Psychopharmacology 64, 123 - 124 (1979) Psychopharmacology 9 by Springer-Verlag 1979 Cortexolone Antagonizes Development of Alcohol Tolerance in Mice Boris Tabakoff and Joseph Yanai* Department of Physiology and Biophysics University of Illinois at the Medical Center Chicago, Illinois 60612 Abstract. Mice treated with cortexolone during a period of chronic ethanol feeding displayed significantly less tolerance to a challenge dose of ethanol than mice fed ethanol but not given cortexolone. This glucocorticoid receptor blocker did not alter the hypnotic effects of ethanol in animals not previously given ethanol and no differences were found in ethanol consumption or blood ethanol levels between ethanol-fed mice receiving daily injections of cortexolone and the vehicle-injected controls. It was concluded that cortexolone interferes with the development of tolerance to ethanol. Key words: Ethanol - Glucocorticoids - Tolerance Recent work from our laboratories has demonstrated that circulating levels of glucocorticoids are increased in mice throughout a period of chronic ethanol con- sumption (Tabakoff et al., 1978), which under our feeding paradigm results in the development of toler- ance to and dependence on ethanol (Ritzmann and Tabakoff, 1976). Since glucocorticoids have been shown to play a "permissive" role in the development of certain signs of physical dependence in mice (Sze et al., 1974), and to affect the development of ethanol tolerance (Wood, 1977), we administered cortexolone, a glucocorticoid receptor blocker (Melnykovych and Bishop, 1971), to mice during the time that the animals were consuming ethanol and tested the effects of this treatment on the development of tolerance to the hypnotic effects of ethanol. Methods Male C57B1/6 mice (24 +_2g) were divided into four groups. Group 1 (vehicle-sucrose) received a subcutaneous injection of corn * Present address: Department of Anatomy and Embryology, Hebrew University Hadassah Medical School, Jerusalem, Israel oil (0.1 ml) daily for 7 days and was fed a liquid diet consisting of Carnation Slender, which contained sucrose (96.8 g/l) and vitamin supplement (ICN Pharmaceuticals,Cleveland,Ohio; 3 g/l). Group 2 (cortexolone-sucrose) received a daily subcutaneous injection of cortexolone (Steraloids, Inc., Pawling, New York) prepared as a suspension in oil in a dose of 20 mg/kg and was fed the sucrose- containing diet as described for Group 1. Group 3 (vehicle-ethanol) received daily injections of corn oil, was fed the sucrose-containing diet for 1 day and then transferred to a diet of Carnation Slender containing ethanol (59.6g/1) and vitamin supplement (3g/l). The ethanol was calculated to be equicaloric to the sucrose contained in the diets of Groups 1 and 2, and the intake of sucrose-containing diet by mice of Groups 1 and 2 was restricted from the 2nd day to equal the volume of diet consumed by mice of Groups 3 and 4. After 5 days of consuming the ethanol-containing diet, the mice assigned to Group 3 were again fed the sucrose diet. Group 4 (cortexolone-etha- nol) was injected daily with cortexolone as was Group 2 but received the ethan61-containing diet beginning on the 2nd day and for 5 days thereafter. Mice of Group 4 again receivedthe sucrose diet on the 7th day of the experiment. The dose of cortexolone used in these experiments was equivalent to the dose previously shown to inhibit induction by dexamethasone of tyrosine hydroxylase in rat superior cervical ganglia (Hanbauer et al., 1975) and was also shown to antagonize the increase in mouse liver tyrosine transaminase pro- duced by dexamethasone (1 mg/kg) (Tabakoff, unpublished obser- vation). The cortexolone was prepared as a suspensionby sonication immediately prior to injection. Tolerance to the hypnotic effects of ethanol was determined 24 h after dietary administration of ethanol was terminated. The adminis- tration of cortexolone or the vehicle for cortexolone was also terminated 24 h prior to testing for tolerance.At the time &tolerance testing, all mice received an i.p. injectionof ethanol, 3 g/kg and were monitored for duration of the loss of righting reflex, "sleep time" (Ritzmann and Tabakoff, 1976; Tabakoff and Ritzmann, 1977). Results The mice of the vehicle-ethanol and cortexolone- ethanol groups consumed similar amounts of ethanol- containing diet and did not differ in their blood ethanol levels during the time that they were consuming ethanol. Ethanol metabolism, measured by previously described methods (Ritzmann and Tabakoff, 1976) at the time of tolerance testing, was also similar in the vehicle-ethanol and cortexolone-ethanol mice. 0033-3158/79/0064/0123/$01.00