Brain corticosterone and alcohol: mechanisms

描述（申请人提供）：糖皮质激素对酒精依赖有重要影响;循环血浆糖皮质激素水平升高与自愿饮酒增加相关。该研究小组最近发现，啮齿动物在长期饮酒后，皮质酮的局部大脑浓度增加，即使这种激素的血液浓度没有变化。这种影响不仅对酒精消费很重要，而且对慢性过量酒精摄入引起的认知缺陷也很重要。药理学预防脑皮质酮增加与预防长期饮酒后戒断期记忆力缺陷有关。本研究的主要目的是通过对啮齿类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，阐明脑皮质酮浓度升高的机制。待检验的假设是，皮质酮脑浓度的增加是由于酒精戒断过程中发生的神经元过度兴奋性和控制神经元组织中皮质酮浓度的酶活性的改变（长期暴露于酒精的结果）的组合。神经化学和分子生物学测量将慢性酒精消费对11-β-类固醇脱氢酶和11-β-羟化酶活性的影响，以及这些酶的mRNA水平。这些酶的抑制剂和糖皮质激素拮抗剂的影响，将检查在大脑皮质酮的增加，认知缺陷和神经元损伤引起的慢性饮酒。促肾上腺皮质激素释放因子的可能参与也将进行检查。另一个目的是确定皮质酮增加的细胞位置以及浓度增加与脑中糖皮质激素受体结合的关系。

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.