Disulfiram and diethyldithiocarbamate intoxication affects the storage and release of striatal dopamine.
Acute intoxication and chronic therapy with the alcohol consumption deterrent dithiocarbamate disulfiram have been associated with several neurological complications perhaps involving the impairment of neurotransmitter pathways. In this study we have tested the hypothesis that dopaminergic malfunction is a critical component in disulfiram-evoked neurotoxicity. Disulfiram antagonized the in vitro striatal binding of [3H]tyramine, a putative marker of the vesicular transporter for dopamine, and the uptake of [3H]dopamine into striatal synaptic vesicles, with inhibitory constants (Ki) in the range of reported blood dithiocarbamate levels in treated alcoholics. Furthermore, disulfiram provoked a loss of radioactivity from [3H]dopamine-preloaded striatal vesicles, when added directly to the incubation mixture. Several metal-containing fungicide analogs were also potent displacers of specifically bound [3H]tyramine. Diethyldithiocarbamate (DDC), the major metabolite of disulfiram, had none of these effects. The intraperitoneal injection of a high dose of disulfiram and DDC into rats, mimicking acute intoxication, induced in vivo overflow of striatal dopamine from both a reserpine-sensitive (vesicular) and an alpha-methyl-p-tyrosine-sensitive (cytoplasmic) pool. The vesicular component of in vivo dopamine release resulted mainly from a direct activity of disulfiram, on the organelles (interaction with the carrier for dopamine plus membrane permeabilization) and indirectly through the mediation of serotonergic 5-HT3 receptors. DDC acted poorly at the vesicle membrane, and the in vivo releasing effect of dopamine was only partially prevented by the inhibition of 5-HT3 receptors, thus suggesting the role of additional mechanisms. It is concluded that disulfiram intoxication may acutely disrupt dopamine balance, an effect probably underlying some of the central neurotoxic, extrapyramidal symptoms associated with dithiocarbamate overdose.
Vaccari
A
A
Department of Neuroscience B. Brodie, Neurotoxicology Unit, Università Degli Studi di Cagliari, Italy.
Saba
P L
PL
Ruiu
S
S
Collu
M
M
Devoto
P
P
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000427:Alcohol Deterrents / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D000931:Antidotes / Q000008:administration & dosage / Q000633:toxicity*; D001667:Binding, Competitive; D002417:Cattle; D002463:Cell Membrane Permeability / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D004221:Disulfiram / Q000008:administration & dosage / Q000633:toxicity*; D004050:Ditiocarb / Q000008:administration & dosage / Q000633:toxicity*; D004298:Dopamine / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D008297:Male; D008781:Methyltyrosines / Q000494:pharmacology; D015388:Organelles / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism; D044406:Receptors, Serotonin, 5-HT3; D012110:Reserpine / Q000494:pharmacology; D013572:Synaptic Vesicles / Q000187:drug effects / Q000378:metabolism; D014439:Tyramine / Q000378:metabolism; D019805:alpha-Methyltyrosine
D018759:Adrenergic Uptake Inhibitors; D000427:Alcohol Deterrents; D000931:Antidotes; D004791:Enzyme Inhibitors; D008781:Methyltyrosines; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D015102:3,4-Dihydroxyphenylacetic Acid; D019805:alpha-Methyltyrosine; D012110:Reserpine; D004050:Ditiocarb; D004221:Disulfiram; D004298:Dopamine; D014439:Tyramine