如果MC4R信号传导需要正常的PKA活性来调节乙醇的操作自我给药（特定AIM 3），并且MC4R信号传导调节了类似复发的行为（特定目标4）。这些研究将为MC4R信号传导调节乙醇的增强特性和寻求乙醇行为的复发的机制提供重要的见解。