We investigated to determine whether acute administration of proteasome inhibitor can cause dopaminergic cell loss in mice, in comparison with that of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The four intraperitoneally administrations of MPTP at 1-h intervals to mice decreased significantly the concentration of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum after 5 days, in comparison with vehicle-treated animals. In contrast, the three subcutaneously administrations of carbobenzoxy-L-γ-t-butyl-L-glutamyl-L-alanyl-L-leucinal (PSI) did not show significant changes in the concentration of dopamine, DOPAC and HVA in the striatum after 5 days, in comparison with vehicle-treated animals. Our Western blot analysis also showed that the four administrations of MPTP at 1-h intervals to mice produced a significant reduction of anti-tyrosine hydroxylase antibody (TH) protein levels in the striatum after 5 days after. In PSI-treated mice. In contrast, no significant change of TH protein levels was observed in the striatum 5 days after the final treatment with PSI. Furthermore, a significant decrease of TH protein levels was observed in the striatum of MPTP-treated mice, as compared with PSI-treated animals. The present study demonstrates that the acute treatment with proteasome inhibitor PSI did not cause the dopaminergic neurotoxicity in mice, as compared with acute treatment with MPTP. Thus, our findings suggest that acute proteasome inhibition is not a reliable model for Parkinson's disease.