Role of Sigma Receptor in Cocaine-Mediated Induction of Glial Fibrillary Acidic Protein: Implications for HAND
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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.
KeywordsCocaine HAND Astrocyte activation σ-1R translocation Egr-1
This work was supported by grants DA020392, DA023397, and DA024442 from the National Institutes of Health.
Conflict of Interest
The authors declare no competing financial interests.
- 19.Yao H, Yang Y, Kim KJ, Bethel-Brown C, Gong N, Funa K, Gendelman HE, Su TP, Wang JQ, Buch S (2010) Molecular mechanisms involving sigma receptor-mediated induction of MCP-1: implication for increased monocyte transmigration. Blood 115(23):4951–4962. doi: 10.1182/blood-2010-01-266221 PubMedCentralCrossRefPubMedGoogle Scholar
- 24.Cayrol R, Wosik K, Berard JL, Dodelet-Devillers A, Ifergan I, Kebir H, Haqqani AS, Kreymborg K, Krug S, Moumdjian R, Bouthillier A, Becher B, Arbour N, David S, Stanimirovic D, Prat A (2008) Activated leukocyte cell adhesion molecule promotes leukocyte trafficking into the central nervous system. Nat Immunol 9(2):137–145. doi: 10.1038/ni1551 CrossRefPubMedGoogle Scholar
- 28.Fan L, Sawbridge D, George V, Teng L, Bailey A, Kitchen I, Li JM (2009) Chronic cocaine-induced cardiac oxidative stress and mitogen-activated protein kinase activation: the role of Nox2 oxidase. J Pharmacol Exp Ther 328(1):99–106. doi: 10.1124/jpet.108.145201 PubMedCentralCrossRefPubMedGoogle Scholar