PharmacologyBiochemistry& Behavior, Vol. 21, pp. 317-319, 1984. ©Ankho International Inc. Printed in the U.S.A. 0091-3057/84 $3.00 + .00 Metronidazole Influences the Development of Neural Tolerance to Ethanol MARY L. A. GIKNIS AND IVAN DAMJANOV Department of Pathology and Laboratory Medicine, Hahnemann University School of Medicine 230 North Broad Street, Philadelphia, PA 19102 Received ll October 1983 GIKNIS, M. L. A. AND I. DAMJANOV. Metronidazole influences the development of neural tolerance to ethanol. PHARMACOL BIOCHEM BEHAV 21(2) 317-319, 1984.--The duration of the loss of the righting reflex (LoRR) was measured in Swiss Webster (SW) and DBA/2 mice following intraperitoneal injection of ethanol or metronidazole alone or together. A single injection of ethanol induced to short LoRR in SW mice and a long LoRR in DBA/2 mice. Metronidazole did not induce LoRR in either strain. When the mice were exposed daily to ethanol for five days, the duration of the LoRR was prolonged in SW mice and shortened in DBA/2 mice. This indicates the development of increased neural sensitivity to ethanol in SW mice and of neural tolerance to ethanol in DBA/2 mice. The response in SW mice to administration of ethanol and metronidazole together did not differ from their response to ethanol alone. However, the duration of the LoRR in DBA/2 mice injected repeatedly with the two drugs was longer than that observed with ethanol alone. Thus metronidazole appears to inhibit the development of neural tolerance to ethanol in DBA/2 mice but has no effect on ethanol induced LoRR in SW mice. Ethanol Metronidazole Flagyl Sleep Genetics METRONIDAZOLE (1-flhydroxyethyl)-2-methyl-5-nitroim- idazole) is a potent trichomonacidal, amebicidal and bac- tericidal compound marketed worldwide [8]. In addition to antiparasitic and antibacterial effects, metronidazole inhibits certain mammalian liver enzymes which are involved in the catabolism of ethanol [4]. The ability of metronidazole to inhibit both alcohol dehydrogenase and aldehyde dehydro- genase has been cited as a possible explanation for the dizzi- ness and nausea which occur in certain individuals following simultaneous ingestion of ethanol and metronidazole [3]. Since metronidazole frequently induces nausea when taken simultaneously with ethanol it has been used as an alterna- tive to disulflram in the treatment of chronic alcoholism [9]. However, nausea following simultaneous ingestion of met- ronidazole and ethanol does not occur in all alcoholics un- dergoing such treatment and therefore is not a universal phe- nomenon [9]. Although there are no clear explanations for the different responses observed among individual patients, the differential sensitivity is perhaps due to genetic differ- ences similar to those which account for individual varia- tions in response to ethanol [6]. In the present study, we have tried to determine whether the response to combined metronidazole-ethanol treatment is a strain-specific phenomenon. To this end we have used mice of two strains known to differ in their response to re- peated injections of ethanol: Swiss Webster mice which de- velop increased neural sensitivity upon repeated exposure to ethanol and DBA/2 mice which develop neural tolerance under identical conditions [2]. We show that metronidazole does not potentiate the effects of ethanol in Swiss Webster mice. On the other hand, it affects the rate at which neural tolerance to ethanol develops in DBA/2 mice. Thus, we show the differential response to combined metronidazole-ethanol treatment could, at least in part, be based on genetic differ- ences between exposed subjects. METHOD Swiss Webster (SW) mice were purchased from Perfec- tion Breeders, Camden, New Jersey and DBA/2 mice from Jackson Laboratories, Bar Harbor, Maine. All experiments were performed on 8-10 week old virgin females, fed Purina Mouse Chow with access to tap water ad lib. The mice were housed, five mice per cage, in a standard animal facility and were maintained on a 12 hour light-dark cycle. All experi- ments were performed between 9 and l0 a.m. in the same animal room. The mice of each strain were divided randomly into four groups of at least l0 animals each. Each group was injected intraperitoneally with one of the following solutions: a 25% solution of ethanol in saline (4 g/kg), a 25% solution of ethanol in saline followed immediately by a solution of met- ronidazole in saline (15 mg/kg), a solution of metronidazole in saline (15 mg/kg) or saline alone. The animals were in- jected every day for a total of five days. They were then allowed to recuperate for one week after which time they were again injected with the test substance(s). Following each injection, the loss of righting reflex (LoRR) of each animal was recorded and the mean duration of the loss of righting reflex after each treatment was calculated for each 'Requests for reprints should be addressed to M. L. A. Giknis, Stein Research Center, 920 Chancellor Street, Philadelphia, PA 19107. 317