DIFFERENTIAL MECHANISMS IN THE EFFECTS OF DISULFIRAM AND DIETHYLDITHIOCARBAMATE INTOXICATION ON STRIATAL RELEASE AND VESICULAR TRANSPORT OFGLUTAMATE

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 dis ulfiram (7 and 500 mg kg(-1) i.p.) and equimolar doses (4 and 290 mg k g(-1) i.p.) of its metabolite diethyldithiocarbamate (DDC), roughly co rresponding to the daily maximum dose in alcohol abusers or to an esti mated nonlethal overdose, respectively. The striatal, extracellular le vels of glutamate in freely moving rats previously implanted with a mi crodialysis probe increased after low and intoxicating doses of disulf iram (126 +/- 3% and 154 +/- 10% of basal values, respectively) and DD C 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-evok ed release of glutamate from striato-cortical synaptic vesicles, where the drug nonspecifically inhibited (K-i approximate to 4 mu M) the up take function and abolished the transmembrane proton gradient (Delta p H). In contrast, DDC did not seem to affect Delta pH, The prompt DDC-p rovoked increase in extracellular levels of glutamate was prevented by 7-nitroindazole, an in vivo specific inhibitor of neuronal nitric oxi de synthase, which suggests that the thiol metabolite also acts via th e nitric oxide synthesis. At variance, the short-acting 7-nitroindazol e did not prevent the sustained in vivo effects of disulfiram and of D DC putatively formed with time. These findings provide new evidence fo r differential mechanisms underlying disulfiram-and DDC-induced increa ses in striatal glutamate release. Present glutamatergic changes, alth ough not appearing dramatic enough to represent the only cause for neu ronal damage from disulfiram overdose, might contribute to the drug ne urotoxicity.