title: Involvement of sigma-1 receptor in astrocyte activation induced by methamphetamine via up-regulation of its own expression.
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.
authors.affiliation: Department of Pharmacology, Medical School of Southeast University, 87 Dingjiaqiao, Nanjing, Jiangsu, 210009, China. 1904334402@qq.com.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Medical School of Southeast University, 87 Dingjiaqiao, Nanjing, Jiangsu, 210009, China. lx_seu@163.com.
authors.forename: Xuan
authors.initials: X
authors.lastname: Lv
authors.affiliation: Department of Pharmacology, Medical School of Southeast University, 87 Dingjiaqiao, Nanjing, Jiangsu, 210009, China. yingyingheart@163.com.
authors.forename: Ying
authors.initials: Y
authors.lastname: Bai
authors.affiliation: Department of Pharmacology, Medical School of Southeast University, 87 Dingjiaqiao, Nanjing, Jiangsu, 210009, China. xinjianzhu@seu.edu.cn.
authors.forename: Xinjian
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Pharmacology, Medical School of Southeast University, 87 Dingjiaqiao, Nanjing, Jiangsu, 210009, China. wuxiaodong@seu.edu.cn.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Physiology, Medical School of Southeast University, 87 Dingjiaqiao, Nanjing, 210009, China. chaoyao75@gmail.com.
authors.forename: Jie
authors.initials: J
authors.lastname: Chao
authors.affiliation: Virosis Laboratory, Key Laboratory of Zoonosis, Ministry of Education, Institute of Zoonosis, Jilin University, 5333 Xi An Road, Changchun, 130062, China. duanmingjxdx2000@163.com.
authors.forename: Ming
authors.initials: M
authors.lastname: Duan
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, 42nd and Emile, Omaha, NE, 68198, USA. sbuch@unmc.edu.
authors.forename: Shilpa
authors.initials: S
authors.lastname: Buch
authors.affiliation: Department of Physiology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, 210029, China. lingchen@njmu.edu.cn.
authors.forename: Ling
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Medical School of Southeast University, 87 Dingjiaqiao, Nanjing, Jiangsu, 210009, China. yaohh@seu.edu.cn.
authors.forename: Honghong
authors.initials: H
authors.lastname: Yao
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects*; D002070:Butadienes / Q000494:pharmacology; D002478:Cells, Cultured; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005029:Ethylenediamines / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009570:Nitriles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects*; D000097605:Sigma-1 Receptor
chemical_list: D002070:Butadienes; D000697:Central Nervous System Stimulants; D004791:Enzyme Inhibitors; D005029:Ethylenediamines; D005904:Glial Fibrillary Acidic Protein; D008694:Methamphetamine; D009570:Nitriles; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C113580:U 0126; C097963:N-(2-(3,4-Dichlorphenyl)ethyl)-N,N',N'-trimethyl-1,2-ethandiamin