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（包括阿黑皮素原（POMC）衍生的b-内啡肽）可调节对乙醇的神经生物学反应，并且乙醇给药可改变POMC和b-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中合成并投射到已知与酒精中毒相关的许多脑区域。Agouti-related protein（Agouti-related protein，Agouti-related protein）是一种天然的MC受体（MCR）拮抗剂，由弓状核合成，与α-MSH分泌于同一终末。与调节对乙醇的神经生物学反应的作用一致，最近的工作表明，MCR激动剂减少，MCR拮抗剂增加啮齿动物的乙醇消耗，MC-4受体（MC 4 R）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应答。下面提出的具体目标将通过测试指导假设来扩展我们最近的发现，即MC 4 R信号传导以脑区域特异性和蛋白激酶A（PKA）依赖性方式调节乙醇和乙醇复发样行为的增强特性。具体地说，我们将确定乙醇的操作性自我给药是否改变特定脑区域中的α-MSH、AgRP、MC 3R和/或MC 4 R IR（具体目标1），如果MC 4 R激动剂调节乙醇强化相关脑区的乙醇自我给药（具体目标2），如果MC 4 R信号传导需要正常PKA活性来调节乙醇的操作性自我给药（具体目标3），以及MC 4 R信号传导是否调节复发样行为（具体目标4）。这些研究将为MC 4 R信号调节乙醇的强化特性和乙醇寻求行为的复发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.