Functional genomics of ethanol craving and naltrexone

描述（由申请人提供）：虽然已经了解了很多关于乙醇作用的分子位点，但仍然很少有有效的治疗酒精中毒的方法。纳洛酮（NTX）可降低酗酒者的再犯率和乙醇消耗量。NTX是一种非选择性阿片类拮抗剂，也已被证明可以减少动物模型中的乙醇饮酒行为，包括阻断复发饮酒模型中增加的乙醇饮酒，即乙醇剥夺效应（EDE）。这些反应的分子机制尚未完全了解。我们推测，通过研究与纳洛酮作用、EDE和纳洛酮对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相关机制有新的认识。在这个项目中，高密度寡核苷酸阵列将首先被用来表征基因表达模式诱发的NTX在幼稚的C57 BL/6小鼠。将研究C57 BL/6小鼠的中脑被盖区、中脑核和内侧前额叶皮质脑区。NTX的表达谱也将与来自减少乙醇饮用的其他两种药剂或EDE、阿坎前列素和mGluR 5谷氨酸受体抑制剂MPEP的表达谱进行比较。目的二将使用阵列研究NTX对乙醇剥夺诱发的基因表达模式的作用，在2瓶选择模型的乙醇自我管理。通过对目标1-2中与NTX作用相关的组合表达模式进行数据挖掘，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，将在2瓶选择模型中评估候选基因在乙醇饮用或EDE中的作用。在行为测试之前，将使用药理学或遗传学（病毒载体、反义寡核苷酸）方法来改变候选基因的表达。这些研究应该提供新的洞察机制的EDE和机制的NTX行动在改变乙醇饮用行为。总之，这些发现可能会为酒精中毒的治疗干预确定新的目标。

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.