Involvement of sigma-1 receptor in astrocyte activation induced by methamphetamine via up-regulation of its own expression

Background: although it has been documented that methamphetamine induces astrocyte activation,the mechanism(s) underlying this effect remain poorly understood. we thus sought to examine the molecular mechanisms involved in methamphetamine-mediated activation of astrocytes with a focus on the role of sigma-1 receptor (σ-1r) in this process. methods: the expression of σ-1r and glial fibrillary acidic protein (gfap) was examined by reverse transcription pcr (rt-pcr),real-time pcr,western blot,and immunofluorescent staining; phosphorylation of cell signaling pathways was detected by western blot analysis. immunoprecipitation was used to determine the interaction between σ-1r and p-src. chromatin immunoprecipitation (chip) assay was employed to discern the binding of camp-response element-binding protein (creb) with the promoter of σ-1r. the role of σ-1r in astrocyte activation was further validated in σ-1r knockout (ko) mice by western blot combined with immunofluorescent staining. results: exposure of primary rat astrocytes to methamphetamine increased the expression of σ-1r via the activation of src,erk mitogen-activated protein kinase,and downstream creb pathways. subsequently,creb translocated into nucleus and interacted with the promoter of σ-1r resulting in increased expression of σ-1r with a concomitant increase in expression of gfap. this effect was inhibited in cells treated with the σ-1r antagonist-bd1047,thereby implicating the role of σ-1r in the activation of astrocytes. in vivo relevance of these findings was further corroborated in σ-1r ko mice that were administered methamphetamine. in the methamphetamine administered mice,there was a failure of the drug to induce activation of astrocytes,an effect that was evident in wild-type (wt) mice exposed to methamphetamine. conclusions: the study presented herein demonstrates that methamphetamine-mediated activation of astrocytes involved up-regulation of σ-1r through a positive-feedback mechanism. understanding the regulation of σ-1r expression could provide insights into the development of potential therapeutic strategies for astrocyte activation induced by methamphetamine. © 2015 zhang et al.; licensee biomed central.