Neuropeptide Y: Role in Ethanol Intake and Sensitivity

神经肽 Y：在乙醇摄入和敏感性中的作用

• 批准号: 8702680
• 负责人: TODD E. THIELE
• 金额: $ 3.82万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8702680
• 关键词: Address; Agonist; Alcohol consumption; Alcohol dependence; Alcoholism; Amygdaloid structure; Animals; Area; Attention; Blood; Blood alcohol level measurement; Brain; Brain region; CRF receptor type 1; Cell Nucleus; Consumption; Corticotropin-Releasing Hormone; Dangerous Behavior; Dependence; Development; Disease; Elements; Epigenetic Process; Ethanol; Ethanol dependence; Genetic; Health; Heart Diseases; Heavy Drinking; Histone Acetylation; Histone Deacetylase Inhibitor; Histone Deacetylation; Histones; Hour; Hypertension; Individual; Infusion procedures; Intervention; Knowledge; Link; Messenger RNA; Mood Disorders; Mus; National Institute on Alcohol Abuse and Alcoholism; Neurobiology; Neuropeptide Y Receptor; Non-Insulin-Dependent Diabetes Mellitus; Pathway interactions; Pattern; Pharmacologic Substance; Plastics; Preparation; Procedures; Receptor Signaling; Recording of previous events; Relapse; Research; Risk; Role; Signal Transduction; Site; Slice; Structure of terminal stria nuclei of preoptic region; Techniques; Testing; Time; Trichostatin A; Whole-Cell Recordings; alcohol response; alcohol sensitivity; binge drinking; drinking; immunoreactivity; inhibitor/antagonist; innovation; insight; neurochemistry; neuropeptide Y; novel; prevent; problem drinker; receptor; receptor expression; transmission process

DESCRIPTION (provided by applicant): Alcoholism and relapse in abstinent alcoholics are major health problems world-wide and current research is underway to identify potential pharmaceutical treatments for these disorders. However, heavy alcohol use and binge alcohol drinking by non-dependent individuals have received far less attention. A 'binge' is defined by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) as a pattern of drinking that produces blood alcohol concentrations (BACs) greater than 0.08% (80 mg/dL) within a short period of time. Frequent binge drinking has been linked to numerous negative consequences, including an increased likelihood of developing mood disorders, high blood pressure and heart disease, and type-2 diabetes. Of greatest concern, regular binge drinking significantly increases ones risk of developing alcohol dependence. Thus, it is of paramount importance to identify neurochemical pathways in the brain that modulate binge drinking as such knowledge will provide insight into novel pharmaceutical treatments that will protect against this dangerous behavior. Neuropeptide Y (NPY) is expressed in brain regions implicated in neurobiological responses to alcohol and NPY protects against excessive alcohol intake associated with dependence. Thus, we recently studied the role of NPY receptor signaling in binge-like drinking. Central administration of NPY significantly blunted binge-like alcohol drinking (in mice that achieved BACs of >100 mg/dL in the absence of NPY) but did not decrease drinking in mice with moderate levels of consumption (associated with BACs of <25 mg/dL). The effects of NPY on binge-like drinking are modulated by the Y1R and Y2R (but not Y5R) receptors. Importantly, our preliminary observations also revealed that binge-like drinking is associated with a significant reduction of NPY immunoreactivity in the central nucleus of the amygdala (CeA) and the bed nucleus of the stria terminalis (BNST). Thus, the guiding hypothesis for the present proposal is that NPY signaling modulates binge- like alcohol intake. The proposed Aims will use powerful and innovative electrophysiological, histological (immunoreactivity), genetic (real-time PCR), and anatomical (site-directed manipulation of NPY signaling) techniques to determine if: A) binge-like alcohol drinking will be associated with altered NPY expression and receptor signaling that become rigid with repeated binge-like episodes (Aims 1 & 3), B) NPY receptor signaling within the extended amygdala modulates binge-like alcohol drinking (Aim 2), and C) the mechanism that triggers blunted NPY signaling and motivates binge-like drinking involves epigenetic elements, specifically alterations of histone acetylation (Aim 2). Expected results from the current project would identify Y1R agonists, Y2R antagonists, and compounds that increase histone acetylation as attractive targets for treating binge drinking. Pharmaceutical interventions useful for curbing and/or preventing binge drinking will not only help individuals avoid many of the dangerous health consequences associated with regular binge drinking, but may protect vulnerable individuals from progressing to the point of alcohol dependence.

描述（由申请人提供）：酗酒和戒酒的复发是全球主要的健康问题，目前正在研究这些疾病的潜在药物治疗方法。但是，非依赖人的大量饮酒和暴饮暴食的关注要少得多。美国国家酒精滥用和酒精中毒研究所（NIAAA）定义了“暴饮暴食”，是一种在短时间内产生大于0.08％（80 mg/dl）的饮酒模式。频繁的暴饮暴食与许多负面后果有关，包括增加情绪障碍，高血压和心脏病以及2型糖尿病的可能性增加。最令人担忧的是，定期的暴饮暴食大大增加了患酒精依赖的风险。因此，识别大脑中的神经化学途径调节暴饮暴食作为这种知识将提供对新型药物治疗的洞察，从而保护这种危险行为至关重要。神经肽Y（NPY）在与酒精的神经生物学反应有关的大脑区域中表达，NPY可以防止与依赖性相关的过多酒精摄入量。因此，我们最近研究了NPY受体信号在暴饮暴食样饮酒中的作用。 NPY的中央给药可显着钝化暴饮暴食（在没有NPY的情况下达到100 mg/dl的BAC的小鼠中），但在消耗量中等的小鼠中不会降低饮酒DL）。 NPY对暴饮暴食的影响由Y1R和Y2R（但不是Y5R）受体调节。重要的是，我们的初步观察结果还表明，暴饮暴食饮酒与杏仁核（CEA）中央核的NPY免疫反应性显着降低有关（CEA）和Stria terminalis（BNST）的床核。因此，本提案的指导假设是NPY信号传导调节了狂欢的酒精摄入量。拟议的目标将使用强大而创新的电生理学，组织学（免疫反应性），遗传（实时PCR）和解剖学（NPY信号的站点指导操作）技术来确定：随着重复的暴饮暴食性发作（目标1和3），NPY表达和受体信号传导变为刚性，b）扩展的杏仁核内的NPY受体信号传导调节了暴饮暴食（AIM 2）和C） NPY信号传导和激励类似暴饮暴食的饮酒涉及表观遗传因素，特别是组蛋白乙酰化的变化（AIM 2）。当前项目的预期结果将确定Y1R激动剂，Y2R拮抗剂以及增加组蛋白乙酰化的化合物，作为治疗暴饮暴食的有吸引力的靶标。用于遏制和/或防止暴饮暴食的药物干预措施不仅可以帮助个人避免与定期暴饮暴食有关的许多危险健康后果，而且可以保护脆弱的个体免于发展到酒精依赖的位置。