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：
7224033
负责人：
VALENTINA SABINO
金额：
$ 7.53万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
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 2008-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7224033
关键词：
Agonist Alcohol abuse Alcohol consumption Alcoholism Alcohols Animal Model Animals Area Attenuated Behavioral Behavioral Model Binding Sites Brain Brain region Chronic Cocaine Commit Communities Dependence Development Plans Disruption Drug abuse Ethanol Ethanol dependence Exposure to Genes Genetic Polymorphism Glutamates Human Intake Ligands Mental disorders Mentors Methamphetamine Methods Modeling Molecular Mus Neurosciences Neurotransmitters Numbers Personal Satisfaction Pharmaceutical Preparations Physiological Play Property Psychological reinforcement Rattus Reporting Research Research Institute Rewards Role Self Administration Signal Transduction Pathway Specificity Structure System Techniques Therapeutic Wild Type Mouse alcohol effect alcohol exposure alcohol preferring rats alcohol reinforcement alcohol reward base career insight mutant mouse model noradrenergic novel post-doctoral training preference protein expression receptor receptor expression research study response sigma receptors tool vapor

项目摘要

DESCRIPTION (provided by applicant): Summary: The application proposes a career development plan for Dr. Valentina Sabino, a pharmacologically-trained post-doctoral fellow committed to a research career in ethanol addiction aimed towards understand its molecular basis. The applicant will be mentored by Dr. George Koob in behavioral neuroscience methods and animal models of alcoholism and co-mentored by Dr. Pietro Sanna in immunohistochemical and molecular techniques. The project, to be conducted at The Scripps Research Institute in the rich neuroscience community of San Diego, 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, subtype-selective ligands or of mutant mouse models that lack sigma receptor subtypes. Furthermore, the role of sigma receptors in voluntary intake or self-administration of ethanol are unknown. The present multipdisciplinary application uses behavioral, pharmacologic, and molecular techniques to determine the modulatory role of sigma receptors with subtype specificity on ethanol reward and reinforcement in distinct models of excessive ethanol consumption. Two models of excess ethanol intake will be studied in Specific Aims 1 and 3 -- genetically selected alcohol-preferring rats and withdrawn outbred rats made dependent during chronic, intermittent exposure to ethanol vapor, emphasizing positive and negative reinforcing properties of ethanol, respectively. Ethanol self-administration will be pharmacologically modulated (in Specific Aim 1), through the administration of novel a receptor ligands, and molecularly (in Specific Aim 2), through the use of o-1 receptor KO mice. The impact of chronic exposure to ethanol and of innate preference for ethanol on o receptor protein expression in discrete limbic brain regions will be investigated in Specific Aim 3. Relevance: The project will define the physiologic and potential therapeutic relevance of an under characterized modulatory receptor system for alcohol abuse and dependence.

描述（由申请人提供）：摘要：该申请为 Valentina Sabino 博士提出了职业发展计划，Valentina Sabino 博士是一位经过药理学培训的博士后研究员，致力于乙醇成瘾的研究生涯，旨在了解其分子基础。申请人将得到 George Koob 博士在行为神经科学方法和酗酒动物模型方面的指导，并由 Pietro Sanna 博士在免疫组织化学和分子技术方面共同指导。该项目将在圣地亚哥神经科学社区的斯克里普斯研究所进行，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，由于缺乏特异性亚型选择性配体或缺乏西格玛受体亚型的突变小鼠模型，对西格玛受体系统的理解一直受到阻碍。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具有亚型特异性的西格玛受体在不同的过量乙醇消耗模型中对乙醇奖励和强化的调节作用。具体目标 1 和 3 将研究两种过量乙醇摄入的模型——基因选择的偏好酒精的大鼠和戒断的近交系大鼠在长期、间歇性暴露于乙醇蒸气期间产生依赖，分别强调乙醇的正增强和负增强特性。乙醇的自我给药将通过给予新型α受体配体进行药理学调节（在具体目标1中），并通过使用o-1受体KO小鼠进行分子调节（在具体目标2中）。长期接触乙醇和对乙醇的先天偏好对离散边缘脑区域的 o 受体蛋白表达的影响将在具体目标 3 中进行研究。相关性：该项目将定义特征不明的调节受体系统的生理和潜在治疗相关性酗酒和依赖。