Abstract
Ecstasy is the popular name of the abuse drug 3,4-methylenedioxymethamphetamine (MDMA) that decreases immunity in animals. The mechanisms that generate such alterations are still controversial. Seven independent pharmacological approaches were performed in mice to identify the possible mechanisms underlying the decrease of neutrophil activity induced by MDMA and the possible effects of MDMA on host resistance to Listeria monocytogenes. Our data showed that MDMA (10 mg kg−1) administration decreases NFκB expression in circulating neutrophils. Metyrapone or RU-486 administration prior to MDMA treatment abrogated MDMA effects on neutrophil activity and NFκB expression, while 6-OHDA or ICI-118,551 administration did not. As MDMA treatment increased the plasmatic levels of adrenaline and noradrenaline, propranolol pre-treatment effects were also evaluated. Propranolol suppressed both MDMA-induced increase in corticosterone serum levels and its effects on neutrophil activity. In a L. monocytogenes experimental infection context, we showed that MDMA: induced myelosuppression by decreasing granulocyte-macrophage hematopoietic progenitors (CFU-GM) in the bone marrow but increased CFU-GM in the spleen; decreased circulating leukocytes and bone marrow cellularity and increased spleen cellularity; decreased pro-inflammatory cytokine (IL-12p70, TNF, IFN-γ, IL-6) and chemokine (MCP-1) production 24 h after the infection; increased the production of pro-inflammatory cytokines and chemokines 72 h after infection and decreased IL-10 levels at all time points analyzed. It was proposed that MDMA immunosuppressive effects on neutrophil activity and host resistance to L monocytogenes rely on NFκB signaling, being mediated by HPA axis activity and corticosterone.
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References
Abraham E (2005) Alterations in cell signaling in sepsis. Clin Infect Dis 41(Suppl 7):S459–464
Basu S, Dasgupta PS (2000) Dopamine, a neurotransmitter, influences the immune system. J Neuroimmunol 102(2):113–124
Boyle NT, Connor TJ (2007) MDMA (“Ecstasy”) suppresses the innate IFN-gamma response in vivo: a critical role for the anti-inflammatory cytokine IL-10. Eur J Pharmacol 572(2–3):228–238
Boyle NT, Connor TJ (2010) Methylenedioxymethamphetamine (‘Ecstasy’)-induced immunosuppression: a cause for concern? Br J Pharmacol 161(1):17–32
Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS et al (2004) Neutrophil extracellular traps kill bacteria. Science 303(5663):1532–1535
Bugajski J, Turon M, Gadek-Michalska A, Borycz JA (1991) Catecholaminergic regulation of the hypothalamic-pituitary-adrenocortical activity. J Physiol Pharmacol 42(1):93–103
Bugajski J, Gadek-Michalska A, Olowska A, Borycz J, Glod R, Bugajski AJ (1995) Adrenergic regulation of the hypothalamic-pituitary-adrenal axis under basal and social stress conditions. J Physiol Pharmacol 46(3):297–312
Camarasa J, Ros C, Pubill D, Escubedo E (2010) Tumour necrosis factor alpha suppression by MDMA is mediated by peripheral heteromeric nicotinic receptors. Immunopharmacol Immunotoxicol 32(2):265–271
Cao L, Filipov NM, Lawrence DA (2002) Sympathetic nervous system plays a major role in acute cold/restraint stress inhibition of host resistance to Listeria monocytogenes. J Neuroimmunol 125(1–2):94–102
Cao L, Hudson CA, Lawrence DA (2003) Acute cold/restraint stress inhibits host resistance to Listeria monocytogenes via beta1-adrenergic receptors. Brain Behav Immun 17(2):121–133
