INIA: Stress, Anxiety of Alcohol Abuse

INIA：酗酒带来的压力和焦虑

• 批准号: 6697331
• 负责人: KATHLEEN A GRANT
• 金额: $ 68.28万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6697331
• 关键词: alcoholic beverage consumption; alcoholism /alcohol abuse; amygdala; anxiety; behavioral /social science research tag; behavioral genetics; biological models; biomedical facility; cooperative study; gene environment interaction; health science research analysis /evaluation; information dissemination; interdisciplinary collaboration; meeting /conference /symposium; neural plasticity; neural transmission; neurotransmitter receptor; neurotransmitters; organized financing; stress; training

DESCRIPTION (provided by applicant): The Administrative Core Component will make sure that all aspects of the INIA consortium work at an optimal level. The core will serve as an identifiable center for entire INIA consortium. This core will be responsible for decisions about research directions, including review of component progress and inclusion and exclusion of investigators. The core will also ensure the proper flow of information between the different consortium components, and flow of information to the larger research community in collaboration with the Bioinformatics Core. The duties of this core will also include organizing and financing all INIA committee meetings, retreats and research presentations. The administrative core will also track the INIA consortium finances and assist in budget planning for the different research components and cores. Stress contributes to excessive drinking and alcoholism, but the molecular and cellular mechanisms that underlie alcohol-stress interactions are not well understood. The brain circuitry involved in coordinating and producing responses to stress is known, and includes the extended amygdala (amygdala, bed nucleus of the stria terminalis and nucleus accumbens (NAc)], the hippocampus (HPC), the prefrontal cortex (PFC) and the hypothalamus. There is also considerable evidence implicating the neurotransmitters glutamate, GABA and serotonin (5-HT) in stress-induced neurophysiological responses in these brain regions. Alcohol effects on synaptic transmission in stress-related brain regions have not been characterized in much detail. Furthermore the role of the aforementioned neurotransmitters in these responses has not been examined. INIA component I will focus on examining synaptic transmission in amygdala, HPC, NAc and PFC in wild-type mice and mice with gene-targeted knockouts of the GABAAbeta3. Delta and gamma2 subunits, the NMDAR2A subunit, theGluRA subunit, the5-HTIA receptor and SERT. Similar experiments will be performed in selected randomly mutagenized mice identified in INIA component 3, and mice from selected BxD recombinant strains identified in INIA component 4. Brain slice preparations and isolated neurons will be examined from all of these groups of mice following chronic alcohol exposure and withdrawal. chronic alcohol self-administration and stress-induced reinstatement of alcohol drinking. Excitatory and inhibitory synaptic transmission will be measured using field potential and intracellular recording in brain slices containing the regions of interest. Synaptic plasticity will also be examined in brain slices. Acutely isolated neurons will be used to examine changes in neurotransmitter receptor function, and single-cell MRNA profiling will be used to identify neuronal subtypes. Serotonin release and reuptake will be examined in brain slices and synaptosomal preparations from the brain regions of interest. These studies will provide crucial information about neuroadaptive changes in synaptic transmission and plasticity induced by ETOH and stress in brain regions implicated in stress responses. We will also gather information about the role of particular neurotransmitter receptors and transporters in these neuroadaptive changes. Findings from this project " Ill be compared to data gathered in INIA components 2, 3 and 4 to generate more integrated information about the neuroadaptive changes related to alcohol-stress interactions. In future studies we will use mice developed by the Knockout Mouse Core and in component 7 in studies such as those proposed at present. Information gained in this component will be compared with that gained in the primate studies proposed in component 5, and will be shared with the larger research community on the INIA web page with the help of the Bioinformatics Core. It is predicted that information from this project will contribute to a better under- standing of the mechanisms underlying stress-alcohol interactions that may lead to better therapies for treating excessive drinking and alcoholism.

描述（由申请人提供）： 行政核心部分将确保INIA的所有方面 联合体在最佳水平上工作。核心将作为可识别的 整个INIA联盟的中心。这个核心将负责决定 关于研究方向，包括审查组成部分的进展， 研究者的入选和排除。核心还将确保适当的 不同联盟组成部分之间的信息流动， 信息向更大的研究界合作， 生物信息学核心。该核心的职责还包括组织和 资助所有INIA委员会会议、务虚会和研究报告。 行政核心还将跟踪INIA财团的财务状况， 协助不同研究部分和核心的预算规划。 压力导致过度饮酒和酒精中毒，但分子和 作为酒精-压力相互作用基础的细胞机制 明白大脑回路参与协调和产生 对压力的反应是已知的，包括延伸的杏仁核（杏仁核， 终纹床核和背侧核（NAc）]， 海马体（HPC）、前额叶皮质（PFC）和下丘脑。有 也有大量证据表明神经递质谷氨酸，GABA 和5-羟色胺（5-HT）在应激诱导的神经生理反应，在这些 大脑区域。酒精对应激相关突触传递的影响 大脑区域还没有被详细描述。此外，作用 在这些反应中的上述神经递质还没有被 考察INIA部分I将集中研究突触传递， 杏仁核，HPC，NAc和PFC在野生型小鼠和小鼠基因靶向 GABAA β 3的敲除。δ和γ 2亚基，NMDAR 2A亚基， GluRA亚单位、5-HTIA受体和SERT。类似的实验将在 在INIA组件中确定的随机诱变小鼠中进行 3，以及来自INIA组分中鉴定的选定BxD重组菌株的小鼠 4.脑切片制备物和分离的神经元将从所有的 这些小鼠在长期酒精暴露和戒断后。 慢性酒精自我管理和压力诱导的恢复 饮酒。兴奋性和抑制性突触传递将 使用脑切片中的场电位和细胞内记录测量 包含感兴趣的区域。突触可塑性也将被检查 在大脑切片中。急性分离的神经元将被用来检查变化， 神经递质受体功能，单细胞mRNA谱将是 用于识别神经元亚型。5-羟色胺的释放和再吸收将是 在脑切片和来自脑区域的突触体制备物中检查 感兴趣这些研究将提供重要信息， ETOH诱导的突触传递和可塑性的神经适应性变化 与压力反应有关的大脑区域。我们还将 收集关于特定神经递质受体的作用的信息， 这些神经适应性变化中的转运蛋白。“疾病”项目的调查结果 与INIA第2、3和4部分收集的数据进行比较， 关于神经适应性变化的综合信息， 酒精与压力的相互作用在未来的研究中，我们将使用 敲除小鼠核心和组分7在研究中，如那些提出的 目前。本部分获得的信息将与 在组成部分5中提议的灵长类动物研究中获得的信息，并将与 更大的研究社区在INIA网页的帮助下， 生物信息学核心。据预测，该项目的信息将 有助于更好地了解 压力与酒精的相互作用可能会导致更好的治疗方法， 过度饮酒和酒精中毒。