Ethanol differentially regulates proadrenocorticotropin/endorphin production and corticosterone secretion in LS and SS lines of mice.

The stimulatory effects of ethanol administration on the hypothalamic-pituitary-adrenal (HPA) axis were investigated in the long sleep (LS) and short sleep (SS) lines of mice, selectively bred for differences in sensitivity to ethanol. To characterize the effects of ethanol exposure on levels of anterior pituitary pro-ACTH/endorphin mRNA, animals were treated with ethanol for either 4 or 7 days. Northern analyses of total RNA extracted from anterior pituitary indicated that ethanol-treated SS mice had 1.5-fold higher pro-ACTH/endorphin mRNA levels on day 4 and 2.5-fold higher mRNA levels on day 7 than SS control mice. Although ethanol-treated LS mice had 4-fold higher pro-ACTH/endorphin mRNA levels on day 4 compared to those in control LS mice, by day 7 pro-ACTH/endorphin mRNA levels in ethanol-treated LS mice were 40% less than LS control levels. Quantitation of pro-ACTH/endorphin-related peptide biosynthesis was determined by immunoprecipitation and sodium dodecyl sulfate-polyacrylamide gel electrophoresis of extracts from [35S]methionine-labeled anterior pituitary explants. Ethanol treatment for 7 days increased pro-ACTH/endorphin biosynthesis in SS mice, but decreased pro-ACTH/endorphin biosynthesis in LS mice. These results parallel the effect of ethanol on pro-ACTH/endorphin mRNA levels. Serum corticosterone levels also paralleled pro-ACTH/endorphin production in both lines of mice. In summary, ethanol acutely activates the HPA axis in SS mice, and this activation is sustained after repeated ethanol administration. In contrast, LS mice have initial activation of the HPA axis, which attenuates after repeated ethanol exposure. LS and SS mice may be appropriate models for understanding the mechanism(s) responsible for the differential activation of the HPA axis by ethanol and the development of pseudo-Cushing's syndrome in man.