title: Role of Sigma Receptor in Cocaine-Mediated Induction of Glial Fibrillary Acidic Protein: Implications for HAND.
abstract: Cocaine abuse has been shown to accelerate the progression of human immunodeficiency virus (HIV)-1-associated neurological disorders (HANDs) partially through increasing neuroinflammatory response mediated by activated astrocytes; however, the detailed molecular mechanism of cocaine-mediated astrocyte activation is unclear. In the current study, we demonstrated increased astrogliosis in the cortical regions of brains from HIV(+) cocaine abusers compared with the HIV(+) group without cocaine abuse. We next sought to explore whether cocaine exposure could result in increased expression of glial fibrillary acidic protein (GFAP), a filament protein critical for astrocyte activation. Exposure of cocaine to astrocytes resulted in rapid translocation of sigma receptor to the plasma membrane with subsequent activation of downstream signaling pathways. Using a pharmacological approach, we provide evidence that cocaine-mediated upregulation of GFAP expression involved activation of mitogen-activated protein kinase (MAPK) signaling with subsequent downstream activation of the early growth response gene 1 (Egr-1). Egr-1 activation, in turn, caused transcriptional regulation of GFAP. Corroboration of these findings in vivo demonstrated increased expression of GFAP in the cortical region of mice treated with cocaine compared with the saline injected controls. A thorough understanding of how cocaine mediates astrogliosis could have implications for the development of therapeutic interventions aimed at HIV-infected cocaine abusers.
authors: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
authors: Lu
authors: L
authors: Yang
authors: Department of Pharmacology, Medical School of Southeast University, Nanjing, 210009, Jiangsu, China.
authors: Honghong
authors: H
authors: Yao
authors: The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
authors: Xufeng
authors: X
authors: Chen
authors: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
authors: Yu
authors: Y
authors: Cai
authors: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
authors: Shannon
authors: S
authors: Callen
authors: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA. sbuch@unmc.edu.
authors: Shilpa
authors: S
authors: Buch
mesh_terms: D015526:AIDS Dementia Complex / Q000150:complications / Q000378:metabolism*; D000328:Adult; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003042:Cocaine / Q000009:adverse effects*; D019970:Cocaine-Related Disorders / Q000150:complications / Q000378:metabolism; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017480:Receptors, sigma / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D051766:Early Growth Response Protein 1; D005904:Glial Fibrillary Acidic Protein; D012333:RNA, Messenger; D017480:Receptors, sigma; D003042:Cocaine
keywords: Astrocyte activation; Cocaine; Egr-1; HAND; σ-1R translocation
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