Impaired Adaptation of the Hypothalamic-Pituitary-Adrenal Axis to Chronic Ethanol Stress in Aged Rats

Acute injection of ethanol in young rats stimulates corticosterone secretion, and repeated daily ethanol injection results in tolerance to this response. This study examined the tolerance development of the corticosterone response to 14 daily ethanol injections (2 g/kg i.p.) in young (3-month-old) and aged (24-month-old) male rats. By day 7 the young rats exhibited complete tolerance to the stimulatory effects of ethanol on corticosterone levels, as measured 1 h after injection. In contrast, the aged rats displayed a fairly large corticosterone response to ethanol on day 7, and they still exhibited a significant corticosterone response to ethanol on day 14. There was no difference between young and aged rats in blood ethanol levels at any time point examined, and blood ethanol levels did not change across days of treatment, indicating that neither the tolerance development, nor the age-related difference in tolerance development could be explained by time- and age-related differences in ethanol metabolism. There also was little evidence for the impaired tolerance development in the aged rats to be secondary to a generalized dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis following 2 weeks of ethanol treatment. Thus, there was no difference in basal corticosterone levels between young and aged rats on each test day, and there was no difference between young and aged rats in the corticosterone response to an acute restraint stress challenge when administered 24 h after the last day of ethanol treatment. This study suggests that in aged rats there are changes in the adaptive mechanisms contributing to tolerance of the HPA axis response to ethanol.