Connor TJ, McNamara MG, Finn D, Currid A, O’Malley M, Redmond AM et al (1998) Acute 3,4-methylenedioxymethamphetamine (MDMA) administration produces a rapid and sustained suppression of immune function in the rat. Immunopharmacology 38(3):253–260
Connor TJ, Kelly JP, McGee M, Leonard BE (2000) Methylenedioxymethamphetamine (MDMA; Ecstasy) suppresses IL-1beta and TNF-alpha secretion following an in vivo lipopolysaccharide challenge. Life Sci 67(13):1601–1612
Connor TJ, Connelly DB, Kelly JP (2001) Methylenedioxymethamphetamine (MDMA; ‘Ecstasy’) suppresses antigen specific IgG2a and IFN-gamma production. Immunol Lett 78(2):67–73
Connor TJ, Harkin A, Kelly JP (2005) Methylenedioxymethamphetamine suppresses production of the proinflammatory cytokine tumor necrosis factor-alpha independent of a beta-adrenoceptor-mediated increase in interleukin-10. J Pharmacol Exp Ther 312(1):134–143
Cousens LP, Wing EJ (2000) Innate defenses in the liver during Listeria infection. Immunol Rev 174:150–159
Dalrymple SA, Lucian LA, Slattery R, McNeil T, Aud DM, Fuchino S et al (1995) Interleukin-6-deficient mice are highly susceptible to Listeria monocytogenes infection: correlation with inefficient neutrophilia. Infect Immun 63(6):2262–2268
de la Torre R, Farre M (2004) Neurotoxicity of MDMA (ecstasy): the limitations of scaling from animals to humans. Trends Pharmacol Sci 25(10):505–508
de Paula VF, Ribeiro A, Pinheiro ML, Sakai M, Lacava MC, Lapachinske SF et al (2009) Methylenedioxymethamphetamine (Ecstasy) decreases neutrophil activity and alters leukocyte distribution in bone marrow, spleen and blood. Neuroimmunomodulation 16(3):191–200
Emoto M, Miyamoto M, Emoto Y, Yoshizawa I, Brinkmann V, van Rooijen N et al (2003) Highly biased type 1 immune responses in mice deficient in LFA-1 in Listeria monocytogenes infection are caused by elevated IL-12 production by granulocytes. J Immunol 171(8):3970–3976
Ferraz-de-Paula V, Stankevicius D, Ribeiro A, Pinheiro ML, Rodrigues-Costa EC, Florio JC et al (2011) Differential behavioral outcomes of 3,4-methylenedioxymethamphetamine (MDMA-ecstasy) in anxiety-like responses in mice. Braz J Med Biol Res 44(5):428–437
Hasui M, Hirabayashi Y, Kobayashi Y (1989) Simultaneous measurement by flow cytometry of phagocytosis and hydrogen peroxide production of neutrophils in whole blood. J Immunol Methods 117(1):53–58
Hayden MS, Ghosh S (2008) Shared principles in NF-kappaB signaling. Cell 132(3):344–362
Hysek CM, Brugger R, Simmler LD, Bruggisser M, Donzelli M, Grouzmann E et al (2012) Effects of the alpha(2)-adrenergic agonist clonidine on the pharmacodynamics and pharmacokinetics of 3,4-methylenedioxymethamphetamine in healthy volunteers. J Pharmacol Exp Ther 340(2):286–294
Jankovic D, Kugler DG, Sher A (2010) IL-10 production by CD4+ effector T cells: a mechanism for self-regulation. Mucosal Immunol 3(3):239–246
Keller SE, Schleifer SJ, Liotta AS, Bond RN, Farhoody N, Stein M (1988) Stress-induced alterations of immunity in hypophysectomized rats. Proc Natl Acad Sci U S A 85(23):9297–9301
Kollet O, Canaani J, Kalinkovich A, Lapidot T (2012) Regulatory cross talks of bone cells, hematopoietic stem cells and the nervous system maintain hematopoiesis. Inflamm Allergy Drug Targets 11(3):170–180
Kostrzewa RM, Jacobowitz DM (1974) Pharmacological actions of 6-hydroxydopamine. Pharmacol Rev 26(3):199–288
