Role of hypothalamic-specific POMC deficiency in alcohol reward and drinking

下丘脑特异性 POMC 缺乏在酒精奖励和饮酒中的作用

基本信息

批准号：
9137600
负责人：
YAN ZHOU
金额：
$ 8.48万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-05 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9137600
关键词：
Address Adrenal Glands Adrenal hormone preparation Alcohol consumption Alcohol dependence Alcohol-Related Disorders Alcoholism Alcohols Animal Model Behavior Behavioral Behavioral Model Brain Cells Chronic Clinical Consumption Corticotropin DNA Development Dose Drug Addiction Endorphins Enhancers Female Gene Expression Genes Genetic Transcription Genotype Goals Health Human Hypothalamic structure Intervention Knockout Mice Maintenance Malignant Neoplasms Measures Mediating Melanocortin 4 Receptor Modeling Molecular Molecular Profiling Mus Naltrexone Neurons Opioid Receptor Parkinson Disease Pattern Pituitary Gland Play Pro-Opiomelanocortin Protocols documentation Public Health Rattus Regulation Regulatory Element Relapse Reporting Rewards Rodent Rodent Model Role Saccharin Structure of nucleus infundibularis hypothalami Sucrose System Testing Therapeutic Agents Tissues Transgenic Mice Withdrawal alcohol behavior alcohol effect alcohol exposure alcohol preferring rats alcohol relapse alcohol reward alcohol seeking behavior alcoholism therapy base beta-Endorphin binge drinking dependence relapse deprivation drinking drinking behavior drug reward gene therapy genetic approach hypothalamic-pituitary-adrenal axis insight male melanocortin receptor men mu opioid receptors neurobiological mechanism novel novel therapeutics preference psychological stressor reinforcer sex sweet taste perception transcription factor

项目摘要

DESCRIPTION (provided by applicant): Opioidergic mechanisms particularly through beta-endorphin are involved in reward and drug addiction. In different rodent models of alcohol intake, opioid receptor antagonists decrease alcohol consumption and relapse-like drinking. Beta-endorphin is encoded by pro-opiomelanocortin (POMC) gene. Using Sardinian alcohol-preferring rats and C57BL/6J, we recently found that voluntary alcohol drinking for 2 weeks increases POMC gene expression in the hypothalamus of both rats and mice. Our hypothesis is that alterations of hypothalamic POMC gene expression are critical to alcohol-induced reward and the development of alcohol drinking behaviors, dependence and relapse. In transgenic mice, deletion of POMC nPEs (hypothalamic- specific POMC enhancers) abolishes POMC expression selectively in the hypothalamus, but with normal pituitary POMC cells. Our first goal (Specific Aim 1) is to determine the roles of hypothalamic POMC neurons in regulating alcohol reward and drinking behaviors in male and female nPE knockout mice, using drinking-in-the- dark (DID), chronic escalation drinking (CED) and conditioned place preference (CPP) models. The hypothesized reduction by POMC nPE deletion of alcohol behaviors would provide the experimental evidence that hypothalamic POMC neurons are involved in alcohol rewarding or relapse-like drinking, and the conserved POMC nPE enhancers between mice and men could provide a valuable platform for the discovery of transcription factors controlling the POMC expression, and then alcohol drinking. New therapeutic agents may target these transcription factors similarly to what is currently studied for cancer and Parkinson's disease. Our second goal (Specific Aim 2) is in parallel to analyze the hypothalamic POMC expression profiles during alcohol drinking that characterize an underlying mechanism. We will determine if region-specific POMC changes occur in the hypothalamus after DID or CED drinking, or CPP. The study may reveal potentially new molecular mechanisms that provide new insights for understanding the molecular basis of alcohol-related disorders and novel targets for intervention in alcoholism.

描述（由申请人提供）：阿片受体拮抗剂尤其通过β-内啡肽参与奖赏和药物成瘾，在不同的酒精摄入模型中，阿片受体拮抗剂减少酒精消耗，并且β-内啡肽原编码复发样饮酒。使用撒丁岛酒精偏好大鼠和 C57BL/6J，我们最近发现自愿饮酒 2 周会增加 POMC 基因表达。我们的假设是，在转基因小鼠中，下丘脑 POMC 基因表达的改变对于酒精诱导的奖赏以及饮酒行为、依赖性和复发的发展至关重要。 POMC 增强剂）在下丘脑中选择性地消除 POMC 表达，但在正常垂体 POMC 细胞中我们的第一个目标（具体目标 1）是确定下丘脑的作用。 POMC 神经元在调节雄性和雌性 nPEout 敲除小鼠的酒精奖赏和饮酒行为方面，使用黑暗饮酒 (DID)、慢性饮酒升级 (CED) 和条件性位置偏好 (CPP) 模型来消除酒精行为。实验证据表明下丘脑 POMC 神经元参与酒精奖赏或复发样饮酒，并且小鼠和男性之间保守的 POMC nPE 增强子可以为发现控制酒精的转录因子提供一个有价值的平台。 POMC 表达，然后饮酒。新的治疗药物可能会针对这些转录因子，类似于目前针对癌症和帕金森病的研究，我们的第二个目标（具体目标 2）是同时分析饮酒期间的下丘脑 POMC 表达谱。我们将确定 DID 或 CED 饮酒或 CPP 后下丘脑是否发生区域特异性 POMC 变化，该研究可能揭示潜在的新分子机制，为理解酒精相关疾病的分子基础提供新的见解。小说酗酒干预的目标。