Altered ACTH and corticosterone responses to interleukin-1 beta in male rats exposed to an alcohol diet: possible role of vasopressin and testosterone.

We have previously shown that female rats exposed to an alcohol (ethanol, E) diet exhibited a blunted ACTH response to systemically administered interleukin-1β (IL-1β). Because of the presence of gender differences in the activity of the hypothalamic-pituitary-adrenal (HPA) axis, and of the possible role played by sex steroids in modulating the inhibitory influence of E in females, we studied the ability of a 10-day E diet to alter ACTH and corticosterone secretion of intact or castrated male rats injected with IL-1β or endotoxin, a releaser of endogenous cytokines. Pituitary responsiveness to secretagogues that mediate the endocrine effects of IL-1β, namely corticotropin-releasing factor (CRF) and vasopressin (VP), was also investigated. The ACTH responses of animals fed ad libitum (C group) or pair-fed (PF group) to the intravenous administration of IL-1β or endotoxin were not statistically different (p > 0.05); therefore, results from these two groups were combined in the initial experiments. Subsequent experiments only used E and C animals. When compared with this latter group, intact E males showed a significant (p < 0.01) decrease in ACTH levels measured 30 and 60 min after the intravenous injection of IL-β or endotoxin. In contrast, E rats released as much corticosterone as C rats in response to IL-10, but significantly (p < 0.05) more following administration of endotoxin (lipopolysaccha-ride). The stimulatory effect of VP on ACTH release was also measurably blunted by alcohol, whereas that of CRF was not. In none of these experiments were any significant differences observed between C and PF rats. As E rats had markedly lowered circulating testosterone (T) concentrations, and as androgens exerted a restraining effect on the activity of the HPA axis, we then tested the hypothesis that these decreased T values might interact with the inhibitory influence of alcohol. Intact, castrated, or castrated/T-replaced rats fed a control or an alcohol diet all showed comparable pituitary responses to CRF. Alcohol decreased ACTH released in response to IL-β in control and castrated rats. Removal of androgens increased the relative responsiveness of the HPA axis of castrated rats to IL-1β, whether or not they were fed alcohol. In contrast, rats administered T exogenously showed an even larger blunting of their ACTH response to VP, compared with castrated animals without androgen therapy. These results indicate that, as previously shown for females, exposure of male rats to an alcohol diet blunts ACTH released by IL-1β or endotoxin, but not CRF. In addition, we show that activation of the males' pituitary by VP was also blunted by alcohol. Decreased plasma T levels caused by alcohol may participate in the blunted response of the HPA axis to IL-1β, but not to VP. Finally, despite the fact that E rats showed lower plasma ACTH levels than control animals in response to IL-1β, their corticosterone secretion was not proportionally altered. Indeed, adrenal responsiveness of rats injected with endotoxin appeared to be increased by alcohol because similar findings were not obtained upon VP administration. It is possible that, in males, alcohol facilitates a direct stimulatory influence of cytokines on adrenal activity.