Target Validation byAccumbal Plasticity Screening

通过 Accumbal 可塑性筛选进行目标验证

• 批准号: 8231597
• 负责人: RICHARD A MORRISETT
• 金额: $ 24.15万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8231597
• 关键词: Alcohol consumption; Alcohol dependence; Animal Model; Back; Behavior; Behavioral; Biological Assay; Brain; Candidate Disease Gene; Chemosensitization; Chronic; Cocaine; Cues; Data; Dependence; Depressed mood; Development; Dopamine Receptor; Ensure; Ethanol; Ethanol dependence; Exhibits; Exposure to; Extinction (Psychology); Frequencies; Gene Targeting; Glutamate Receptor; Glutamates; Goals; Heavy Drinking; Heroin; In Vitro; Individual; Injection of therapeutic agent; Intake; Location; Long-Term Depression; Measures; Methods; Modeling; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Negative Reinforcer; Neurons; Nucleus Accumbens; Pathway interactions; Peptide Fragments; Pharmaceutical Preparations; Positive Reinforcer; Process; Publishing; RNA Interference; Reporting; Research; Research Personnel; Rodent; Screening procedure; Self Administration; Slice; Structure; Synapses; Synaptic Transmission; Synaptic plasticity; Testing; Validation; Work; alcohol exposure; behavioral sensitization; conditioned fear; conditioning; design; drug of abuse; drug seeking behavior; experience; in vivo; neuroadaptation; novel; novel therapeutics; prevent; psychostimulant; reinforcer; research study; response; vapor

DESCRIPTION (provided by applicant): A major goal of INIA-West is to identify novel therapeutics for excessive alcohol consumption and prior INIA-West efforts have identified and characterized rodent animal models of excessive intake, and candidate genes and associated targets that are altered in these models. The next iteration of INIA-West is directed at identifying which of these gene targets should be targeted for further analysis. Therefore, a simple yet functionally meaningful assay to test whether a target may exhibit efficacy for excessive ethanol intake would be extremely valuable. We and our co-investigators have developed substantial evidence that changes in glutamatergic synaptic plasticity in the nucleus accumbens constitute a critical neuroadaptive response to repeated exposure to positive and negative reinforcers. Furthermore, disruption of the processes underlying the changes in glutamate receptor location and function (GluR2 subunit internalization) modulates behavioral responses to such reinforcers. Therefore, we propose that accumbal plasticity constitutes exactly such a functionally meaningful assay. We propose two main hypotheses to investigate the utility of NAc plasticity as a functional screen for novel targets for ethanol dependence. In Specific Aim 1 we propose to identify how prolonged disruption of GluR2 subunit internalization in vivo modulates excessive ethanol intake using two models: CIE with two-bottle choice and operant ethanol self-administration. In Specific Aim 2 we propose to screen novel gene targets identified by INIA-West components for modulation of accumbal plasticity under baseline conditions and following CIE exposure. This aim will use the INIA-West RNA interference (RNAi) core and we will work in close coordination with our INIA-West colleagues who are focused upon detailed analyses of these individual INIA-West targets. Thus, in aim 2, we will determine whether interference with INIA-West target expression modulates NAc LTD. Finally, as we show in our preliminary data, NAc LTD is predominant in NAc MSNs ofthe direct pathway that express Dl-dopamine receptors, we will ensure that plasticity will be screened for all experiments in DI-NAc MSNs using mice derived from MIVIRRC GENSAT drdl-eGFP Swiss Webster mice back-crossed to the C57BI6/J background. PUBLIC HEALTH RELEVANCE: This project is designed to work within a larger research consortium to optimize the likelihood that novel therapeutics for the treatment of alcohol dependence are discovered. We propose to determine whether candidates alter brain functions implicated in the development of dependence to a variety of drugs of abuse.

描述（由申请人提供）：INIA-WEST的一个主要目标是确定过度饮酒的新型治疗剂，并且先前的Inia-West努力已经确定并表征了过度摄入的啮齿动物模型，以及这些模型中改变的候选基因和相关靶标。 Inia-West的下一次迭代旨在确定应将哪些基因靶标的目标作为进一步分析。因此，一个简单而功能上有意义的测定方法，用于测试目标是否可能对过度乙醇摄入表现出疗效，这将是非常有价值的。我们和我们的共同投资者已经开发了大量证据，表明伏隔核中谷氨酸能突触可塑性的变化构成了对反复暴露于正面和负增强剂的重复暴露的关键神经适应反应。此外，破坏谷氨酸受体位置和功能变化（GLUR2亚基内部化）的过程的破坏会调节对此类增强剂的行为反应。因此，我们提出伏托塑性恰好构成了这种功能有意义的测定法。我们提出了两个主要假设，以研究NAC可塑性作为乙醇依赖性新目标的功能屏幕的实用性。在特定目的1中，我们建议确定使用两个模型使用两个模型：具有两瓶选择和操作乙醇自我给药的CIE延长体内Glur2亚基内在化的延长中断。在特定的目标2中，我们建议筛选由INIA-West成分确定的新型基因靶标，以调节基线条件和CIE暴露后的副伏塑性。这个目标将使用INIA-West RNA干扰（RNAI）核心，我们将与我们的Inia-West同事密切协调，这些同事专注于对这些个体INIA-West目标的详细分析。因此，在AIM 2中，我们将确定干扰INIA-WEST目标表达是否会调节NAC LTD。最后，正如我们在初步数据中所示，NAC LTD在表达DL-多巴胺受体的直接途径的NAC MSN中占主导地位，我们将确保使用从MIVIRRC Gensat Drdl-EGFP swisst drdl-Egfp swisster jebformes c51的di-NAC MSN中筛选所有实验的可塑性，以筛选出可塑性。 公共卫生相关性：该项目旨在在较大的研究联盟内运行，以优化发现用于治疗酒精依赖性的新型治疗方法的可能性。我们建议确定候选人是否改变了与各种滥用药物依赖的发展有关的大脑功能。