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.
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| Jacquot, Catherine; Croft, Adam P; Prendergast, Mark A et al. (2008) Effects of the glucocorticoid antagonist, mifepristone, on the consequences of withdrawal from long term alcohol consumption. Alcohol Clin Exp Res 32:2107-16 |
| Little, H J; Croft, A P; O'Callaghan, M J et al. (2008) Selective increases in regional brain glucocorticoid: a novel effect of chronic alcohol. Neuroscience 156:1017-27 |
