Melanocortin Neuropeptides & Ethanol Intake

黑皮质素神经肽

• 批准号: 6985128
• 负责人: TODD E. THIELE
• 金额: $ 26.32万
• 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 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6985128
• 关键词: alcoholic beverage consumption; autoradiography; behavior test; behavioral /social science research tag; biological signal transduction; ethanol; genetically modified animals; hormone inhibitor; hormone receptor; hormone regulation /control mechanism; immunocytochemistry; laboratory mouse; melanocyte stimulating hormone; neurobiology; neurotransmitter antagonist; proopiomelanocortin; receptor expression; self medication; substance abuse related behavior

DESCRIPTION (provided by applicant): Endogenous opioid peptides, including proopiomelanocortin (POMC)-derived beta-endorphin, modulate neurobiological responses to ethanol and administration of ethanol alters the expression of POMC and beta- 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 alpha-melanocyte stimulating hormone (alpha-MSH), which is synthesized in the arcuate nucleus of the hypothalamus, the nucleus of the solitary tract, and the medulla, regions that project to many brain regions of known relevance to alcoholism. Pre-treatment with MC receptor (MCR) agonists reduce heroin self-administration and chronic administration of morphine or cocaine increases MC-4 receptor (MC4R) levels in striatum rats. Interestingly, rats selectively bred for high ethanol consumption have abnormal levels of MC-3 receptor (MC3R) and MC4R in the nucleus accumbens (NAc) and hypothalamus, and we have provided preliminary findings indicating that intracerebroventricular (i.c.v.) infusion of a selective MC4R agonist reduces, while i.c.v. infusion of a non-selective MCR antagonist increases, ethanol drinking by C57BL/6J mice. Hence, the specific aims proposed below will test the guiding hypothesis that MCR signaling modulates ethanol consumption and neurobiological responses to ethanol. Specifically, we will determine if MC3R and/or MC4R signaling limits self-administration of ethanol by mice (Specific Aim 1), if the endogenous MCR antagonist, agouti-related protein (AgRP), promotes ethanol self-administration by mice (Specific Aim 2), if MCR agonists and antagonists influence ethanol consumption by acting on the MC3R and/or MC4R (Specific Aim 3), and if administration of ethanol will increase alpha-MSH and MC3R/MC4R levels while at the same time decrease AgRP levels, a response that could theoretically protect against uncontrolled ethanol drinking (Specific Aim 4).

描述（由申请人提供）：内源性阿片类肽，包括蛋白酶类皮质素（POMC）衍生的β-内啡肽，调节对乙醇的神经生物学反应和乙醇的给药改变了POMC和β-内啡肽的表达。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α-甲状腺细胞刺激激素（α-MSH），该激素是在下丘脑的弧形核中合成的，孤立的核的核和髓质，这些区域，这些区域向许多已知与酒精中毒相关的大脑区域投射出来。用MC受体（MCR）激动剂进行预处理减少海洛因自我给药和长期给药吗啡或可卡因的慢性给药会增加纹状体大鼠中的MC-4受体（MC4R）水平。有趣的是，在高乙醇消耗的高乙醇中有选择性地繁殖的大鼠具有异常水平的MC-3受体（MC3R）和MC4R水平，在伏支核（NAC）和下丘脑中，我们提供了初步的发现，表明脑内脑室内（I.C.V.）的脑中有选择性MC4R Agoniss Reduc.c.c.c.c.cc.c. inc。输注非选择性MCR拮抗剂会增加，C57BL/6J小鼠饮用乙醇。因此，下面提出的具体目的将检验指导假设，即MCR信号传导调节乙醇的消耗和对乙醇的神经生物学反应。具体而言，我们将确定MC3R和/或MC4R信号传导是否限制了小鼠乙醇对乙醇的自我给药（特定目的1）（是否是内源性MCR拮抗剂，Agouti相关蛋白（AGRP），是否会促进小鼠乙醇自我促进乙醇自我给药2来促进小鼠的乙醇自我和乙醇（特定目标2），如果MCR Agonists和MC的MC 3，如果MC3或拮抗剂或抗抗元素或抗敌人的特定目的（如果在乙醇中或拮抗作用），则在乙醇中或拮抗作用或抗体或抗体的特定目标（如果在乙醇中或抗体），或3），如果乙醇的给药会增加α-MSH和MC3R/MC4R水平，而同时降低了AGRP水平，则可以从理论上预防不受控制的乙醇饮酒（特定目标4）。