Ingestive Peptide Controls of Alcohol Intake

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 在治疗和丧失生产力方面。导致酒精的基本机制 对食物的渴望还不清楚。与摄食行为相关的多肽似乎是 对控制酒精摄取很重要。神经肽的研究 Y(NPY)-基因敲除小鼠表明缺乏NPY的动物消耗更多 酒精，而过度表达NPY的小鼠则减少了酒精摄入量。 此外，神经肽Y在边缘系统的区域被发现是较低的，例如 酒精偏爱大鼠的杏仁核、海马体和前额叶皮质。 总而言之，这些数据表明饮酒偏好是相反的 与大脑中神经肽Y水平相关。我们的研究计划考察了 3只行为与酒精摄入量不同的啮齿动物模型中的NPY。 两个模型，Zucker胖子和区域后病变大鼠，一直是 这是许多关于能量平衡和食物摄入量研究的焦点。这些研究 结果显示，这些模型的下丘脑NPY水平升高。研究 酒精偏好表明这些大鼠倾向于避免饮酒 添加到它们各自的控件。因此，根据拟议的作用， NPY在酒精摄入量调节中的作用。使用反义技术， 免疫中和或受体拮抗剂减弱神经肽Y的活性 在这些模型中应该增加饮酒偏好。第三种模式是 抗味道厌恶(TAR)大鼠。这种大鼠模型被开发成 抵抗条件性的味觉厌恶。还发现焦油 老鼠有很强的饮酒偏好。对焦油大鼠的神经化学研究已经 揭示了生物胺水平和生物胺效率的差异 5-羟色胺转运体。然而，在这个模型中，神经肽的活性 饮酒偏好还没有被研究过。因此，对此的初步研究 该模型将边缘NPY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 在此模型中，升高NPY应减少酒精摄入量。焦油老鼠， 与Zucker脂肪和区域后皮损大鼠相比，提供了 有趣而独特的机会来研究神经肽的作用 在控制酒精摄入量方面，对摄食行为很重要。我们最初的 研究重点是NPY，但未来的研究将涉及胃肠道 多肽以及其他据报道可改变消化的中枢神经肽 行为。对这些神经肽的操纵将提供对 酒精摄入量的控制以及多肽对摄食的重要性 行为会影响大脑中的奖赏路径。

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.