Pn. Karamanakos et al., Differentiation of disulfiram effects on central catecholamines and hepatic ethanol metabolism, PHARM TOX, 88(2), 2001, pp. 106-110
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.