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Sigma-1 receptor ( σ  1 R) has been reported to be decreased in nigrostriatal motor system of Parkinson's disease patients. Using heterozygous and homozygous  σ  1 R knockout ( σ  1 R +/−  and  σ  1 R −/− ) mice, we investigated the influence of  σ  1 R deficiency on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-impaired nigrostriatal motor system. The injection of MPTP for 5 weeks in wild-type mice (MPTP-WT mice), but not in  σ  1 R +/−  or  σ  1 R −/−  mice (MPTP- σ  1 R +/−  or MPTP- σ  1 R −/−  mice), caused motor deficits and ~40% death of dopaminergic neurons in substantia nigra pars compacta with an elevation of  N -methyl- d -aspartate receptor (NMDAr) NR2B phosphorylation. The  σ  1 R antagonist NE100 or the NR2B inhibitor Ro25-6981 could alleviate the motor deficits and the death of dopaminergic neurons in MPTP-WT mice. By contrast, MPTP- σ  1 R +/−  mice treated with the  σ  1 R agonist PRE084 or MPTP- σ  1 R −/−  mice treated with the NMDAr agonist NMDA appeared to have similar motor deficits and loss of dopaminergic neurons as MPTP-WT mice. The pharmacological or genetic inactivation of  σ  1 R suppressed the expression of dopamine transporter (DAT) in substantia nigra, which was corrected by NMDA. The activation of  σ  1 R by PRE084 enhanced the DAT expression in WT mice or  σ  1 R +/−  mice. By contrast, the level of vesicular monoamine transporter 2 (VMAT2) in  σ  1 R +/−  mice or  σ  1 R −/−  mice had no difference from WT mice. Interestingly, MPTP-WT mice showed the reduction in the levels of DAT and VMAT2, but MPTP- σ  1 R −/−  mice did not. The inactivation of  σ  1 R by NE100 could prevent the reduction of VMAT2 in MPTP-WT mice. In addition, the activation of microglia cells in substantia nigra was equally enhanced in MPTP-WT mice and MPTP- σ  1 R −/−  mice. The number of activated astrocytes in MPTP- σ  1 R −/−  mice was less than that in MPTP-WT mice. The findings indicate that the  σ  1 R deficiency through suppressing NMDAr function and DAT expression can reduce MPTP-induced death of dopaminergic neurons and parkinsonism.

Sigma-1 receptor deficiency reduces MPTP-induced parkinsonism and death of dopaminergic neurons