Kruszewska B, Felten SY, Moynihan JA (1995) Alterations in cytokine and antibody production following chemical sympathectomy in two strains of mice. J Immunol 155(10):4613–4620
Lacava M, Ferraz-de-Paula V, Lapachinske SF, Palermo-Neto J, Moreau RLM (2007) Simultaneous determination of methylenodioxymethamphetamine (MDMA) and methylenodioxyamphetamine (MDA) in plasma by gas chromatography with nitrogen-phosphorus detection (GC-NPD) and in vitro effects on the neutrophil activity of mice. III Encuentro Regional de Toxicologia Forense, Bogotá, pp 97–104, TIAFT
Lafarge S, Hamzeh-Cognasse H, Chavarin P, Genin C, Garraud O, Cognasse F (2007) A flow cytometry technique to study intracellular signals NF-kappaB and STAT3 in peripheral blood mononuclear cells. BMC Mol Biol 8:64
Ligeiro de Oliveira AP, Lazzarini R, Cavriani G, Quinteiro-Filho WM, Tavares de Lima W, Palermo-Neto J (2008) Effects of single or repeated amphetamine treatment and withdrawal on lung allergic inflammation in rats. Int Immunopharmacol 8(9):1164–1171
Mackaness GB (1962) Cellular resistance to infection. J Exp Med 116:381–406
Massoco C, Palermo-Neto J (2003) Effects of midazolam on equine innate immune response: a flow cytometric study. Vet Immunol Immunopathol 95(1–2):11–19
Metcalf D (1986) The molecular biology and functions of the granulocyte-macrophage colony-stimulating factors. Blood 67(2):257–267
Mizruchin A, Gold I, Krasnov I, Livshitz G, Shahin R, Kook AI (1999) Comparison of the effects of dopaminergic and serotonergic activity in the CNS on the activity of the immune system. J Neuroimmunol 101(2):201–204
Necela BM, Cidlowski JA (2004) Mechanisms of glucocorticoid receptor action in noninflammatory and inflammatory cells. Proc Am Thorac Soc 1(3):239–246
Nelson DA, Nirmaier JL, Singh SJ, Tolbert MD, Bost KL (2008) Ecstasy (3,4-methylenedioxymethamphetamine) limits murine gammaherpesvirus-68 induced monokine expression. Brain Behav Immun 22(6):912–922
Newton CA, Lu T, Nazian SJ, Perkins I, Friedman H, Klein TW (2004) The THC-induced suppression of Th1 polarization in response to Legionella pneumophila infection is not mediated by increases in corticosterone and PGE2. J Leukoc Biol 76(4):854–861
Pacifici R, Farre M, Pichini S, Ortuno J, Roset PN, Zuccaro P et al (2001a) Sweat testing of MDMA with the Drugwipe analytical device: a controlled study with two volunteers. J Anal Toxicol 25(2):144–146
Pacifici R, Zuccaro P, Farre M, Pichini S, Di Carlo S, Roset PN et al (2001b) Effects of repeated doses of MDMA (“ecstasy”) on cell-mediated immune response in humans. Life Sci 69(24):2931–2941
Pacifici R, Zuccaro P, Farre M, Pichini S, Di Carlo S, Roset PN et al (2002) Cell-mediated immune response in MDMA users after repeated dose administration: studies in controlled versus noncontrolled settings. Ann N Y Acad Sci 965:421–433
Pacifici R, Pichini S, Zuccaro P, Farre M, Segura M, Ortuno J et al (2004) Paroxetine inhibits acute effects of 3,4-methylenedioxymethamphetamine on the immune system in humans. J Pharmacol Exp Ther 309(1):285–292
Pacifici R, Zuccaro P, Farre M, Poudevida S, Abanades S, Pichini S et al (2007) Combined immunomodulating properties of 3,4-methylenedioxymethamphetamine (MDMA) and cannabis in humans. Addiction 102(6):931–936
Parrott AC (2013) Human psychobiology of MDMA or ‘Ecstasy’: an overview of 25 years of empirical research. Hum Psychopharmacol 28(4):289–307
