Effects of probenecid on striatal dopamine depletion in acute and long-term 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice.

1. The effect of probenecid on striatal dopamine depletion in acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice was examined. 2. Mice treated with a single dose of MPTP (15 mg/kg, s.c.) showed a significant depletion of striatal dopamine throughout a time-course of 7 days. Interestingly, this MPTP-induced striatal dopamine depletion was potentiated by a concomitant injection with a single dose of probenecid (250 mg/kg, i.p.). 3. However, this potentiation of dopamine depletion by probenecid was only a transient phenomenon seen at 4-5 days after the treatment. 4. In a long-term study, mice were treated with the same dosages of MPTP or probenecid plus MPTP twice a week for 5 weeks, we detected that probenecid plus MPTP caused a persistent depletion of striatal DA for 6 months. 5. During this period a partial recovery of DA levels was seen with MPTP alone-treated mice. 6. The detailed mechanisms by which probenecid causes acute potentiation and persistent long-term depletion of striatal dopamine by MPTP are still unclear. 7. With the evidence presented in this study, we determined that after the administration of MPTP in mice, the drug was rapidly metabolized in the periphery and excreted as MPTP N-oxide. 8. Probenecid was shown to inhibit the excretion of urine and urinary MPTP N-oxide shortly after MPTP administration, which may directly or indirectly increase the neurotoxic action of MPTP in mice.