Glucocorticoid receptor antagonism and cognition in alcoholics

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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 former symptoms are very difficult to treat, largely because the changes in the brain that cause the memory problems are not yet understood, and also because there are different patterns of excess alcohol drinking. If the mechanisms involved in the memory problems are understood, this will enable effective treatments to be developed that will improve quality of life and reduce health costs. Recent laboratory and clinical studies have suggested that changes in the brain when someone stops drinking excessively are responsible for memory deficits. Excess of the stress hormones known as glucocorticoids is known to result in damage to nerves in the brain and to result in memory loss, and these are released in high concentrations during alcohol detoxification. Work has also shown that a drug, mifepristone, that prevents actions of the important stress hormone cortisol on a particular brain protein, known as the Type II glucocorticoid receptor, has beneficial effects in those who suffer from memory problems and also in people who are clinically depressed, but this has not yet been studied in alcoholics. Laboratory studies, however, demonstrated that prevention of actions of cortisol at this receptor protein decreases the nerve damage caused by cessation of long term alcohol consumption. This project will measure the effects of the drug mifepristone in a group of alcoholics who enter the treatment unit to undergo alcohol detoxification. Measures will be made of performance in tests of cognitive ability, and also depressive symptoms, since the latter can contribute to memory loss. If the results of this project are positive it will suggest that the receptor protein is involved in the genesis of the memory deficits and/or the depressive symptoms. Such knowledge will aid the development of new treatments that would provide effective therapy for these problems that are suffered by large numbers of alcoholics.