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: 8898474
• 负责人: A LESLIE MORROW
• 金额: $ 2.45万
• 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/8898474
• 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）：该项目的目的是系统地描述慢性间歇性乙醇（CIE）暴露对GABA能神经活性类固醇的影响及其在压力挑战后边缘大脑区域的调节。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气相色谱质量光谱法（GC-MS）分析微料疗法和/或组织样品，从而首次研究边缘脑区域。我们建议测试乙醇暴露失调的基础或应力诱导的这些类固醇水平的假设，这些变化与乙醇消耗有关。我们将进一步探讨对神经类固醇水平或反应中适应的遗传贡献。第一个目的将确定CIE对边缘/奖励大脑区域中神经元与细胞外3A的影响，包括前额叶皮层，伏伏核，杏仁核和C57BL/6J小鼠的基质末端的床核。 AIM 2将描述急性应力挑战对神经元与细胞外3A的影响，边缘大脑区域中的5A-THP以及在C57BL/6J小鼠中五个CIE之后，应力挑战的影响。 AIM 3将确定边缘/奖励大脑区域中与基础或CIE相关的神经活性类固醇水平是否与BXD小鼠菌株之间的乙醇偏好饮酒有关。 AIM 4将扩展并比较我们对小鼠CIE神经活性类固醇适应的研究与灵长类动物的研究。我们将描述长时间乙醇饮用对恒河猴边缘大脑区域3A，5A-THP水平的影响。我们的结果将与我们的合作者在相同的实验条件下的神经元功能，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中GABA能神经活性类固醇的作用，并为基础和应激诱导的神经活性类固醇在各种同种异体适应性适应慢性间歇性乙醇暴露中的作用提供新的见解。