Role of sigma receptors in ethanol reinforcement

西格玛受体在乙醇强化中的作用

• 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
• 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

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。申请人将由乔治Koob博士指导行为神经科学方法和酒精中毒动物模型，并由Pietro Sanna博士共同指导免疫组织化学和分子技术。该项目将在圣地亚哥丰富的神经科学社区的斯克里普斯研究所进行，涉及sigma受体，独特的哺乳动物结合位点，调节其他神经递质系统，并在边缘脑结构中丰富表达。药理学研究表明，σ受体调节可卡因和甲基苯丙胺的作用。最近，σ受体也被提出来调节乙醇的激励特性，与人类酒精中毒中σ受体多态性的发现一致。 然而，直到最近，对σ受体系统的理解一直受到特定的、亚型选择性配体或缺乏σ受体亚型的突变小鼠模型的不可用性的阻碍。此外，σ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在不同的过度饮酒模型中，具有亚型特异性的σ受体对乙醇奖励和强化的调节作用。在具体目标1和3中，将研究两种过量乙醇摄入的模型--在慢性、间歇性暴露于乙醇蒸汽期间，分别强调乙醇的积极和消极强化特性，使遗传选择的酒精偏好大鼠和撤回的远系大鼠产生依赖性。乙醇自身给药将通过给予新的α受体配体而进行分子调节（在特定目标1中），并通过使用o-1受体KO小鼠而进行分子调节（在特定目标2中）。长期暴露于乙醇和先天偏好乙醇对离散边缘脑区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：该项目将确定生理和潜在的治疗相关性下的特点调节受体系统的酒精滥用和依赖。