Molecular Neurobiology

, Volume 53, Issue 2, pp 1329–1342 | Cite as

Role of Sigma Receptor in Cocaine-Mediated Induction of Glial Fibrillary Acidic Protein: Implications for HAND

  • Lu Yang
  • Honghong Yao
  • Xufeng Chen
  • Yu Cai
  • Shannon Callen
  • Shilpa Buch


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.


Cocaine 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.


  1. 1.
    Sacktor N, Lyles RH, Skolasky R, Kleeberger C, Selnes OA, Miller EN, Becker JT, Cohen B, McArthur JC (2001) HIV-associated neurologic disease incidence changes: Multicenter AIDS Cohort Study, 1990-1998. Neurology 56(2):257–260CrossRefPubMedGoogle Scholar
  2. 2.
    Anthony IC, Ramage SN, Carnie FW, Simmonds P, Bell JE (2005) Influence of HAART on HIV-related CNS disease and neuroinflammation. J Neuropathol Exp Neurol 64(6):529–536CrossRefPubMedGoogle Scholar
  3. 3.
    Albright AV, Soldan SS, Gonzalez-Scarano F (2003) Pathogenesis of human immunodeficiency virus-induced neurological disease. J Neurovirol 9(2):222–227. doi: 10.1080/13550280390194073 CrossRefPubMedGoogle Scholar
  4. 4.
    Purohit V, Rapaka R, Shurtleff D (2011) Drugs of abuse, dopamine, and HIV-associated neurocognitive disorders/HIV-associated dementia. Mol Neurobiol 44(1):102–110. doi: 10.1007/s12035-011-8195-z CrossRefPubMedGoogle Scholar
  5. 5.
    Grassi MP, Perin C, Clerici F, Zocchetti C, Borella M, Cargnel A, Mangoni A (1997) Effects of HIV seropositivity and drug abuse on cognitive function. Eur Neurol 37(1):48–52CrossRefPubMedGoogle Scholar
  6. 6.
    Goodkin K, Shapshak P, Metsch LR, McCoy CB, Crandall KA, Kumar M, Fujimura RK, McCoy V, Zhang BT, Reyblat S, Xin KQ, Kumar AM (1998) Cocaine abuse and HIV-1 infection: epidemiology and neuropathogenesis. J Neuroimmunol 83(1–2):88–101CrossRefPubMedGoogle Scholar
  7. 7.
    Fan Y, Zou W, Green LA, Kim BO, He JJ (2011) Activation of Egr-1 expression in astrocytes by HIV-1 Tat: new insights into astrocyte-mediated Tat neurotoxicity. J Neuroimmune Pharmacol 6(1):121–129. doi: 10.1007/s11481-010-9217-8 PubMedCentralCrossRefPubMedGoogle Scholar
  8. 8.
    Stanley LC, Mrak RE, Woody RC, Perrot LJ, Zhang S, Marshak DR, Nelson SJ, Griffin WS (1994) Glial cytokines as neuropathogenic factors in HIV infection: pathogenic similarities to Alzheimer's disease. J Neuropathol Exp Neurol 53(3):231–238CrossRefPubMedGoogle Scholar
  9. 9.
    Fattore L, Puddu MC, Picciau S, Cappai A, Fratta W, Serra GP, Spiga S (2002) Astroglial in vivo response to cocaine in mouse dentate gyrus: a quantitative and qualitative analysis by confocal microscopy. Neuroscience 110(1):1–6CrossRefPubMedGoogle Scholar
  10. 10.
    Eddleston M, Mucke L (1993) Molecular profile of reactive astrocytes—implications for their role in neurologic disease. Neuroscience 54(1):15–36CrossRefPubMedGoogle Scholar
  11. 11.
    Haile CN, Hiroi N, Nestler EJ, Kosten TA (2001) Differential behavioral responses to cocaine are associated with dynamics of mesolimbic dopamine proteins in Lewis and Fischer 344 rats. Synapse 41(3):179–190. doi: 10.1002/syn.1073 CrossRefPubMedGoogle Scholar
  12. 12.
    Bowers MS, Kalivas PW (2003) Forebrain astroglial plasticity is induced following withdrawal from repeated cocaine administration. Eur J Neurosci 17(6):1273–1278CrossRefPubMedGoogle Scholar
  13. 13.
    Hemby SE (2006) Assessment of genome and proteome profiles in cocaine abuse. Prog Brain Res 158:173–195. doi: 10.1016/S0079-6123(06)58009-4 PubMedCentralCrossRefPubMedGoogle Scholar
