Melanocortin Neuropeptides & Ethanol Intake

描述（由申请人提供）：内源性阿片肽，包括阿黑皮素原（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了POMC和β-内啡肽的表达。鉴于乙醇对POMC活性有直接影响，可能其他POMC衍生肽，即黑皮质素（MC），也参与对乙醇的神经生物学反应。MC肽包括α-黑素细胞刺激激素（α-MSH），其在下丘脑的弓状核、孤束核和髓质中合成，这些区域投射到已知与酒精中毒相关的许多脑区域。用MC受体（MCR）激动剂预处理可减少海洛因自我给药，长期给予吗啡或可卡因可增加纹状体大鼠MC-4受体（MC 4 R）水平。有趣的是，选择性饲养的高酒精消耗大鼠在丘脑核（NAc）和下丘脑中有异常水平的MC-3受体（MC 3R）和MC 4 R，我们提供的初步研究结果表明，脑室内（i. c. v.）输注选择性MC 4 R激动剂减少C57 BL/6 J小鼠的乙醇饮用，而i. c. v.输注非选择性MCR拮抗剂增加C57 BL/6 J小鼠的乙醇饮用。因此，下文提出的具体目标将检验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。具体地，我们将确定MC 3R和/或MC 4 R信号传导是否限制小鼠自我施用乙醇（具体目标1），如果内源性MCR拮抗剂，刺豚鼠相关蛋白（AgRP），促进小鼠乙醇自我给药（具体目标2），如果MCR激动剂和拮抗剂通过作用于MC 3R和/或MC 4 R影响乙醇消耗（具体目标3），并且如果给予乙醇将增加α-MSH和MC 3R/MC 4 R水平，同时降低AgRP水平，则理论上可以防止不受控制的乙醇饮用（具体目标4）。

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).