Edinger-Westphal Urocortin-1 Involvement in Binge Ethanol Intake and Reward

Edinger-Westphal Urocortin-1 参与暴饮暴食乙醇摄入和奖励

• 批准号: 8356258
• 负责人: William J Giardino
• 金额: $ 2.44万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8356258
• 关键词: Abstinence; Adult; Affect; Affinity; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Animal Model; Area; Attenuated; Behavior; Behavioral; Behavioral Genetics; Behavioral Model; Binding; Blood; Brain; Brain region; Breeding; CARTPT gene; Cell Nucleus; Cocaine; Complex; Consumption; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Cues; Development; Dopamine; Ethanol; FOS gene; Financial compensation; Gene Expression; Genes; Genetic Predisposition to Disease; Genetic Techniques; Heavy Drinking; Human; Individual; Infusion procedures; Intake; Knock-out; Knockout Mice; Laboratories; Lesion; Ligands; Light; Maps; Mediating; Methods; Modeling; Molecular Genetics; Mus; National Institute on Alcohol Abuse and Alcoholism; Neurons; Neuropeptides; Nucleus Accumbens; Operative Surgical Procedures; Oral; Outcome; Pattern; Phenotype; Play; Population; Predisposition; Procedures; Proteins; RNA Interference; Regulation; Relapse; Rewards; Rodent; Role; Self Administration; Site; Societies; Stress; Structure; Subfamily lentivirinae; System; Tactile; Technology; Testing; Tissues; Transcript; Ventral Tegmental Area; Viral; Virus; Wild Type Mouse; Work; alcohol reward; alcohol seeking behavior; alcohol use disorder; alcoholism therapy; base; binge drinking; brain pathway; conditioning; cost; drinking; endophenotype; ghrelin receptor; innovation; interest; knock-down; lentiviral-mediated; male; preference; problem drinker; receptor; relating to nervous system; research study; response; small hairpin RNA; tool; urocortin

Stress plays a key role in precipitating relapse to excessive ethanol (EtOH) consumption in dependent alcoholics. Even in non-dependent populations, evidence supports a role for neural stress networks, such as the corticotropin-releasing factor (CRF) system, in excessive EtOH intake. Unfortunately, the complex neuroanatomical and pharmacological features of the CRF system have hindered our understanding of the roles of its specific components in EtOH-related behaviors. To this end, we have devoted years of study to the examination of Urocortin-1 (Ucn1), an endogenous ligand of the CRF system that is closely related to the prototypical ligand CRF, yet binds to both CRF receptors with higher affinity than CRF itself. While the fields of alcohol abuse and addiction have typically focused on the mesolimbic dopamine pathway and brain structures such as the ventral tegmental area and nucleus accumbens, our laboratory has provided converging lines of evidence to support a role for the centrally-projecting neurons of the Edinger-Westphal nucleus (EWcp) in EtOH intake and sensitivity. The primary site of Ucn1 expression in the brain is within the EWcp, and a relationship between EWcp-Ucn1 expression and a genetic predisposition to excessive EtOH intake has been identified. Further interest in the EWcp as a brain region involved in EtOH intake is based on the observation that in addition to Ucn1, the cocaine- and amphetamine-regulated transcript (CART) neuropeptide, and the ghrelin receptor (Ghsr) are both highly expressed within EWcp. Intriguingly, these proteins have also been implicated in excessive EtOH consumption and EtOH-induced reward, and we have hypothesized that the role of the EWcp in excessive EtOH consumption is dependent on the interactions between Ucn1 and CART, Ghsr, and additional proteins. Thus, Specific Aim 1 of this proposal seeks to use quantitative PCR array technology elucidate interactions between Ucn1 and other EWcp-enriched genes that are relevant for EtOH-related behaviors, and Specific Aim 2 of my proposal seeks to examine well-characterized behavioral models of EtOH binge-drinking and EtOH- induced reward following knockdown of Ucn1 expression within the EWcp, using lentiviral-mediated RNA interference. These highly innovative experiments will not only conclusively determine the importance of EWcp-Ucn1 in two relevant behavioral endophenotypes of alcoholism, but will also use quantitative gene expression analyses to aid in unraveling the complex role that the EWcp plays in excessive EtOH intake.

压力在促进依赖性酒精中毒的过度乙醇（ETOH）消耗中起着关键作用。即使在非依赖人群中，证据也支持神经应激网络的作用，例如过度的ETOH摄入量，例如促肾上腺皮质激素释放因子（CRF）系统。不幸的是，CRF系统的复杂神经解剖学和药理特征阻碍了我们对其在与EtOH相关行为中特定组成部分的作用的理解。为此，我们专门研究了多年的研究，研究了泌尿科素-1（UCN1），这是CRF系统的内源性配体，与原型配体CRF密切相关，但与CRF本身更高的CRF受体结合。虽然酒精滥用和成瘾的领域通常集中在中唇多巴胺的途径和大脑结构（例如腹侧段盖区域和八核）上，但我们的实验室提供了融合的证据，以支持eTer-teger-tingphal核（Ewcp）（Ewcp）（Ewcp）中心射击神经元的作用。大脑中UCN1表达的主要位点在EWCP内，并且已经鉴定出EWCP-UCN1表达与过度ETOH摄入的遗传倾向之间的关系。对EWCP作为ETOH摄入涉及的大脑区域的进一步兴趣是基于这样的观察结果：除了UCN1，可卡因和苯丙胺调节的转录本（CART）神经肽（CART）神经肽以及GHRELIN受体（GHSR）外，都在EWCP中高度表达。有趣的是，这些蛋白质也与过度的ETOH消耗和EtOH诱导的奖励有关，我们假设EWCP在过度的ETOH消耗中的作用取决于UCN1和CART，GHSR和其他蛋白质之间的相互作用。因此，该提案的具体目的1试图使用定量的PCR阵列技术阐明了与EtOH相关行为相关的UCN1与其他EWCP富含基因之间的相互作用，而我的提案的具体目的2旨在研究ETOH繁殖和ETOH奖励的表达eRCS的表达，EEW在UCN中的ETOH奖励效果良好的行为模型，慢病毒介导的RNA干扰。这些高度创新的实验不仅将最终确定EWCP-UCN1在两种相关的酒精中毒行为内表型中的重要性，而且还将使用定量基因表达分析来帮助揭示EWCP在过度eTOH摄入中发挥的复杂作用。