Tolerance to disulfiram induced by chronic alcohol intake in the rat.
BACKGROUND
Disulfiram, an inhibitor of aldehyde dehydrogenase used in the treatment of alcoholism, is an effective medication when its intake is supervised by a third person. However, its therapeutic efficacy varies widely, in part due to the fact that disulfiram is a pro-drug that requires its transformation into an active form and because it shows a wide range of secondary effects which often prevent the use of doses that ensure full therapeutic effectiveness. In this preclinical study in rats we report the development of tolerance to disulfiram induced by the chronic ingestion of ethanol, an additional source of variation for the actions of disulfiram with possible therapeutic significance, We also addresses the likely mechanism of this effect.


METHODS
Wistar-derived rats bred for generations as high ethanol drinkers (UChB) were trained for either 3 days (Group A) or 30 days (Group B) to choose between ethanol (10% v/v) or water, which were freely available from 2 bottles on a 24-hour basis. Subsequently, animals in both groups were administered disulfiram or cyanamide (another inhibitor of aldehyde dehydrogenase) and ethanol intake in this free choice paradigm was determined. Animals were also administered a standard dose of 1 g ethanol/kg (i.p) and arterial blood acetaldehyde was measured.


RESULTS
Disulfiram (12.5 and 25 mg/kg) and cyanamide (10 mg/kg) markedly inhibited ethanol intake (up to 60 to 70%) in animals that had ethanol access for only 3 days (Group A). However both drugs were inactive in inhibiting ethanol intake in animals that had consumed ethanol for 30 days (Group B). Following the injection of 1 g ethanol/kg, arterial blood acetaldehyde levels reached levels of 150 and 300 microM for disulfiram and cyanamide respectively, values which were virtually identical regardless of the length of prior ethanol intake of the animals.


CONCLUSIONS
Chronic ethanol intake in high-drinker rats leads to marked tolerance to the aversive effects of disulfiram and cyanamide on ethanol intake despite the presence of consistently high levels of blood acetaldehyde. These findings may have implications for the use of disulfiram for the treatment of alcoholism in humans.
Tampier
Lutske
L
Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile. ltampier@med.uchile.cl
Quintanilla
María Elena
ME
Israel
Yedy
Y
D000079:Acetaldehyde / Q000097:blood; D000426:Alcohol Dehydrogenase / Q000037:antagonists & inhibitors; D000427:Alcohol Deterrents / Q000494:pharmacology*; D000428:Alcohol Drinking / Q000188:drug therapy*; D000437:Alcoholism / Q000188:drug therapy; D000818:Animals; D003484:Cyanamide / Q000494:pharmacology / Q000627:therapeutic use; D004221:Disulfiram / Q000494:pharmacology* / Q000627:therapeutic use; D004361:Drug Tolerance; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000431:Ethanol / Q000008:administration & dosage*; D005260:Female; D051381:Rats; D017208:Rats, Wistar
D000427:Alcohol Deterrents; D004791:Enzyme Inhibitors; D000431:Ethanol; D003484:Cyanamide; D000426:Alcohol Dehydrogenase; D000079:Acetaldehyde; D004221:Disulfiram