Objective:Estrogen-mediated neuroprotection in the nigrostriatal dopamine system,depend on the estrogen receptors (ERs),is now widely accepted. In the present study,the role of the two ERs in MPTP toxicity was investigated. Methods:Adult male wild type (WT),ERs knock out (αERKO and βERKO) mice were treated with MPTP. To determine the degree of bradykinesia,pole test was performed. Quantitative real time PCR was used to examine selective genes of the dopaminergic system. Results:Our data demonstrated that administration of 1-methyl-4-phenyl-1,2,3,6-tetrapyridine (MPTP,11 mg/kg) to WT mice led to depletion of DA,DOPAC and HVA. The degree of DA depletion in the αERKO mice was greater than WT mice. Behavioral testing showed that MPTP-injected mice exhibited motor deficits in the pole test. After 2 days of MPTP treatment,a significant prolongation of T-LA was observed in αERKO mice. We also observed that mRNA expression of ERα was significantly increased in the striatum and midbrain in MPTP-treated animals,while the expression of ERβ decreased. The expression of tyrosine hydroxylase(TH),dopamine transporter(DAT) and vesicular monoamine transporter subtype 2(VMAT2) mRNA were decreased in αERKO and βERKO mice. The down-regulation of TH and DAT mRNAs by MPTP in the midbrain acted on both ERα and ERβ,whereas MPTP treatment lead to decreased mRNA expression of VMAT2 via ERα. Conclusion:Our results suggested that estrogen acting via ERs is an important regulative factor for the nigrostriatal dopamine system,ERα may play a more significant role.