Skip to main content

Advertisement

SpringerLink
Log in

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

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Reference

  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):257–260

    Article  CAS  PubMed  Google Scholar 

  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):529–536

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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):48–52

    Article  CAS  PubMed  Google Scholar 

  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):88–101

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  PubMed  Google Scholar 

  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):231–238

    Article  CAS  PubMed  Google Scholar 

  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):1–6

    Article  CAS  PubMed  Google Scholar 

  10. Eddleston M, Mucke L (1993) Molecular profile of reactive astrocytes—implications for their role in neurologic disease. Neuroscience 54(1):15–36

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  12. Bowers MS, Kalivas PW (2003) Forebrain astroglial plasticity is induced following withdrawal from repeated cocaine administration. Eur J Neurosci 17(6):1273–1278

    Article  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Sharkey J, Glen KA, Wolfe S, Kuhar MJ (1988) Cocaine binding at sigma receptors. Eur J Pharmacol 149(1–2):171–174

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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):5764–5768

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  PubMed  Google Scholar 

  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):1427–1431

    Article  CAS  PubMed  Google 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

    Article  CAS  PubMed  Google Scholar 

  25. Van Dyke C, Barash PG, Jatlow P, Byck R (1976) Cocaine: plasma concentrations after intranasal application in man. Science 191(4229):859–861

    Article  PubMed  Google Scholar 

  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):1–10

    Article  PubMed  Google Scholar 

  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):1041–1048

    Article  CAS  PubMed  Google 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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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):813–823

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  32. Larrat EP, Zierler S (1993) Entangled epidemics: cocaine use and HIV disease. J Psychoactive Drugs 25(3):207–221

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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):259–275

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Walker JM, Bowen WD, Walker FO, Matsumoto RR, De Costa B, Rice KC (1990) Sigma receptors: biology and function. Pharmacol Rev 42(4):355–402

    CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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 50:191–224

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

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.

Author information

Authors and Affiliations

  1. Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA

    Lu Yang, Yu Cai, Shannon Callen & Shilpa Buch

  2. Department of Pharmacology, Medical School of Southeast University, Nanjing, 210009, Jiangsu, China

    Honghong Yao

  3. The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China

    Xufeng Chen

Authors
  1. Lu Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Honghong Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xufeng Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yu Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shannon Callen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shilpa Buch
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shilpa Buch.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, L., Yao, H., Chen, X. et al. Role of Sigma Receptor in Cocaine-Mediated Induction of Glial Fibrillary Acidic Protein: Implications for HAND. Mol Neurobiol 53, 1329–1342 (2016). https://doi.org/10.1007/s12035-015-9094-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-015-9094-5

Keywords

Search

Navigation