The purpose of this study was to examine the relationship between the development of tolerance to ethanol and the hypothalamic-pituitary-adrenal cortex (H-P-AC) system by modifying the H-P-AC system through the use of a synthetic glucocorticoid, dexamethasone. Also this study determined whether repeated drug administration and environmental adaptation would facilitate development of tolerance. Rats injected daily with dexamethasone and ethanol showed an antagonism to the acute effects of ethanol and a higher rate of tolerance development to the depressant effect of ethanol than animals administered ethanol only. These results were discussed in relation to a possible stimulant effect of dexamethasone on behavior, an increase in the metabolism of ethanol, and a possible accumulation of dexamethasone in the brain, affecting an organism's response to ethanol. It also was shown that daily ethanol administration and adaptation to the testing environment facilitated the development of tolerance, compared to ethanol administration only.