Differentiation of disulfiram effects on central catecholamines and hepatic ethanol metabolism

Disulfiram is used in the treatment of chronic alcoholism, because of the u npleasant symptoms it provokes after ethanol intake. The underlying mechani sm is believed to be the accumulation of acetaldehyde in the blood, due to inhibition of the liver aldehyde dehydrogenases. In addition, it is known t hat disulfiram also has some neurotoxic properties. The aim of our study wa s to investigate the relationship between the pharmacological and neurotoxi cological properties of disulfiram with respect to the doses applied. Incre asing doses of disulfiram (25, 50, 75, 100 and 150 mg/kg) were administered intraperitoneally to Wistar rats and the hepatic enzyme activities of alco hol and aldehyde dehydrogenases were measured. Also, in two brain subregion s (midbrain and hypothalamus) the levels of noradrenaline, dopamine, 3,4-di hydroxyphenylacetic acid and homovanillic acid were determined. The higher dose of disulfiram (150 mg/kg) produced lethal effects in all treated anima ls. Aldehyde dehydrogenase activities were inhibited by disulfiram in a dos e-dependent way, while alcohol dehydrogenase was not affected at all. Conce rning the levels of brain biogenic amines, disulfiram produced a significan t reduction in noradrenaline and an increase in dopamine levels in both str uctures of the brain, in a dose-dependent way. However, the lowest dose app lied (25 mg/kg) had no effects on brain catecholamines. It is known that hi gh doses of disulfiram may cause severe encephalopathy and peripheral neuro pathy in humans, which could be attributed to the impairment of the metabol ism of brain biogenic amines, due to inhibition of dopamine-beta -hydroxyla se. Our experimental data show that disulfiram affects the level of brain b iogenic amines at dose levels higher than those inhibiting the activity of aldehyde dehydrogenase. Therefore, in clinical practice 'disulfiram reactio n' could still be achieved with a low dosage regimen not producing neurotox icity.