Ingestive Peptide Controls of Alcohol Intake

摄入肽控制酒精摄入量

• 批准号: 6384027
• 负责人: GAYLEN L EDWARDS
• 金额: $ 7.24万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6384027
• 关键词: alcoholic beverage consumption; alcoholism /alcohol abuse; area postrema; behavior test; behavioral /social science research tag; bioenergetics; craving; dissection; hypothalamus; immunocytochemistry; in situ hybridization; laboratory rat; limbic system; neuropeptide Y; neuropeptide receptor; neuroregulation; neurotransmitters; oligonucleotides; protein localization; radioimmunoassay

DESCRIPTION (provided by applicant): Alcohol abuse is a major health problem costing millions of dollars annually in treatment and lost productivity. The basic mechanisms that lead to alcohol craving are unclear. Peptides related to ingestive behavior appear to be important to control of alcohol ingestion. Studies with neuropeptide Y(NPY)-knockout mice demonstrate that animals lacking NPY consume more alcohol, while mice that overexpress NPY have decreased alcohol intake. Moreover, NPY is found to be lower in regions of the limbic system such as the amygdala, hippocampus and prefrontal cortex of alcohol preferring rats. Collectively, these data indicate that alcohol preference is inversely correlated to NPY levels in the brain. Our research plan examines the role of NPY in 3 rodent models with contrasting behaviors relative to alcohol intake. Two models, the Zucker fatty and the area postrema-lesioned rat, have been the focus of many studies of energy balance and food intake. These studies revealed that these models have elevated levels of hypothalamic NPY. Studies of alcohol preference indicate that these rats tend to avoid alcohol compared to their respective controls. Thus, in accordance with the proposed role of NPY in the regulation of alcohol intake. Use of antisense technology, immunoneutralization or receptor antagonists to attenuate the activity of NPY in these models should increase alcohol preference. The third model is the Taste Aversion-Resistant (TAR) rat. This rat model was developed to be resistant to conditioned taste aversion. It has also been found that the TAR rat has a strong alcohol preference. Neurochemical studies in the TAR rat have revealed differences in biogenic amine levels and in the efficiency of the serotonin transporter. However, the activity of neuropeptides in this model of alcohol preference has not been explored. Thus, initial studies with this model will correlate the activity of limbic NPY systems with alcohol intake. We predict that neuropeptide Y levels are lower in the TAR rat. Manipulations to elevate NPY in this model should decrease alcohol intake. The TAR rat, contrasted with the Zucker fatty and area postrema-lesioned rat, offers an interesting and unique opportunity to study the role of neuropeptides important to ingestive behavior in the control of alcohol intake. Our initial studies focus on NPY, but future studies will involve gastrointestinal peptides as well as other central neuropeptides reported to alter ingestive behavior. Manipulation of these neuropeptides will provide insights into controls of alcohol intake as well as how peptides important to ingestive behavior impact reward pathways in the brain.

描述（由申请人提供）： 酗酒是一个主要的健康问题，每年造成数百万美元的损失。 治疗和生产力的损失。导致酒精的基本机制 欲望不明确。与摄食行为有关的肽似乎是 对控制酒精摄入很重要。神经肽研究 Y（NPY）基因敲除小鼠表明，缺乏NPY的动物消耗更多的 酒精，而过度表达NPY的小鼠酒精摄入量减少。 此外，发现NPY在边缘系统的区域中较低，例如 杏仁核、海马和前额叶皮质。 总的来说，这些数据表明，酒精偏好是相反的， 与大脑中的NPY水平相关。我们的研究计划探讨了 3种啮齿动物模型中的NPY，具有与酒精摄入相关的对比行为。 两种模型，Zucker脂肪和区域损伤后大鼠，已经被 能量平衡和食物摄入的许多研究的焦点。这些研究 揭示了这些模型具有升高的下丘脑NPY水平。研究 酒精偏好表明，这些大鼠倾向于避免酒精相比， 各自的控制。因此，根据拟议的作用， NPY在酒精摄入调节中的作用利用反义技术， 免疫中和或受体拮抗剂以减弱NPY活性 应该会增加酒精偏好。第三种模式是 味觉厌恶抗性（TAR）大鼠。这种大鼠模型是为了 抵抗条件性味觉厌恶。还发现TAR 老鼠有强烈的酒精偏好。TAR大鼠的神经化学研究 揭示了生物胺水平的差异，以及 血清素转运体然而，在这种模型中，神经肽的活性 酒精偏好尚未被探索。因此，初步研究表明， 该模型将边缘神经肽Y系统的活动与酒精摄入量相关联。 我们预测TAR大鼠的神经肽Y水平较低。操纵 在该模型中升高NPY应减少酒精摄入。TAR大鼠， 与Zucker脂肪和区域后损伤大鼠相比， 一个有趣而独特的机会来研究神经肽 对控制酒精摄入的摄食行为很重要。我们最初 研究集中在NPY，但未来的研究将涉及胃肠道 肽以及其他中枢神经肽，据报道， 行为对这些神经肽的操纵将提供对以下方面的见解： 酒精摄入量的控制，以及如何重要的肽摄取 行为会影响大脑中的奖励路径。