Stress-induced increases of ethanol intake: The role of neuropeptide Y (NPY)

压力引起的乙醇摄入量增加：神经肽 Y (NPY) 的作用

• 批准号: 7545140
• 负责人: Angela M. Sparrow
• 金额: $ 2.96万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-05 至 2011-05-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7545140
• 关键词: Address; Alcohol consumption; Alcoholism; Amygdaloid structure; Anxiety; Attenuated; Behavior; Blood; Brain region; Complex; Environment; Ethanol; Exposure to; Hour; Hypothalamic structure; Infusion procedures; Injection of therapeutic agent; Label; Lateral; Left; Literature; Modeling; Monitor; Mus; Mutant Strains Mice; Neuropeptides; Neurotoxins; Noise; Play; Procedures; Rate; Recording of previous events; Regulation; Relapse; Relative (related person); Research; Rodent; Rodent Model; Role; Saline; Schedule; Signal Transduction; Site; Specificity; Stress; Testing; Thinking; Traumatic Stress Disorders; alcoholism/alcohol abuse; biological adaptation to stress; cell killing; day; design; drinking; insight; neuropeptide Y; neuropeptide Y-Y1 receptor; novel; problem drinker; receptor; receptor function; research study; response; stressor; therapeutic target

DESCRIPTION (provided by applicant): Studies have shown that exposure to a stressor can increase ethanol consumption. One of the potential modulators of this effect is neuropeptide Y (NPY), which is involved in the regulation of both anxiety-like behavior and ethanol consumption in rodents. Thus, increased NPY signaling has been shown to reduce ethanol consumption and anxiety-like behaviors. The experiments described in the present proposal are designed to test the guiding hypothesis that NPY plays a protective role against stress-induced increases of ethanol consumption. All of the proposed studies will use a complex stressor, which consists of saline injections followed by simultaneous exposure to a novel environment and noise. Specific aim 1 will use mutant mice lacking NPY or the NPY Y1 receptor to determine the role of NPY signaling in stress-induced increases in ethanol consumption. Specific aim 2 will utilize a neurotoxin that is conjugated to NPY to target and kill cells expressing Y1 receptors. This neurotoxin allows the study of blunted NPY signaling in specific brain regions and aim 2 will determine the role of NPY signaling in the amygdala and the lateral hypothalamus on stress-induced increases in ethanol consumption. Specific aim 3 will study the effects of NPY signaling on limited access ethanol consumption in mice with or without prior exposure to a stressor. Specifically, mutant mice lacking NPY (or wild-type controls) with a prior history of stress exposure will be given access to ethanol for 2-4 hours/day, beginning 3 hours into the dark cycle. These procedures, labeled drinking-in-the-dark (DID), induce high levels of ethanol consumption and physiologically relevant blood ethanol concentrations and are thought to model binge-like ethanol drinking. Results from the proposed studies will provide insight on the importance of NPY signaling in modulating stress-induced increases of ethanol consumption. Since stress disorders are comorbid with alcoholism and as stress can trigger relapse in abstinent alcoholics, results from the present research may provide insight into potential therapeutic targets aimed at treated alcohol abuse and alcoholism.

描述（由申请人提供）：研究表明，暴露于压力源会增加乙醇消耗量。这种效应的潜在调节剂之一是神经肽Y (NPY)，它参与调节啮齿动物的焦虑样行为和乙醇消耗。因此，增加的NPY信号传导已被证明可以减少乙醇消耗和焦虑样行为。本提案中描述的实验旨在测试NPY对应激诱导的乙醇消耗增加起保护作用的指导假设。所有拟议的研究都将使用一个复杂的应激源，包括生理盐水注射，然后同时暴露在一个新的环境和噪音中。特异性目的1将使用缺乏NPY或NPY Y1受体的突变小鼠来确定NPY信号在应激诱导的乙醇消耗增加中的作用。特异性靶2将利用与NPY结合的神经毒素靶向并杀死表达Y1受体的细胞。这种神经毒素允许研究特定大脑区域的钝化NPY信号，目的2将确定杏仁核和外侧下丘脑中NPY信号在应激诱导的乙醇消耗增加中的作用。具体目标3将研究NPY信号对有或没有事先暴露于应激源的小鼠有限获取乙醇消耗的影响。具体来说，具有应激暴露史的缺乏NPY的突变小鼠（或野生型对照）将被给予2-4小时/天的乙醇，从黑暗周期的第3小时开始。这些过程，被标记为夜间饮酒（DID），诱导高水平的乙醇消耗和生理相关的血液乙醇浓度，被认为是模拟狂欢式乙醇饮酒。拟议研究的结果将为NPY信号在调节应激诱导的乙醇消耗增加中的重要性提供见解。由于应激障碍是酒精中毒的合并症，而且压力会引发戒酒者的复发，本研究的结果可能为治疗酒精滥用和酒精中毒的潜在治疗靶点提供见解。