Functional genomics of ethanol craving and naltrexone

描述(由申请人提供)：尽管对乙醇的分子作用部位已经了解很多，但仍然没有多少有效的酒精中毒治疗方法。纳曲酮(NTX)可减少酗酒者的再犯率和酒精消耗量。非选择性阿片类拮抗剂NTX也被证明可以减少动物模型中的酒精饮酒行为，包括在反复饮酒的模型中阻止酒精饮用量的增加，即乙醇剥夺效应(EDE)。这些反应的分子机制(S)还不完全清楚。我们假设，通过研究与纳曲酮作用、EDE和纳曲酮对EDE的影响相关的全基因组基因表达模式，我们可能会对复发饮酒行为的相关机制获得新的见解。在这个项目中，高密度寡核苷酸阵列将首先被用来表征NTX在幼小C57BL/6小鼠中引起的基因表达模式。将对C57BL/6小鼠的腹侧被盖区、伏隔核和内侧前额叶皮质脑区进行研究。NTX的表达谱也将与另外两种减少酒精饮酒的药物或EDE、acamproste和mGluR5谷氨酸受体的抑制剂MPEP的表达谱进行比较。目的二将使用阵列来研究NTX在酒精自我给药的两瓶选择模型中对酒精剥夺诱发的基因表达模式的作用。通过数据挖掘在AIMS 1-2中与NTX作用相关的组合表达模式，然后我们将根据其表达变化的细胞模式来表征特定的候选基因。在目标3中，候选基因将在两瓶选择模型中评估它们在酒精饮用或EDE中的作用。在行为测试之前，将使用药物或遗传(病毒载体、反义寡核苷酸)手段来改变候选基因的表达。这些研究将为EDE的机制和NTX改变酒精饮酒行为的机制提供新的见解。总而言之，这些发现可能会确定酒精中毒治疗干预的新靶点。

DESCRIPTION (provided by applicant): Although much has been learned about molecular sites of action for ethanol, there remains few effective treatments for alcoholism. Naltrexone (NTX) reduces recidivism and ethanol consumption in alcoholics. NTX, an un-selective opioid antagonist, has also been shown to decrease ethanol drinking behavior in animal models, including blocking increased ethanol drinking in a model of relapse drinking, the ethanol deprivation effect (EDE). The molecular mechanism(s) for these responses are not entirely understood. We hypothesize that by studying genome-wide gene expression patterns associated with naltrexone action, EDE and naltrexone effects on EDE, we might gain novel insight into mechanisms relevant to relapse drinking behavior. In this project high-density oligonucleotide arrays will first be used to characterize gene expression patterns evoked by NTX in naive C57BL/6 mice. Ventral tegmental area, nucleus accumbens and medial prefrontal cortex brain regions in C57BL/6 mice will be studied. Expression profiles of NTX will also be compared to those from two other agents that decrease ethanol drinking or the EDE, acamproste and MPEP, an inhibitor of the mGluR5 glutamate receptor. Aim two will then use arrays to study action of NTX on gene expression patterns evoked by ethanol-deprivation in a 2-bottle choice model of ethanol self administration. Through data mining the combined expression patterns related to NTX action in aims 1-2, we will then characterize particular candidate genes in regard to cellular patterns of their expression changes. In Aim 3, candidate genes will be evaluated for their role in ethanol drinking or the EDE in a 2-bottle choice model. Pharmacological or genetic (viral vectors, antisense oligonucleotides) means will be used to alter the expression of candidate genes prior to behavioral testing. These studies should provide novel insight into the mechanisms of the EDE and mechanisms of NTX action in altering ethanol drinking behavior. Together, these findings may identify novel targets for therapeutic intervention in alcoholism.