DISULFIRAM AND DIETHYLDITHIOCARBAMATE INTOXICATION AFFECTS THE STORAGE AND RELEASE OF STRIATAL DOPAMINE

Acute intoxication and chronic therapy with the alcohol consumption de terrent dithiocarbamate disulfiram have been associated with several n eurological complications perhaps involving the impairment of neurotra nsmitter pathways. In this study we have tested the hypothesis that do paminergic malfunction is a critical component in disulfiram-evoked ne urotoxicity. Disulfiram antagonized the in vitro striatal binding of [ H-3]tyramine, a putative marker of the vesicular transporter for dopam ine, and the uptake of [H-3]dopamine into striatal synaptic vesicles, with inhibitory constants (K-i) in the range of reported blood dithioc arbamate levels in treated alcoholics. Furthermore, disulfiram provoke d a loss of radioactivity from [H-3]dopamine-preloaded striatal vesicl es, when added directly to the incubation mixture. Several metal-conta ining fungicide analogs were also potent displacers of specifically bo und [H-3]tyramine. Diethyldithiocarbamate (DDC), the major metabolite of disulfiram, had none of these effects. The intraperitoneal injectio n of a high dose of disulfiram and DDC into rats, mimicking acute into xication, induced in vivo overflow of striatal dopamine from both a re serpine-sensitive (vesicular) and an alpha-methyl-p-tyrosine-sensitive (cytoplasmic) pool. The vesicular component of in vivo dopamine relea se resulted mainly from a direct activity of disulfiram on the organel les (interaction with the carrier for dopamine plus membrane permeabil ization) and indirectly through the mediation of serotonergic 5-HT3 re ceptors. DDC acted poorly at the vesicle membrane, and the in vivo rel easing effect of dopamine was only partially prevented by the inhibiti on of 5-HT3 receptors, thus suggesting the role of additional mechanis ms. It is concluded that disulfiram intoxication may acutely disrupt d opamine balance, an effect probably underlying some of the central neu rotoxic, extrapyramidal symptoms associated with dithiocarbamate overd ose. (C) 1996 Academic Press, Inc.