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Astrocyte-derived TNF and glutamate critically modulate microglia activation by methamphetamine

Abstract

Methamphetamine (Meth) is a powerful illicit psychostimulant, widely used for recreational purposes. Besides disrupting the monoaminergic system and promoting oxidative brain damage, Meth also causes neuroinflammation, contributing to synaptic dysfunction and behavioral deficits. Aberrant activation of microglia, the largest myeloid cell population in the brain, is a common feature in neurological disorders triggered by neuroinflammation. In this study, we investigated the mechanisms underlying the aberrant activation of microglia elicited by Meth in the adult mouse brain. We found that binge Meth exposure caused microgliosis and disrupted risk assessment behavior (a feature that usually occurs in individuals who abuse Meth), both of which required astrocyte-to-microglia crosstalk. Mechanistically, Meth triggered a detrimental increase of glutamate exocytosis from astrocytes (in a process dependent on TNF production and calcium mobilization), promoting microglial expansion and reactivity. Ablating TNF production, or suppressing astrocytic calcium mobilization, prevented Meth-elicited microglia reactivity and re-established risk assessment behavior as tested by elevated plus maze (EPM). Overall, our data indicate that glial crosstalk is critical to relay alterations caused by acute Meth exposure.

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Fig. 1: Meth triggers microglial activation in the brain.
Fig. 2: Microglia activation triggered by Meth requires Astrocytes.
Fig. 3: Meth activates microglia via astrocytic TNF production.
Fig. 4: TNF or IP3R2 deficiency prevents Meth-induced microgliosis and behavioral changes.
Fig. 5: Meth-induced microglia activation occurs via astrocytes.

References

  1. Thanos PK, Kim R, Delis F, Ananth M, Chachati G, Rocco MJ, et al. Chronic methamphetamine effects on brain structure and function in rats. PLoS One. 2016;11:e0155457.

    PubMed  PubMed Central  Google Scholar 

  2. Chang X, Sun Y, Zhang Y, Muhai J, Lu L, Shi J. A review of risk factors for methamphetamine-related psychiatric symptoms. Front Psychiatry. 2018;9:603.

    PubMed  PubMed Central  Google Scholar 

  3. Cadet JL, Bisagno V, Milroy CM. Neuropathology of substance use disorders. Acta Neuropathol. 2014;127:91–107.

    CAS  PubMed  Google Scholar 

  4. Moszczynska A, Callan SP. Molecular, behavioral, and physiological consequences of methamphetamine neurotoxicity: implications for treatment. J Pharm Exp Ther. 2017;362:474–88.

    CAS  Google Scholar 

  5. Northrop NA, Halpin LE, Yamamoto BK. Peripheral ammonia and blood brain barrier structure and function after methamphetamine. Neuropharmacology. 2016;107:18–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Shaerzadeh F, Streit WJ, Heysieattalab S, Khoshbouei H. Methamphetamine neurotoxicity, microglia, and neuroinflammation. J Neuroinflammation. 2018;15:341.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Yamamoto BK, Raudensky J. The role of oxidative stress, metabolic compromise, and inflammation in neuronal injury produced by amphetamine-related drugs of abuse. J Neuroimmune Pharm. 2008;3:203–17.

    Google Scholar 

  8. Cadet JL, Bisagno V. Glial-neuronal ensembles: partners in drug addiction-associated synaptic plasticity. Front Pharm. 2014;5:204.

    Google Scholar 

  9. Miguel-Hidalgo JJ. The role of glial cells in drug abuse. Curr Drug Abus Rev. 2009;2:72–82.

    Google Scholar 

  10. Beardsley PM, Hauser KF. Glial modulators as potential treatments of psychostimulant abuse. Adv Pharm. 2014;69:1–69.

    CAS  Google Scholar 

  11. Araque A, Carmignoto G, Haydon PG, Oliet SH, Robitaille R, Volterra A. Gliotransmitters travel in time and space. Neuron 2014;81:728–39.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Tzschentke TM, Schmidt WJ. Glutamatergic mechanisms in addiction. Mol Psychiatry. 2003;8:373–82.

