Role of sigma receptors in ethanol reinforcement

西格玛受体在乙醇强化中的作用

基本信息

批准号：
7932988
负责人：
VALENTINA SABINO
金额：
$ 24.65万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-12-01 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7932988
关键词：
Agonist Alcohol abuse Alcohol consumption Alcoholism Alcohols Animals Area Attenuated Behavioral Behavioral Model Binding Sites Boston Brain Brain region Chronic Cocaine Communities Dependence Drug abuse Ethanol Exposure to Genes Genetic Polymorphism Glutamates Human Intake Ligands Mental disorders Methamphetamine Modeling Molecular Mus Neurosciences Neurotransmitters Pharmaceutical Preparations Physiological Play Property Psychological reinforcement Rattus Reporting Rewards Role Self Administration Signal Transduction Pathway Structure System Techniques Universities Wild Type Mouse alcohol effect alcohol exposure alcohol preferring rats alcohol reinforcement alcohol reward insight mutant mouse model noradrenergic novel preference protein expression receptor receptor expression research study response sigma receptors sigma-1 receptor tool vapor

项目摘要

The project, to be conducted at the Boston University in the rich neuroscience community of Boston, concerns Sigma receptors, unique mammalian binding sites that modulate other neurotransmitter systems and which are richly expressed in limbic brain structures. Pharmacological studies indicate that sigma receptors modulate actions of cocaine and methamphetamine. Recently, sigma receptors also have been proposed to modulate motivating properties of ethanol, consistent with findings of sigma receptor polymorphisms in human alcoholism. Until very recently, however, the understanding of sigma receptor systems had been hampered by the unavailability of specific, subtj^je-selective ligands or of mutant mouse models that lack sigma receptor subt5T)es. Furthermore, the role of sigma receptors in voluntary intake or self-administration of ethanol are unknown. The present multipdisciplinary application uses behavioral, pharmacological, and molecular techniques to determine the modulatory role of sigma receptors on ethanol reward and reinforcement in distinct models of excessive ethanol consumption. Two models of excess ethanol intake will be studied, genetically selected alcohol-preferring rats and withdrawn outbred rats niade dependent during chronic, intermittent exposure to ethanol vapor, emphasizing positive and negative reinforcing properties of ethanol, respectively. Ethhanol self-admlnistrartation will be pharmacologically modulated (Specific Aim 1), through the administration of novel sigma receptor ligands, and molecularly (in Specific Aim 2), Through the use of sigma-1 receptor KO mice. The impact of chronic exposure to ethanol and of innate preference for ethanol on sigm receptor protein expression in discrete limbic brains regions wil lbe investigated in Specific Aim 3. impact of chronic exposure to ethanol and of innate preference for ethanol on a receptor protein expression in discrete limbic brain regions will be investigated in Specific Aim 3.

该项目将在波士顿丰富的神经科学社区的波士顿大学进行，涉及西格玛受体，这是调节其他神经递质系统的独特哺乳动物结合位点，并且在边缘脑结构中丰富表达。药理学研究表明西格玛受体调节可卡因和甲基苯丙胺的作用。最近，西格玛受体也被提议调节乙醇的激励特性，这与人类酒精中毒中西格玛受体多态性的发现一致。然而，直到最近，对σ受体系统的理解还因缺乏特异性、亚选择性配体或缺乏σ受体亚基的突变小鼠模型而受到阻碍。此外，西格玛受体在自愿摄入或自我施用乙醇中的作用尚不清楚。目前的多学科应用使用行为、药理学和分子技术来确定西格玛受体在不同的过量乙醇消耗模型中对乙醇奖赏和强化的调节作用。将研究两种过量乙醇摄入的模型，即基因选择的偏好酒精的大鼠和在慢性、间歇性暴露于乙醇蒸气期间依赖于尼亚德的撤回远交大鼠，分别强调乙醇的正增强和负增强特性。乙醇的自我给药将受到药理学调节（具体目标 1），通过给予新型 sigma 受体配体，以及分子（具体目标 2），通过使用 sigma-1 受体 KO 小鼠。长期接触乙醇和对乙醇的先天偏好对离散边缘脑区域 sigm 受体蛋白表达的影响将在具体目标 3 中进行研究。长期接触乙醇和对乙醇的先天偏好对受体蛋白表达的影响离散的边缘脑区域将在具体目标 3 中进行研究。