Melanocortin Neuropeptides & Ethanol Intake

描述(由申请人提供)：越来越多的证据表明，内源性阿片肽，包括由前阿片黑素皮质素(POMC)衍生的b-内啡肽，可以调节对乙醇的神经生物学反应，并且乙醇的使用改变了POMC和b-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(a-MSH)，它在下丘脑的弓状核合成，投射到许多已知与酒精中毒相关的大脑区域。刺鼠相关蛋白是一种天然的MC受体拮抗剂，在弓状核合成，与α-MSH在同一终末分泌。最近的工作表明，MCR激动剂减少了啮齿动物的酒精消耗量，而MCR拮抗剂增加了啮齿类动物的酒精消耗量，MC-4受体(MC4R)调节了MCR化合物对酒精饮酒的影响，这与调节乙醇的神经生物学反应相一致。此外，暴露于乙醇可显著降低中枢a-MSH免疫反应性(IR)，增加中枢AgRP免疫反应性，表明这些内源性MCR配体调节对乙醇的神经生物学反应。下面提出的具体目标将通过测试指导性假设来扩展我们最近的发现，即MC4R信号以脑区特异性和蛋白激酶A(PKA)依赖的方式调节乙醇和乙醇复发样行为的增强特性。具体地说，我们将确定操作员乙醇自我给药是否改变了特定脑区的a-MSH、AgRP、MC3R和/或MC4R IR(特定目标1)，MC4R激动剂是否调节与乙醇强化相关的大脑区域的乙醇自我给药(特定目标2)，MC4R信号是否需要正常的PKA活性来调节操作员乙醇的自我给药(特定目标3)，以及MC4R信号是否调节复发样行为(特定目标4)。这些研究将对MC4R信号调节酒精强化特性和酒精寻求行为复发的机制提供重要的见解。 公共卫生相关性：尽管进行了多年的研究和大量的重要信息，但使一些人容易受到酒精滥用和酒精中毒影响的神经生物学因素仍然不清楚。一种假设是，一些人对酒精的强化特性表现出更高的敏感度，导致更早使用酒精，随后增加依赖的风险。目前提案中概述的工作将表明，黑素皮质素神经肽调节酒精的强化特性和戒酒后寻求酒精行为的复发。

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. PUBLIC HEALTH RELEVANCE: Despite years of research and a wealth of important information, the neurobiological factors that leave some individuals vulnerable to alcohol abuse and alcoholism remain unclear. One hypothesis is that some individuals show increased sensitivity to the reinforcing properties of alcohol, leading to increased early use and a subsequent increased risk of dependence. The work that is outlined in the current proposal will show that melanocortin neuropeptides modulate the reinforcing properties of alcohol and relapse of alcohol-seeking behavior following abstinence.