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Using heterozygous and homozygous\n \u03c3<\/jats:italic>\n 1<\/jats:sub>\n R knockout (\n \u03c3<\/jats:italic>\n 1<\/jats:sub>\n R\n +\/\u2212<\/jats:sup>\n and\n \u03c3<\/jats:italic>\n 1<\/jats:sub>\n R\n \u2212\/\u2212<\/jats:sup>\n ) mice, we investigated the influence of\n \u03c3<\/jats:italic>\n 1<\/jats:sub>\n 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\n \u03c3<\/jats:italic>\n 1<\/jats:sub>\n R\n +\/\u2212<\/jats:sup>\n or\n \u03c3<\/jats:italic>\n 1<\/jats:sub>\n R\n \u2212\/\u2212<\/jats:sup>\n mice (MPTP-\n \u03c3<\/jats:italic>\n 1<\/jats:sub>\n R\n +\/\u2212<\/jats:sup>\n or MPTP-\n \u03c3<\/jats:italic>\n 1<\/jats:sub>\n R\n \u2212\/\u2212<\/jats:sup>\n mice), caused motor deficits and ~40% death of dopaminergic neurons in substantia nigra pars compacta with an elevation of\n N<\/jats:italic>\n -methyl-\n d<\/jats:sc>\n -aspartate receptor (NMDAr) NR2B phosphorylation. The\n \u03c3<\/jats:italic>\n 1<\/jats:sub>\n 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-\n \u03c3<\/jats:italic>\n 1<\/jats:sub>\n R\n +\/\u2212<\/jats:sup>\n mice treated with the\n \u03c3<\/jats:italic>\n 1<\/jats:sub>\n R agonist PRE084 or MPTP-\n \u03c3<\/jats:italic>\n 1<\/jats:sub>\n R\n \u2212\/\u2212<\/jats:sup>\n 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\n \u03c3<\/jats:italic>\n 1<\/jats:sub>\n R suppressed the expression of dopamine transporter (DAT) in substantia nigra, which was corrected by NMDA. The activation of\n \u03c3<\/jats:italic>\n 1<\/jats:sub>\n R by PRE084 enhanced the DAT expression in WT mice or\n \u03c3<\/jats:italic>\n 1<\/jats:sub>\n R\n +\/\u2212<\/jats:sup>\n mice. By contrast, the level of vesicular monoamine transporter 2 (VMAT2) in\n \u03c3<\/jats:italic>\n 1<\/jats:sub>\n R\n +\/\u2212<\/jats:sup>\n mice or\n \u03c3<\/jats:italic>\n 1<\/jats:sub>\n R\n \u2212\/\u2212<\/jats:sup>\n mice had no difference from WT mice. Interestingly, MPTP-WT mice showed the reduction in the levels of DAT and VMAT2, but MPTP-\n \u03c3<\/jats:italic>\n 1<\/jats:sub>\n R\n \u2212\/\u2212<\/jats:sup>\n mice did not. The inactivation of\n \u03c3<\/jats:italic>\n 1<\/jats:sub>\n 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-\n \u03c3<\/jats:italic>\n 1<\/jats:sub>\n R\n \u2212\/\u2212<\/jats:sup>\n mice. The number of activated astrocytes in MPTP-\n \u03c3<\/jats:italic>\n 1<\/jats:sub>\n R\n \u2212\/\u2212<\/jats:sup>\n mice was less than that in MPTP-WT mice. The findings indicate that the\n \u03c3<\/jats:italic>\n 1<\/jats:sub>\n R deficiency through suppressing NMDAr function and DAT expression can reduce MPTP-induced death of dopaminergic neurons and parkinsonism.\n <\/jats:p>","DOI":"10.1038\/cddis.2015.194","type":"journal-article","created":{"date-parts":[[2015,7,23]],"date-time":"2015-07-23T08:48:02Z","timestamp":1437641282000},"page":"e1832-e1832","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":61,"title":["Sigma-1 receptor deficiency reduces MPTP-induced parkinsonism and death of dopaminergic neurons"],"prefix":"10.1038","volume":"6","author":[{"given":"J","family":"Hong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S","family":"Sha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,7,23]]},"reference":[{"key":"BFcddis2015194_CR1","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1016\/S0197-4580(02)00065-9","volume":"24","author":"H Braak","year":"2003","unstructured":"Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E . 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