We have investigated the effect of the prolonged administration of melatonin on the plasma concentration of glucocorticoids in rats and palm squirrels, whose hypothalamo-pituitaryadrenal axis and renin-angiotensin system were suppressed by the simultaneous administration of dexamethasone and captopril. Dexamethasone and captopril administration for two weeks markedly lowered the blood level of corticosterone in rats and cortisol in palm squirrels. The injection of melatonin during the second week of treatment caused a further significant lowering in the glucocorticoid plasma concentration. These findings suggest that melatonin exerts a sizeable glucocorticoid antisecretagogue effect in rats and squirrels, acting directly on the adrenal glands.Melatonin is a multifunctional hormone, mainly secreted by the pineal gland, the effects of which on the hypothalamo-pituitary-adrenal (HPA) axis are well established (14). To summarize, melatonin is reported to be a potent inhibitor of the central branch of the HPA axis (16), as well as to reset dysregulation of this axis, at least in the rat (7). However, there is a marked disagreement as far as the direct effect of this hormone on the secretory activity of adrenal cortex is concerned. In fact, both stimulating (2, 4, 13, 15) and inhibitory effects have been described (5, 9, 11, 17). All these study were carried out using dispersed or cultured adrenocortical cells, i.e. experimental models which do not reproduce in viva physiolog- ical conditions. It, therefore, seemed worthwhile to study the effect of the prolonged melatonin administration on the blood concentrations of glucocorticoid in rats and palm squirrels, whose HPA axis and renin-angiotensin system (RAS) were pharmacologically interrupted.Adult Sprague-Dawley male rats (ZOO--250g body weight, obtained from Charles-River; Como, Italy), and palm squirrels (Fzmambzzlus pennanri, Wrougton) (300-350g body weight, obtained from the breeding facilities of our Zoology Department) were housed two per cage, kept under a 12:12 h light-dark cycle, and maintained on a standard diet and tap water ad Zibitrzzm. After being adapted to the laboratory conditions for 15 days, the animals were divided into three equal groups (rats: 11:10; palm squirrels: 11:50), which were treated as follows: 1) dexamethasone (2.5 mg/kg; Sigma Chemical Company, St. Louis, MO, U.S.A.) and captopril (8.3 mg/kg; Squibb, Rome, Italy) for 14 days; they were subcutaneously injected twice a day, at 1 a.m. and 1 p.m. to counteract circadian rhythm of glucocorticoids secretion which depends on both HPA axis and