Excessive alcohol drinking and CNS regional changes in gene expression

过量饮酒与中枢神经系统区域基因表达变化

• 批准号: 7680285
• 负责人: WILLIAM J MCBRIDE
• 金额: $ 19.06万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 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 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7680285
• 关键词: Alcohol abuse; Alcohol consumption; Alcoholism; Alcohols; Amygdaloid structure; Animal Model; Animals; Blood alcohol level measurement; Boutos; Breeding; Cell Nucleus; Chronic; Colorado; Complex; Consumption; Data; Development; Elements; Environmental Risk Factor; Ethanol; Event; Gene Expression; Genes; Genetic; Goals; Heavy Drinking; In Situ Hybridization; Indiana; Maintenance; Measurement; Meta-Analysis; Molecular; Mus; Neurobiology; Neuronal Plasticity; Nucleus Accumbens; Procedures; Protocols documentation; Rat Strains; Rattus; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Sampling; Schedule; Signal Pathway; Signal Transduction; Synapses; Techniques; Testing; Texas; Time; Work; alcohol exposure; binge drinking; design; drinking; neuroimaging; neurotransmission; research study

DESCRIPTION (provided by applicant): The long-range goals of this proposal are to better understand the molecular neurobiological events that underlie the development of excessive alcohol drinking, and contribute to the long-range consequences of excessive alcohol drinking. The overall hypothesis to be tested is that changes in the expression of genes involved in neurotransmission, neuroplasticity, and intracellular signaling pathways within discrete regions of the extended amydala (E-AMYG) contribute to the development of excessive alcohol drinking. Excessive drinking is defined as sustainable blood alcohol concentrations (BACs) in the range of 100-150 mg% that are repeatedly attained over a chronic period. The overall hypothesis will be tested using selectively bred alcohol-preferring (P) and high-alcohol-drinking (HAD) rats. Micro-punch techniques will be used to obtain samples containing the nucleus accumbens shell (ACB-sh) and central nucleus of the amygdala (CeA). Changes in gene expression will be determined using Affymetrix microarrays. RT-PCR and in situ hybridization will be used to verify key findings from the microarray experiments. The excessive alcoholdrinking paradigm to be used will be the 'drinking in the dark multiple scheduled access' (DID-MSA) procedure. Time-course changes in gene expression will be determined following a drinking episode, and during the development of excessive alcohol drinking. The specific aims will be designed to determine changes in gene expression within the ACB-sh and CeA of P and HAD rats prior to, during initiation of, and following development of excessive alcohol drinking. The effects of chronic alcohol exposure and the development of excessive alcohol drinking are influenced by multiple genetic and environmental factors. This project will provide important molecular neurobiological information in discrete regions of the E-AMYG of genetically vulnerable subjects that could more comprehensively describe the complex inter- and intracellular events leading to the development, maintenance, and consequences of excessive alcohol drinking. Such information would be critically important for developing pharmacotherapeutic strategies to treat alcoholism and alcohol abuse.

描述（由申请人提供）：该提案的长期目标是更好地了解导致过量饮酒的分子神经生物学事件，并促成过量饮酒的长期后果。要测试的总体假设是，扩展杏仁核（E-AMYG）离散区域内涉及神经传递、神经可塑性和细胞内信号通路的基因表达的变化导致了过度饮酒的发生。过量饮酒被定义为在长期时间内反复达到的可持续血液酒精浓度 (BAC) 在 100-150 mg% 的范围内。总体假设将使用选择性饲养的嗜酒 (P) 和高度饮酒 (HAD) 大鼠进行测试。将使用微冲压技术来获取含有伏隔核壳（ACB-sh）和杏仁核中央核（CeA）的样本。 将使用 Affymetrix 微阵列测定基因表达的变化。 RT-PCR 和原位杂交将用于验证微阵列实验的关键发现。所使用的过量饮酒范例将是“黑暗中饮酒多次计划访问”(DID-MSA) 程序。基因表达的时程变化将在饮酒事件后以及过量饮酒的发展过程中确定。具体目标是确定 P 和 HAD 大鼠在过量饮酒之前、开始期间和之后 ACB-sh 和 CeA 内基因表达的变化。长期接触酒精的影响和过度饮酒的发展受到多种遗传和环境因素的影响。该项目将在遗传易感受试者的 E-AMYG 离散区域提供重要的分子神经生物学信息，这些信息可以更全面地描述导致过量饮酒的发展、维持和后果的复杂的细胞间和细胞内事件。 这些信息对于制定治疗酗酒和酒精滥用的药物治疗策略至关重要。