Differential mechanisms in the effects of disulfiram and diethyldithiocarbamate intoxication on striatal release and vesicular transport of glutamate.
Intoxication with the alcohol-aversive drug disulfiram (Antabuse) and related dithiocarbamates may provoke neuropathies and, in some cases, damage the basal ganglia. Rats received a single administration of disulfiram (7 and 500 mg kg-1 i.p.) and equimolar doses (4 and 290 mg kg-1 i.p.) of its metabolite diethyldithiocarbamate (DDC), roughly corresponding to the daily maximum dose in alcohol abusers or to an estimated nonlethal overdose, respectively. The striatal, extracellular levels of glutamate in freely moving rats previously implanted with a microdialysis probe increased after low and intoxicating doses of disulfiram (126 +/- 3% and 154 +/- 10% of basal values, respectively) and DDC as well (135 +/- 10% and 215 +/- 14%, respectively), a partially Ca++-dependent effect. The prolonged (>7 hr) disulfiram-induced increase in glutamate observed in vivo may reflect the in vitro disulfiram-evoked release of glutamate from striato-cortical synaptic vesicles, where the drug nonspecifically inhibited (Ki approximately 4 microM) the uptake function and abolished the transmembrane proton gradient (DeltapH). In contrast, DDC did not seem to affect DeltapH. The prompt DDC-provoked increase in extracellular levels of glutamate was prevented by 7-nitroindazole, an in vivo specific inhibitor of neuronal nitric oxide synthase, which suggests that the thiol metabolite also acts via the nitric oxide synthesis. At variance, the short-acting 7-nitroindazole did not prevent the sustained in vivo effects of disulfiram and of DDC putatively formed with time. These findings provide new evidence for differential mechanisms underlying disulfiram- and DDC-induced increases in striatal glutamate release. Present glutamatergic changes, although not appearing dramatic enough to represent the only cause for neuronal damage from disulfiram overdose, might contribute to the drug neurotoxicity.
Vaccari
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A
"Bernard B. Brodie" Department of Neuroscience, Neurotoxicology Unit, University of Cagliari, Cagliari, Italy.
Ferraro
L
L
Saba
P
P
Ruiu
S
S
Mocci
I
I
Antonelli
T
T
Tanganelli
S
S
D000427:Alcohol Deterrents / Q000506:poisoning*; D000818:Animals; D000931:Antidotes / Q000506:poisoning*; D001692:Biological Transport / Q000187:drug effects; D004221:Disulfiram / Q000506:poisoning*; D004050:Ditiocarb / Q000506:poisoning; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D008744:Methylamines / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014793:Visual Cortex / Q000187:drug effects / Q000502:physiology
D000427:Alcohol Deterrents; D000931:Antidotes; D008744:Methylamines; D018698:Glutamic Acid; D004050:Ditiocarb; C027451:methylamine; D004221:Disulfiram