Abstract
Mice withdrawn from exposure for 14 days to ethanol inhalation showed the expected signs of ethanol withdrawal including convulsive behaviour. Injection of chlormethiazole (100 mg/kg) 5 h after the start of withdrawal, at the time that the convulsive behaviour was near maximal, resulted in the virtual disappearance of the withdrawal — induced behaviour within 30 min, with its reappearance by 60 min. A dose of chlormethiazole of 40 mg/kg was without effect. The time course of the effect of chlormethiazole (100 mg/kg) in the withdrawal test was similar to its effect in raising seizure threshold and decreasing locomotor activity. Chlormethiazole did not alter in vitro binding of [3H]-PN 200-110 to the dihydropyridine sensitive Ca2+ channel. Chlormethiazole, a drug used clinically to treat ethanol withdrawal, has therefore been shown to be effective in this animal model of withdrawal. Dihydropyridine calcium antagonists are also active in the model but chlormethiazole is likely to work by a different mechanism and it is suggested that this may be by increasing GABAergic function.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Bone GHA, Majchrowiez E, Martin PR, Linnoila M, Nutt DJ (1989) A comparison of calcium antagonists and diazepam in reducing ethanol withdrawal tremors. Psychopharmacology 99:386–388
Burroughs AK, Morgan MY, Sherlock S (1985) Double blind controlled trial of bromocriptine, chlordiazepoxide and chlormethiazole for alcohol withdrawal symptoms. Alcohol Alcoholism 20:263–271
Cross AJ, Stirling JM, Robinson TN, Bowen DM, Francis PT, Green AR (1989) The modulation by chlormethiazole of the GABAA receptor complex in the rat brain. Br J Pharmacol 98:284–290
Evans JG, Feuerlein W, Glatt MM, Kanowski S, Scott DB (1986) Chlormethiazole 25 years: recent developments and historical perspectives. Acta Psychiatr Scand [Suppl 329] 73:1–198
Goldstein DB, Pal N (1971) Alcohol dependence produced in mice by inhalation of ethanol; grading the withdrawal reaction. Science. 172:288–290
Harrison NL, Simmonds MA (1983) Two distinct interactions of barbiturates and chlormethiazole with the GABAA receptor complex in rat cuneate nucleus in vitro. Br J Pharmacol 80:387–394
Jostell KG, Fagan D, Bjork M, Broberg F, Mitchell RM, Scott DB, Ulff B (1986) The bioavailability and pharmacodynamics of chlormethiazole in healthy young and elderly volunteers: preliminary findings. Acta Psychiatr Scand [Suppl 329] 73:32–33
Littleton JM, Little HJ, Whittington MA (1990) Effects of dihydropyridine calcium channel antagonists in ethanol withdrawal; doses required, stereospecificity and actions of Bay K8644. Psychopharmacology 100:387–392
Liljequist S, Culp S, Tabakoff B (1986) Effect of ethanol on the binding of 35S-T-butylbicyclophosphorothionate to mouse brain membranes. Life Sci 38:1931–1939
Moody EJ, Skolnick P (1989) Chlormethiazole: neurochemical interactions at the γ-aminobutyric acid receptor complex. Eur J Pharmacol 164:153–158
Nutt DJ, Cowen PJ, Green AR (1981) Studies on the post-ictal rise in seizure threshold. Eur J Pharmacol 71:287–293
Ogren S-O (1986) Chlormethiazole — mode of action. Acta Psychiatr Scand [Suppl 329] 73:13–27
Robinson BJ, Robinson GM, Maling TJB, Johnson RH (1989) Is clonidine useful in the treatment of alcohol withdrawal? Alcoholism: Exp Res 13:95–98
Thyagarajan R, Ticku MK (1985) The effect of in vitro and in vivo ethanol administration on [35S]-t-butylbicyclophosphorothionate binding in C57 mice. Brain Res Bull 15:343–345
Ticku MK (1980) The effect of acute and chronic ethanol administration and its withdrawal on gamma-aminobutyric acid receptor binding in rat brain. Br J Pharmacol 70:403–410
Whittington MA, Little HJ (1988) Nitrendipine prevents the ethanol withdrawal syndrome when administered chronically with ethanol prior to withdrawal. Br J Pharmacol 94:385P
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Green, A.R., Davies, E.M., Little, H.J. et al. Action of chlormethiazole in a model of ethanol withdrawal. Psychopharmacology 102, 239–242 (1990). https://doi.org/10.1007/BF02245928
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF02245928