Importance of 11-beta-hydroxysteroid dehydrogenase (HSD-1) in the consequences of chronic alcohol consumption

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Alcohol dependence is a chronic relapsing disease, the incidence of which was recently estimated by the Department of Health to be 7% of the adult population. Currently, up to 90% of alcoholics who manage to stop drinking relapse back to the alcohol within a year. Alcohol dependence is a major health problem, and the alcohol consumption causes many other medical disorders and extensive social problems. Between 50 and 80% of alcoholics suffer from memory problems caused by the alcohol consumption and many also have other medical problems, particularly depression. The memory problems have serious effects not only on the quality of life but on the ability of alcoholics to benefit from treatment programmes, since these frequently involve learning new ways of behaviour. The memory loss is very difficult to treat, largely because the changes in the brain that cause the memory problems are not yet understood. If the mechanisms involved in the memory problems are understood, this will enable effective treatments to be developed that will improve quality of life for alcoholics, enable them to obtain more benefit from treatment programmes and reduce health costs. Recent laboratory and clinical studies have suggested that changes in the brain that take place when someone stops drinking excessively are largely responsible for memory deficits. Stopping alcohol drinking also increase the concentrations in the brain of stress hormones known as glucocorticoids. High concentrations of these are known to cause damage to nerves in the brain, and to result in memory problems.Laboratory studies have shown that prevention of the increases in glucocorticoid hormones, or prevention of the actions of these hormones, decreases the nerve damage caused by cessation of long term alcohol consumption. Treatments which have this effect also prevented the memory loss see after withdrawal from chronic alcohol consumption. The aim of the current project is to investigate the mechanism of the increases in brain glucocorticoid concentrations, in particular the role of an enzyme, called HSD-1. The effects of two drugs that prevent the effects of HSD-1 will also be studied to see if these prevent the memory loss caused by long-term alcohol intake and withdrawal. Such knowledge will aid the development of new treatments that would provide effective therapy for these problems, which are suffered by large numbers of alcoholics.