Diethyldithiocarbamate causes nigral cell loss and dopamine depletion withnontoxic doses of MPTP

Although nontoxic when administered alone, diethyldithiocarbamate (DDC) is known to enhance the dopamine-depleting effects of 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP) in the mouse striatum. The purpose of the prese nt study was twofold: (i) to carefully characterize the effects of DDC on M PTP-induced degeneration of dopaminergic neurons in substantia nigra pars c ompacts using unbiased, stereological cell counting techniques and (ii) to determine whether or not DDC can convert a nontoxic dose of MPTP into one w hich is clearly toxic on dopaminergic neurons in the substantia nigra. A si ngle low dose of MPTP (15 mg/kg intraperitoneally (ip)) was used for these studies, which failed to induce any neurochemical or histological effects o n the nigrostriatal system of C57BL/6 mice when administered alone. However , when animals were pretreated with DDC (400 mg/kg ip), the same dose of MP TP resulted in a 50% loss of neurons in the substantia nigra pars compacta, as well as a 70% reduction in striatal dopamine (DA). A 31% reduction of D A in the ventral mesencephalon was also seen. This combined regimen of DDC and MPTP was not significantly different from a maximally tolerated "toxic" dose of MPTP alone (15 mg/kg x 4, 1 h apart, ip). As expected, animals rec eiving DDC alone did not show any dopamine depletion nor nigral neuronal lo ss. The present study confirms previous work suggesting that DDC enhances M PTP-induced nigral cell loss and shows for the first time that DDC can "unm ask" MPTP toxicity. These observations could have implications for theories on the cause of Parkinson's disease. (C) 1999 Academic Press.