Melanocortin Neuropeptides & Ethanol Intake

黑皮质素神经肽

• 批准号: 7101925
• 负责人: TODD E. THIELE
• 金额: $ 25.7万
• 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/7101925
• 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）：内源性阿片肽，包括阿片黑皮质素原（POMC）衍生的β-内啡肽，调节对乙醇的神经生物学反应，并且乙醇的施用改变POMC和β-内啡肽的表达。鉴于乙醇对 POMC 活性有直接影响，其他 POMC 衍生肽，即黑皮质素 (MC)，也可能参与对乙醇的神经生物学反应。 MC 肽包括 α-促黑素细胞激素 (α-MSH)，它是在下丘脑的弓状核、孤束核和髓质中合成的，这些区域投射到许多已知与酒精中毒相关的大脑区域。 MC受体（MCR）激动剂预处理可减少海洛因的自我给药，而长期服用吗啡或可卡因会增加纹状体大鼠的MC-4受体（MC4R）水平。有趣的是，选择性饲养的高乙醇消耗大鼠的伏隔核 (NAc) 和下丘脑中 MC-3 受体 (MC3R) 和 MC4R 水平异常，我们提供的初步结果表明，脑室内 (i.c.v.) 输注选择性 MC4R 激动剂减少，而 i.c.v.输注非选择性 MCR 拮抗剂会增加 C57BL/6J 小鼠的乙醇饮用量。因此，下面提出的具体目标将测试 MCR 信号调节乙醇消耗和对乙醇的神经生物学反应的指导假设。具体来说，我们将确定 MC3R 和/或 MC4R 信号传导是否限制小鼠自行施用乙醇（具体目标 1），内源性 MCR 拮抗剂刺鼠相关蛋白 (AgRP) 是否促进小鼠自行施用乙醇（具体目标2)、MCR 激动剂和拮抗剂是否通过作用于 MC3R 和/或 MC4R 影响乙醇消耗（具体目标 3），以及如果施用乙醇将增加 alpha-MSH 和 MC3R/MC4R 水平，同时降低 AgRP 水平，这种反应理论上可以防止不受控制的乙醇饮用（具体目标 4）。