Melanocortin Neuropeptides & Ethanol Intake

描述(申请人提供)：内源性阿片肽，包括前阿片黑素皮质素(POMC)衍生的β-内啡肽，调节对乙醇的神经生物学反应，给予乙醇改变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衍生的多肽，即黑素皮质素(MCs)，也可能参与对乙醇的神经生物学反应。MC多肽包括α-黑素细胞刺激素(α-MSH)，它在下丘脑的弓状核、孤束核和延髓合成，这些区域投射到许多已知与酒精中毒相关的大脑区域。用MC受体(MCR)激动剂预处理可减少海洛因的自身给药，长期给予吗啡或可卡因可增加纹状体内MC-4受体(MC4R)的水平。有趣的是，选择性高酒精摄入的大鼠在伏核(NAC)和下丘脑(NAC)存在MC-3受体(MC3R)和MC4R的异常水平，我们提供的初步结果表明，脑室内(I.C.V.)选择性MC4R激动剂的输注减少，而i.c.v。非选择性MCR拮抗剂的输注增加了C57BL/6J小鼠的酒精饮用量。因此，下面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这一指导性假设。具体地说，我们将确定MC3R和/或MC4R信号是否限制小鼠乙醇的自我给药(特定目标1)，如果内源性MCR拮抗剂刺鼠相关蛋白(AgRP)促进小鼠乙醇自我给药(特定目标2)，MCR激动剂和拮抗剂是否通过作用于MC3R和/或MC4R影响酒精消耗(特定目标3)，以及是否给药酒精会增加α-MSH和MC3R/MC4R水平，同时降低AgRP水平，这一反应在理论上可以防止失控饮酒(特定目标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).