Pennock JW, Stegall R, Bubar MJ, Milligan G, Cunningham KA, Bourne N (2009) 3,4-Methylenedioxymethamphetamine increases susceptibility to genital herpes simplex virus infection in mice. J Infect Dis 200(8):1247–1250
Quax RA, Manenschijn L, Koper JW, Hazes JM, Lamberts SW, van Rossum EF et al (2013) Glucocorticoid sensitivity in health and disease. Nat Rev 9(11):670–686
Queiroz Jde S, Torello CO, Palermo-Neto J, Valadares MC, Queiroz ML (2008) Hematopoietic response of rats exposed to the impact of an acute psychophysiological stressor on responsiveness to an in vivo challenge with Listeria monocytogenes: modulation by Chlorella vulgaris prophylactic treatment. Brain Behav Immun 22(7):1056–1065
Rice PA, Boehm GW, Moynihan JA, Bellinger DL, Stevens SY (2001) Chemical sympathectomy increases the innate immune response and decreases the specific immune response in the spleen to infection with Listeria monocytogenes. J Neuroimmunol 114(1–2):19–27
Segal AW (2005) How neutrophils kill microbes. Annu Rev Immunol 23:197–223
Serbina NV, Kuziel W, Flavell R, Akira S, Rollins B, Pamer EG (2003) Sequential MyD88-independent and -dependent activation of innate immune responses to intracellular bacterial infection. Immunity 19(6):891–901
Sparwasser T, Hultner L, Koch ES, Luz A, Lipford GB, Wagner H (1999) Immunostimulatory CpG-oligodeoxynucleotides cause extramedullary murine hemopoiesis. J Immunol 162(4):2368–2374
Stankevicius D, Ferraz-de-Paula V, Ribeiro A, Pinheiro ML, Ligeiro de Oliveira AP, Damazo AS et al (2012) 3,4-methylenedioxymethamphetamine (ecstasy) decreases inflammation and airway reactivity in a murine model of asthma. Neuroimmunomodulation 19(4):209–219
Torello CO, de Souza QJ, Oliveira SC, Queiroz ML (2010) Immunohematopoietic modulation by oral beta-1,3-glucan in mice infected with Listeria monocytogenes. Int Immunopharmacol 10(12):1573–1579
Tufail S, Badrealam KF, Owais M, Zubair S (2013) Illuminating the petite picture of T cell memory responses to. Biomed Res Int 2013:121684
van den Engh G, Bol S (1975) The presence of a CSF enhancing activity in the serum of endotoxin-treated mice. Cell Tissue Kinet 8(6):579–587
Verheyden SL, Henry JA, Curran HV (2003) Acute, sub-acute and long-term subjective consequences of ‘ecstasy’ (MDMA) consumption in 430 regular users. Hum Psychopharmacol 18(7):507–517
Williams MA, Schmidt RL, Lenz LL (2012) Early events regulating immunity and pathogenesis during Listeria monocytogenes infection. Trends Immunol 33(10):488–495
Zemishlany Z, Aizenberg D, Weizman A (2001) Subjective effects of MDMA (‘Ecstasy’) on human sexual function. Eur Psychiatr 16(2):127–130
Zenewicz LA, Shen H (2007) Innate and adaptive immune responses to Listeria monocytogenes: a short overview. Microbes Infect 9(10):1208–1215
Acknowledgments
The authors thank FAPESP and CNPq for financial support (FAPESP grant n° 2011/15115-2, 2009/51886-3 and CNPq grant n° 300764/2010-3). Viviane Ferraz-de-Paula is a FAPESP post-graduate fellow (grant n° 07/57614-0).
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Ferraz-de-Paula, V., Ribeiro, A., Souza-Queiroz, J. et al. 3,4-Methylenedioxymethamphetamine (MDMA – Ecstasy) Decreases Neutrophil Activity Through the Glucocorticoid Pathway and Impairs Host Resistance to Listeria Monocytogenes Infection in Mice. J Neuroimmune Pharmacol 9, 690–702 (2014). https://doi.org/10.1007/s11481-014-9562-0
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DOI: https://doi.org/10.1007/s11481-014-9562-0