Involvement of sigma-1 receptor in astrocyte activation induced by methamphetamine via up-regulation of its own expression
Authors: Xuan Lv
Ming Duan
Xiaodong Wu
Jie Chao
Honghong Yao
Xinjian Zhu
Ling Chen
Yuan Zhang
Shilpa Buch
Ying Bai
Journal: Journal of Neuroinflammation (2015)
Discipline: NEUROSCIENCE & BEHAVIOR
Keywords: methamphetamine; astrocyte activation; sigma-1 receptor (σ-1R); CREB; GFAP
Affiliations: Department of Pharmacology, Medical School of Southeast University, 87 Dingjiaqiao, Nanjing, Jiangsu, 210009, China. ., Department of Physiology, Medical School of Southeast University, 87 Dingjiaqiao, Nanjing, 210009, China. ., Virosis Laboratory, Key Laboratory of Zoonosis, Ministry of Education, Institute of Zoonosis, Jilin University, 5333 Xi An Road, Changchun, 130062, China. ., Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, 42nd and Emile, Omaha, NE, 68198, USA. ., Department of Physiology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, 210029, China. .

Abstract:  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. 

Retracted: No

PubPeer comments:
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