  14. 14.
    Sharkey J, Glen KA, Wolfe S, Kuhar MJ (1988) Cocaine binding at sigma receptors. Eur J Pharmacol 149(1–2):171–174CrossRefPubMedGoogle Scholar
  15. 15.
    Liu Y, Chen GD, Lerner MR, Brackett DJ, Matsumoto RR (2005) Cocaine up-regulates Fra-2 and sigma-1 receptor gene and protein expression in brain regions involved in addiction and reward. J Pharmacol Exp Ther 314(2):770–779. doi: 10.1124/jpet.105.084525 CrossRefPubMedGoogle Scholar
  16. 16.
    Romieu P, Phan VL, Martin-Fardon R, Maurice T (2002) Involvement of the sigma(1) receptor in cocaine-induced conditioned place preference: possible dependence on dopamine uptake blockade. Neuropsychopharmacology 26(4):444–455. doi: 10.1016/S0893-133X(01)00391-8 CrossRefPubMedGoogle Scholar
  17. 17.
    Roth MD, Whittaker KM, Choi R, Tashkin DP, Baldwin GC (2005) Cocaine and sigma-1 receptors modulate HIV infection, chemokine receptors, and the HPA axis in the huPBL-SCID model. J Leukoc Biol 78(6):1198–1203. doi: 10.1189/jlb.0405219 CrossRefPubMedGoogle Scholar
  18. 18.
    Gekker G, Hu S, Sheng WS, Rock RB, Lokensgard JR, Peterson PK (2006) Cocaine-induced HIV-1 expression in microglia involves sigma-1 receptors and transforming growth factor-beta1. Int Immunopharmacol 6(6):1029–1033. doi: 10.1016/j.intimp.2005.12.005 CrossRefPubMedGoogle Scholar
  19. 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
  20. 20.
    Jouvert P, Revel MO, Lazaris A, Aunis D, Langley K, Zwiller J (2004) Activation of the cGMP pathway in dopaminergic structures reduces cocaine-induced EGR-1 expression and locomotor activity. J Neurosci 24(47):10716–10725. doi: 10.1523/JNEUROSCI. 1398-04.2004 CrossRefPubMedGoogle Scholar
  21. 21.
    Hope B, Kosofsky B, Hyman SE, Nestler EJ (1992) Regulation of immediate early gene expression and AP-1 binding in the rat nucleus accumbens by chronic cocaine. Proc Natl Acad Sci U S A 89(13):5764–5768PubMedCentralCrossRefPubMedGoogle Scholar
  22. 22.
    Yang Y, Yao H, Lu Y, Wang C, Buch S (2010) Cocaine potentiates astrocyte toxicity mediated by human immunodeficiency virus (HIV-1) protein gp120. PLoS One 5(10):e13427. doi: 10.1371/journal.pone.0013427 PubMedCentralCrossRefPubMedGoogle Scholar
  23. 23.
    Khachigian LM, Lindner V, Williams AJ, Collins T (1996) Egr-1-induced endothelial gene expression: a common theme in vascular injury. Science 271(5254):1427–1431CrossRefPubMedGoogle Scholar
  24. 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
  25. 25.
    Van Dyke C, Barash PG, Jatlow P, Byck R (1976) Cocaine: plasma concentrations after intranasal application in man. Science 191(4229):859–861CrossRefPubMedGoogle Scholar
  26. 26.
    Stephens BG, Jentzen JM, Karch S, Mash DC, Wetli CV (2004) Criteria for the interpretation of cocaine levels in human biological samples and their relation to the cause of death. Am J Forensic Med Pathol 25(1):1–10CrossRefPubMedGoogle Scholar
  27. 27.
    Kalasinsky KS, Bosy TZ, Schmunk GA, Ang L, Adams V, Gore SB, Smialek J, Furukawa Y, Guttman M, Kish SJ (2000) Regional distribution of cocaine in postmortem brain of chronic human cocaine users. J Forensic Sci 45(5):1041–1048CrossRefPubMedGoogle Scholar
  28. 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
  29. 29.
    Li G, Xiao Y, Zhang L (2005) Cocaine induces apoptosis in fetal rat myocardial cells through the p38 mitogen-activated protein kinase and mitochondrial/cytochrome c pathways. J Pharmacol Exp Ther 312(1):112–119. doi: 10.1124/jpet.104.073494 CrossRefPubMedGoogle Scholar
