Novel Mechanism of Ethanol Discrimination

乙醇歧视的新机制

• 批准号: 7027586
• 负责人: JOYCE BESHEER
• 金额: $ 10.49万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7027586
• 关键词: GABA receptor; NMDA receptors; amygdala; behavioral /social science research tag; confocal scanning microscopy; diazepam; discrimination learning; dizocilpine; ethanol; fos protein; glutamate receptor; hippocampus; immunocytochemistry; inhibitor /antagonist; laboratory rat; light microscopy; microinjections; nucleus accumbens; protein protein interaction; psychopharmacology; receptor expression; stimulant /agonist; substance abuse related behavior

DESCRIPTION (provided by applicant): The overall goal of this proposal is to provide mentored career development for a young scientist. The training and research support detailed in this proposal will enable the Candidate to utilize a multidisciplinary approach to understand factors that modulate the stimulus properties of ethanol. Importantly, this training will contribute to her development as an independent investigator. The Candidate will receive broad-based training in alcoholism research as well as several methods that will be required to address the research plan including immunohistochemistry techniques, confocal microscopy, stereotaxic surgeries and microinjection of drugs. The research plan will focus on the role of metabotropic glutamate receptors (mGluRs) in ethanol's discriminative stimulus effects. mGluRs have been shown to influence GABAA and glutamate functioning which are major components of ethanol's stimulus properties. The Candidate will test the hypothesis that mGluRS and mGluR2/3 can modulate ethanol discrimination by interaction with GABAA and NMDA receptor systems. Specific Aim 1 will utilize behavioral pharmacology techniques to determine if an antagonist of mGluRS and an agonist of mGluR2/3 will modulate ethanol discrimination, and the ethanol-like stimulus properties of GABAA positive modulators and NMDA antagonists. Specific Aim 2 will use dual-label immunohistochemistry with confocal visualization to evaluate if mGluRS and mGluR2/3 are co-expressed with GABAA and NMDA receptor subunits in ethanol discrimination trained rats. Specific Aim 3 will use immunohistochemisty techniques (Fos-like immunoreactivity) to assess brain regional involvement in ethanol discrimination and in mGluRS and mGluR2/3 modulation of ethanol discrimination and ethanol substitutes (diazepam and MK-801). Specific Aim 4 will use microinjection techniques to assess ethanol discrimination and the substitution of diazepam and MK-801 after administration of the mGluRS antagonist and the mGluR2/3 agonist into specific brain regions that show high levels of mGluR co-expression with GABAA and NMDA receptors as determined from Aim 2 and show anatomical involvement as determined from Aim 3. We predict that these experiments will reveal a modulatory role of mGluRS and mGluR2/3 in ethanol discrimination. Further, incorporating these techniques is highly innovative, and these studies will generate novel findings regarding the involvement of mGluRS and mGluR2/3 in the stimulus properties of ethanol. Understanding these mechanisms is important to basic science and has numerous implications for development of therapeutic interventions in alcoholism, especially given that the discriminative stimulus properties of drugs can be important determinants of abuse liability.

描述（由申请人提供）：该提案的总体目标是为年轻科学家提供指导的职业发展。本提案中详细介绍的培训和研究支持将使候选人能够利用多学科方法来了解调节乙醇刺激特性的因素。重要的是，这项培训将有助于她作为独立调查员的发展。候选人将接受基于酒精中毒研究的广泛培训，以及几种应对研究计划所需的方法，包括免疫组织化学技术，共聚焦显微镜，立体定位手术和对药物的显微注射。该研究计划将重点介绍代谢型谷氨酸受体（MGLURS）在乙醇判别刺激效应中的作用。已显示MGLUR会影响GABAA和谷氨酸功能，这是乙醇刺激特性的主要组成部分。候选人将测试MGLURS和MGLUR2/3可以通过与GABAA和NMDA受体系统相互作用来调节乙醇歧视的假设。具体目标1将利用行为药理学技术来确定mglurs的拮抗剂和mglur2/3的激动剂是否会调节乙醇歧视，以及GABAA阳性调节剂和NMDA拮抗剂的乙醇样刺激特性。特定的目标2将使用共聚焦可视化使用双标签免疫组织化学来评估MGLURS和MGLUR2/3是否与乙醇歧视训练的大鼠中的GABAA和NMDA受体亚基共表达。具体目标3将使用免疫组织化学技术（FOS样免疫反应性）来评估大脑区域参与乙醇歧视，MGLURS和MGLUR2/3调节乙醇鉴别和乙醇替代品（致致变氧素和MK-801）。具体目标4将使用微注射技术来评估乙醇歧视并在给药MGlurs拮抗剂和MGLUR2/3激动剂后给予地西epam和Mk-801取代特定的大脑区域，这些特定的大脑区域显示出高水平的MGLUR共同表达与GABAA和NMDA受到的启用，并显示了这些目标2和NMDA受到的范围2，并显示了ANSON的范围。 mglurs和mglur2/3在乙醇歧视中的调节作用。此外，结合这些技术具有高度创新性，这些研究将产生有关mglurs和mglur2/3参与乙醇刺激特性的新发现。了解这些机制对基础科学很重要，并且对酒精中毒的治疗干预措施具有许多影响，尤其是考虑到药物的歧视性刺激特性可能是滥用责任的重要决定因素。