Brain corticosterone and alcohol: mechanisms

脑皮质酮和酒精：机制

• 批准号: 6559663
• 负责人: HILARY J LITTLE
• 金额: $ 24.3万
• 依托单位: U OF L ST. GEORGE'S HOSPITAL MEDICAL SCH
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6559663
• 关键词: alcoholism /alcohol abuse; brain metabolism; corticosteroid receptors; corticosterone; corticotropin releasing factor; drug withdrawal; enzyme activity; enzyme inhibitors; high performance liquid chromatography; hydroxysteroid dehydrogenases; laboratory mouse; laboratory rat; neurochemistry; neurohormones; neuropharmacology; polymerase chain reaction; receptor binding; steroid 11beta monooxygenase

DESCRIPTION (provided by applicant): Glucocorticoid hormones have important influences in alcohol dependence; raised circulating plasma glucocorticoid levels are associated with increased voluntary consumption of alcohol. This research group has recently found regional brain concentrations of corticosterone are increased after withdrawal from chronic alcohol intake in rodents, even though the blood concentrations of this hormone are unchanged. This effect is of importance not only with respect to alcohol consumption, but also the cognitive deficits caused by chronic excess alcohol intake. Pharmacological prevention of the increase in brain corticosterone paralleled the prevention of the deficits in memory during the abstinence phase after chronic alcohol intake. The primary aim of the current work is to elucidate the mechanism(s) by which the brain corticosterone concentrations are increased, by neurochemical and molecular biological examination of corticosterone metabolism in brain tissue after prolonged alcohol consumption by rodents. The hypothesis to be tested is that the increases in brain concentrations of corticosterone are due to the combination of the neuronal hyperexcitability that occurs during alcohol withdrawal and alterations in activity of the enzymes controlling corticosterone concentrations in neuronal tissue, as a result of prolonged exposure to alcohol. Neurochemical and molecular biological measurements will be made of the effects of chronic alcohol consumption on the activity of 11-beta-steroid dehydrogenase and 11-beta-hydroxylase, and levels of mRNA for these enzymes. Effects of inhibitors of these enzymes, and of glucocorticoid antagonists, will be examined on the increases in brain corticosterone, the cognitive deficits and neuronal damage caused by chronic alcohol consumption. The possible involvement of corticotrophin releasing factor will also be examined. A further objective is to determine the cellular location of the increases in corticosterone and the relationship of the concentration increases to glucocorticoid receptor binding in the brain.

描述(申请人提供)：糖皮质激素在酒精依赖中有重要影响；循环血浆糖皮质激素水平升高与自愿饮酒增加有关。这个研究小组最近发现，在啮齿动物停止长期饮酒后，大脑局部皮质酮的浓度会增加，尽管这种激素的血液浓度没有变化。这种影响不仅对饮酒很重要，而且对长期过量饮酒造成的认知缺陷也很重要。在长期饮酒后的戒酒阶段，药物预防大脑皮质酮的增加与预防记忆缺陷是平行的。本工作的主要目的是通过对啮齿动物长期饮酒后脑组织皮质酮代谢的神经化学和分子生物学检测，阐明啮齿动物长期饮酒后脑组织皮质酮浓度升高的机制(S)。需要检验的假设是，大脑皮质酮浓度的增加是由于酒精戒断过程中神经元的过度兴奋，以及由于长期接触酒精而导致神经元组织中控制皮质酮浓度的酶的活性发生变化的结果。神经化学和分子生物学测量将对长期饮酒对11-β-类固醇脱氢酶和11-β-羟基酶活性的影响，以及这些酶的mRNA水平的影响。这些酶的抑制剂和糖皮质激素拮抗剂的效果将被检查，以增加大脑皮质酮，认知缺陷和长期饮酒造成的神经元损伤。促肾上腺皮质激素释放因子的可能参与也将被检测。另一个目标是确定皮质酮增加的细胞位置以及浓度增加与大脑中糖皮质激素受体结合的关系。