Adrenal glucocorticoids as a required factor in the development of ethanol tolerance in mice

Male C57BL/6J mice were given chronic ethanol treatment by two procedures. One was by a liquid diet containing 6.4% (v/v) ethanol; the other was by repeated injections of ethanol (3.5 g/kg, i.p. twice daily). After 5 days of the liquid diet treatment, sleep time following a challenge dose of ethanol (3.0 g/kg i.p.) was reduced to 10 min as compared with 30 min in the controls not previously exposed to ethanol. After 10 days, none of the ethanol-treated animals slept. Bilateral adrenalectomy (Adx) had no effect on sleep time (34 min). However, the reduction of sleep time in ethanol-treated Adx animals was much less: 19 min after 5 days, and 20 min after 10 days. Replacement with corticosterone in Adx animals restored the reduction of sleep time to the same levels as intact animals, indicating that glucocorticoids are the hormonal factor involved in the Adx effect. By the injection procedure for short-term administration of moderate doses of ethanol, sleep time following the injection of 3.5 g/kg ethanol was reduced from 95 min on day 1 to 57 min on day 3. There was no difference between intact and Adx animals. The results from both treatment procedures suggest that Adx abolished the later, severe stage of tolerance development but not the initial stage. Functional tolerance to ethanol occurring in this advanced stage may be a glucocorticoid-dependent process.