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：
7893284
负责人：
VALENTINA SABINO
金额：
$ 24.9万
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/7893284
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 Two models of excess ethanol intake will be studied, genetically selected alcohol-preferring rats and withdrawn outbred rats niade dependent during chronic, intermittent exposure to ethanol vapor, emphasizing positive and negative reinforcing properties of ethanol,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界的波士顿大学进行，涉及Sigma受体，独特的哺乳动物结合位点，这些哺乳动物结合位点调节其他神经递质系统，并且在边缘大脑结构中丰富表达。药理学研究表明，Sigma受体调节可卡因和甲基苯丙胺的作用。最近，还提出了Sigma受体来调节乙醇的激励性能，这与人类酒精中毒中Sigma受体多态性的发现一致。然而，直到最近，特异性，微妙的选择性配体或缺乏Sigma受体受体stt5t的突变小鼠模型的不可用而阻碍了对Sigma受体系统的理解。此外，Sigma受体在自愿摄入或乙醇自我管理中的作用尚不清楚。目前的多学科应用使用行为，药理学和分子技术来确定Sigma受体在过度乙醇消耗的不同模型中Sigma受体在乙醇奖励和增强中的调节作用。将研究两个模型的乙醇摄入量过多的模型，在慢性，间歇性暴露于乙醇蒸气期间，依赖于基因选择的饮酒大鼠NIADE依赖于乙醇，分别强调乙醇的阳性和负增强特性。 Ethhanol自我Admlnistrartation将进行药理学调节（特定目标1），通过使用新型Sigma受体配体的给药，并通过使用Sigma-1受体KO小鼠（在特定目标2中）（在特定目标2中）。在特定目标3中研究的离散边缘大脑区域中，长期暴露于乙醇和对乙醇的先天偏爱对SIGM受体蛋白表达的影响。长期暴露于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大脑区域将在特定目标3中进行研究。