Aged, cognitively-impaired rats (and humans) show hypothalamic-pituitary-adrenal (HPA) hyperactivity that correlates with hippocampal damage. The resultant increase in plasma glucocorticoid exposure is thought to contribute to impaired hippocampal function and to potentiate hippocampal neuron death. In young, adult rats antidepressant drugs increase corticosteroid receptor expression in brain regions known to regulate the HPA axis, leading to increased negative-feedback control and decreased HPA activity. In the present study we examined basal levels of plasma adrenocorticotropin hormone (ACTH) and corticosterone in aged, cognitively-impaired (AI), aged, cognitively-unimpaired (AU) and young, adult (Yg) rats. Plasma ACTH and corticosterone levels were significantly elevated in the AI rats, but only in samples obtained during the diurnal peak. Five weeks of treatment with desipramine (15 mg/kg) significantly reduced evening levels of both ACTH and corticosterone in all groups, and eliminated the group differences. We then examined delayed, glucocorticoid negative feedback in these animals. Among vehicle-treated animals, a bolus injection of corticosterone (10 mg/kg), administered 3 hours prior to testing, completely inhibited the plasma ACTH response to restraint in AU and Yg, but not AI animals. In contrast, plasma ACTH responses to restraint were completely inhibited in AI rats following chronic treatment with desipramine. These findings indicate that the antidepressant, desipramine, decreases HPA activity and increases glucocorticoid negative-feedback sensitivity in AI rats, suggesting that antidepressant drugs may form a useful therapeutic approach to HPA dysfunction in elderly human populations.