  30. 30.
    Drago J, Gerfen CR, Westphal H, Steiner H (1996) D1 dopamine receptor-deficient mouse: cocaine-induced regulation of immediate-early gene and substance P expression in the striatum. Neuroscience 74(3):813–823CrossRefPubMedGoogle Scholar
  31. 31.
    Hayashi T, Su TP (2003) Intracellular dynamics of sigma-1 receptors (sigma(1) binding sites) in NG108-15 cells. J Pharmacol Exp Ther 306(2):726–733. doi: 10.1124/jpet.103.051292 CrossRefPubMedGoogle Scholar
  32. 32.
    Larrat EP, Zierler S (1993) Entangled epidemics: cocaine use and HIV disease. J Psychoactive Drugs 25(3):207–221CrossRefPubMedGoogle Scholar
  33. 33.
    Sofroniew MV (2009) Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci 32(12):638–647. doi: 10.1016/j.tins.2009.08.002 PubMedCentralCrossRefPubMedGoogle Scholar
  34. 34.
    Laping NJ, Teter B, Nichols NR, Rozovsky I, Finch CE (1994) Glial fibrillary acidic protein: regulation by hormones, cytokines, and growth factors. Brain Pathol 4(3):259–275CrossRefPubMedGoogle Scholar
  35. 35.
    Yao H, Allen JE, Zhu X, Callen S, Buch S (2009) Cocaine and human immunodeficiency virus type 1 gp120 mediate neurotoxicity through overlapping signaling pathways. J Neurovirol 15(2):164–175. doi: 10.1080/13550280902755375 PubMedCentralCrossRefPubMedGoogle Scholar
  36. 36.
    Walker JM, Bowen WD, Walker FO, Matsumoto RR, De Costa B, Rice KC (1990) Sigma receptors: biology and function. Pharmacol Rev 42(4):355–402PubMedGoogle Scholar
  37. 37.
    Sabino V, Cottone P, Blasio A, Iyer MR, Steardo L, Rice KC, Conti B, Koob GF, Zorrilla EP (2011) Activation of sigma-receptors induces binge-like drinking in Sardinian alcohol-preferring rats. Neuropsychopharmacology 36(6):1207–1218. doi: 10.1038/npp.2011.5 PubMedCentralCrossRefPubMedGoogle Scholar
  38. 38.
    Barber SA, Uhrlaub JL, DeWitt JB, Tarwater PM, Zink MC (2004) Dysregulation of mitogen-activated protein kinase signaling pathways in simian immunodeficiency virus encephalitis. Am J Pathol 164(2):355–362. doi: 10.1016/S0002-9440(10)63125-2 PubMedCentralCrossRefPubMedGoogle Scholar
  39. 39.
    Gadea A, Schinelli S, Gallo V (2008) Endothelin-1 regulates astrocyte proliferation and reactive gliosis via a JNK/c-Jun signaling pathway. J Neurosci 28(10):2394–2408. doi: 10.1523/JNEUROSCI. 5652-07.2008 PubMedCentralCrossRefPubMedGoogle Scholar
  40. 40.
    Beck H, Semisch M, Culmsee C, Plesnila N, Hatzopoulos AK (2008) Egr-1 regulates expression of the glial scar component phosphacan in astrocytes after experimental stroke. Am J Pathol 173(1):77–92. doi: 10.2353/ajpath.2008.070648 PubMedCentralCrossRefPubMedGoogle Scholar
  41. 41.
    Gashler A, Sukhatme VP (1995) Early growth response protein 1 (Egr-1): prototype of a zinc-finger family of transcription factors. Prog Nucleic Acid Res Mol Biol 50:191–224CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Lu Yang
    • 1
  • Honghong Yao
    • 2
  • Xufeng Chen
    • 3
  • Yu Cai
    • 1
  • Shannon Callen
    • 1
  • Shilpa Buch
    • 1
  1. 1.Department of Pharmacology and Experimental NeuroscienceUniversity of Nebraska Medical CenterOmahaUSA
  2. 2.Department of PharmacologyMedical School of Southeast UniversityNanjingChina
  3. 3.The First Affiliated Hospital of Nanjing Medical UniversityNanjingChina

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