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，包括原黑素皮质素（POMC）衍生的b-内啡肽，可以调节对乙醇的神经生物学反应，并且乙醇的管理改变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肽包括a-黑素细胞刺激激素（a-MSH），它在下丘脑弓状核中合成，并投射到许多已知与酒精中毒相关的大脑区域。agouti相关蛋白是一种天然的MCR拮抗剂，在弓形核中合成，与a- msh在相同的末端分泌。与调节对乙醇的神经生物学反应的作用一致，最近的研究表明，MCR激动剂可以减少啮齿类动物对乙醇的消耗，MCR拮抗剂可以增加乙醇消耗，MC-4受体（MC4R）可以调节MCR化合物对乙醇饮用的影响。此外，暴露于乙醇显著降低中枢a-MSH免疫反应性（IR），并增加中枢AgRP IR，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扩展我们最近的发现，通过测试指导性假设，即MC4R信号以脑区域特异性和蛋白激酶a （PKA）依赖的方式调节乙醇和乙醇复发样行为的增强特性。具体来说，我们将确定乙醇的操作性自我给药是否会改变特定大脑区域的a- msh、AgRP、MC3R和/或MC4R IR（特异性目标1），MC4R激动剂是否调节涉及乙醇强化的大脑区域的乙醇自我给药（特异性目标2），MC4R信号是否需要正常的PKA活性来调节乙醇的操作性自我给药（特异性目标3），以及MC4R信号是否调节复发样行为（特异性目标4）。这些研究将为了解MC4R信号调节乙醇强化特性和酒精寻求行为复发的机制提供重要的见解。

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.