Vaccari A, Saba P L, Ruiu S, Collu M, Devoto P
Department of Neuroscience B. Brodie, Neurotoxicology Unit, Università Degli Studi di Cagliari, Italy.
Toxicol Appl Pharmacol. 1996 Jul;139(1):102-8. doi: 10.1006/taap.1996.0147.
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.
戒酒硫（双硫仑）作为一种酒精摄入阻滞剂，其急性中毒和长期治疗与多种神经并发症有关，可能涉及神经递质通路的损害。在本研究中，我们检验了多巴胺能功能障碍是戒酒硫诱发神经毒性的关键组成部分这一假设。戒酒硫拮抗了[3H]酪胺在体外纹状体的结合，[3H]酪胺是多巴胺囊泡转运体的一种假定标志物，同时也拮抗了[3H]多巴胺向纹状体突触囊泡的摄取，其抑制常数（Ki）在报道的接受治疗的酗酒者血液中双硫仑代谢物水平范围内。此外，当直接添加到孵育混合物中时，戒酒硫会导致预先加载了[3H]多巴胺的纹状体囊泡放射性丧失。几种含金属的杀真菌剂类似物也是特异性结合的[3H]酪胺的有效置换剂。戒酒硫的主要代谢产物二乙胺基二硫代甲酸盐（DDC）没有这些作用。向大鼠腹腔注射高剂量的戒酒硫和DDC以模拟急性中毒，在体内诱导了纹状体多巴胺从对利血平敏感（囊泡）和对α-甲基-p-酪氨酸敏感（细胞质）的池中溢出。体内多巴胺释放的囊泡成分主要源于戒酒硫对细胞器的直接作用（与多巴胺载体相互作用并使膜通透性增加），并间接通过血清素能5-HT3受体介导。DDC在囊泡膜上作用较弱，多巴胺的体内释放作用仅部分被5-HT3受体的抑制所阻止，因此提示存在其他机制。结论是，戒酒硫中毒可能会急性破坏多巴胺平衡,这种作用可能是与二硫代氨基甲酸盐过量相关的一些中枢神经毒性锥体外系症状的潜在原因。
