Neuroactive Steroids and Allostasis Induced by Ethanol/Stress

乙醇/压力诱导的神经活性类固醇和动态平衡

• 批准号: 8423704
• 负责人: A LESLIE MORROW
• 金额: $ 20.32万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-10 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8423704
• 关键词: Adrenal Glands; Affinity; Age; Air; Alcohol consumption; Alcoholism; Amygdaloid structure; Antibodies; Area; Beds; Brain; Brain region; Breathing; Cell Nucleus; Chronic; Collaborations; Control Animal; Detection; Electrophysiology (science); Ethanol; Exhibits; Gas Chromatography; Gene Expression; Genetic; Goals; Grant; Heavy Drinking; Hypothalamic structure; Immunohistochemistry; Individual; Investigation; Lead; Macaca mulatta; Mass Spectrum Analysis; Measures; Monkeys; Mouse Strains; Mus; Neurons; Nucleus Accumbens; Pituitary Gland; Prefrontal Cortex; Primates; Rattus; Recording of previous events; Regulation; Rewards; Role; Specimen; Steroids; Stress; Structure of terminal stria nuclei of preoptic region; Testing; Time; Tissues; Universities; Work; acute stress; addiction; alcohol effect; alcohol exposure; allostasis; base; chronic alcohol ingestion; drinking; drinking behavior; extracellular; forest; immunoreactivity; insight; male; neurochemistry; neurosteroids; novel; novel therapeutics; preference; pregnane-20-one; response; stressor; stria terminalis

DESCRIPTION (provided by applicant): The goal of this project is to systematically delineate the effects of chronic intermittent ethanol (CIE) exposure on GABAergic neuroactive steroids and their regulation in limbic brain areas after stress challenge. Both neuronal and extracellular neuroactive steroid levels will be examined by immunohistochemistry as well as gas chromatography-mass spectroscopy (GC-MS) analysis of microdialysates and/or tissue specimens, allowing investigation of limbic brain regions for the first time. We propose to test the hypotheses that ethanol exposure dysregulates basal or stress-induced levels of these steroids and these changes are related to ethanol consumption. We will further explore genetic contributions to adaptations in neurosteroid levels or responses. The first aim will determine the effects of CIE on neuronal vs. extracellular 3a,5a-THP levels in limbic/reward brain areas, including the prefrontal cortex, nucleus accumbens, amygdala, and bed nucleus of the stria terminalis of C57BL/6J mice. Aim 2 will delineate the effect of acute stress challenge on neuronal vs. extracellular 3a,5a-THP in limbic brain areas and the effect of stress challenge following five cycles of CIE in C57BL/6J mice. Aim 3 will determine if basal or CIE-related neuroactive steroid levels in limbic/reward brain areas are correlated with ethanol preference drinking across BXD mouse strains. Aim 4 will extend and compare our studies on neuroactive steroid adaptations to CIE in mice to primates. We will delineate the effects of prolonged ethanol drinking on 3a,5a-THP levels in limbic brain areas of rhesus monkeys. Our results will be integrated with changes in neuronal function, neurochemistry, gene expression and ethanol drinking behavior studies by our collaborators under the same experimental conditions. These studies will elucidate the effects of ethanol on GABAergic neuroactive steroids in limbic regions of brain and provide novel insights into the role of basal and stress-induced neuroactive steroids in various allostatic adaptations to chronic intermittent ethanol exposure.

描述（由申请人提供）：该项目的目标是系统地描述慢性间歇性乙醇（CIE）暴露对 GABA 神经活性类固醇的影响及其在应激挑战后对边缘脑区域的调节。神经元和细胞外神经活性类固醇水平将通过免疫组织化学以及微透析液和/或组织标本的气相色谱-质谱（GC-MS）分析进行检查，从而首次对边缘脑区域进行研究。我们建议测试以下假设：乙醇暴露会调节这些类固醇的基础或应激诱导水平，并且这些变化与乙醇消耗有关。我们将进一步探索遗传对神经类固醇水平或反应适应的贡献。第一个目标是确定 CIE 对边缘/奖励脑区域神经元与细胞外 3a,5a-THP 水平的影响，包括 C57BL/6J 小鼠的前额皮质、伏隔核、杏仁核和终纹床核。目标 2 将描述急性应激挑战对边缘脑区域神经元与细胞外 3a,5a-THP 的影响，以及 C57BL/6J 小鼠 CIE 五个周期后应激挑战的影响。目标 3 将确定边缘/奖励大脑区域的基础或 CIE 相关神经活性类固醇水平是否与 BXD 小鼠品系的乙醇偏好饮用相关。目标 4 将扩展并比较我们关于小鼠和灵长类动物对 CIE 的神经活性类固醇适应的研究。我们将描述长期饮用乙醇对恒河猴边缘脑区域 3a,5a-THP 水平的影响。我们的结果将与我们的合作者在相同实验条件下进行的神经元功能、神经化学、基因表达和乙醇饮用行为研究的变化相结合。这些研究将阐明乙醇对大脑边缘区域 GABA 能神经活性类固醇的影响，并为基础和应激诱导的神经活性类固醇在慢性间歇性乙醇暴露的各种稳态适应中的作用提供新的见解。