    CAS  PubMed  Google Scholar 

  13. Bazargani N, Attwell D. Astrocyte calcium signaling: the third wave. Nat Neurosci. 2016;19:182–9.

    CAS  PubMed  Google Scholar 

  14. Clark KH, Wiley CA, Bradberry CW. Psychostimulant abuse and neuroinflammation: emerging evidence of their interconnection. Neurotox Res. 2013;23:174–88.

    CAS  PubMed  Google Scholar 

  15. Krasnova IN, Justinova Z, Cadet JL. Methamphetamine addiction: involvement of CREB and neuroinflammatory signaling pathways. Psychopharmacol (Berl). 2016;233:1945–62.

    CAS  Google Scholar 

  16. Salter MW, Beggs S. Sublime microglia: expanding roles for the guardians of the CNS. Cell 2014;158:15–24.

    CAS  PubMed  Google Scholar 

  17. Harms AS, Lee JK, Nguyen TA, Chang J, Ruhn KM, Trevino I, et al. Regulation of microglia effector functions by tumor necrosis factor signaling. Glia. 2012;60:189–202.

    PubMed  Google Scholar 

  18. Prinz M, Priller J. Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease. Nat Rev Neurosci. 2014;15:300–12.

    CAS  PubMed  Google Scholar 

  19. Biber K, Moller T, Boddeke E, Prinz M. Central nervous system myeloid cells as drug targets: current status and translational challenges. Nat Rev Drug Disco. 2016;15:110–24.

    CAS  Google Scholar 

  20. Stephenson J, Nutma E, van der Valk P, Amor S. Inflammation in CNS neurodegenerative diseases. Immunology. 2018;154:204–19.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Subhramanyam CS, Wang C, Hu Q, Dheen ST. Microglia-mediated neuroinflammation in neurodegenerative diseases. Semin Cell Dev Biol. 2019;94:112–20.

    CAS  PubMed  Google Scholar 

  22. Socodato R, Henriques JF, Portugal CC, Almeida TO, Tedim-Moreira J, Alves RL, et al. Daily alcohol intake triggers aberrant synaptic pruning leading to synapse loss and anxiety-like behavior. Sci Signal. 2020;13:eaba5754.

    CAS  PubMed  Google Scholar 

  23. ter Horst JP, de Kloet ER, Schachinger H, Oitzl MS. Relevance of stress and female sex hormones for emotion and cognition. Cell Mol Neurobiol. 2012;32:725–35.

    PubMed  Google Scholar 

  24. Li X, Zima AV, Sheikh F, Blatter LA, Chen J. Endothelin-1-induced arrhythmogenic Ca2+ signaling is abolished in atrial myocytes of inositol-1,4,5-trisphosphate(IP3)-receptor type 2-deficient mice. Circ Res. 2005;96:1274–81.

    CAS  PubMed  Google Scholar 

  25. Guerra-Gomes S, Sousa N, Pinto L, Oliveira JF. Functional roles of astrocyte calcium elevations: from synapses to behavior. Front Cell Neurosci. 2018;11:427.

    PubMed  PubMed Central  Google Scholar 

  26. Thomas DM, Walker PD, Benjamins JA, Geddes TJ, Kuhn DM. Methamphetamine neurotoxicity in dopamine nerve endings of the striatum is associated with microglial activation. J Pharm Exp Ther. 2004;311:1–7.

    CAS  Google Scholar 

  27. Nakajima A, Yamada K, Nagai T, Uchiyama T, Miyamoto Y, Mamiya T, et al. Role of tumor necrosis factor-alpha in methamphetamine-induced drug dependence and neurotoxicity. J Neurosci. 2004;24:2212–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Krasnova IN, Cadet JL. Methamphetamine toxicity and messengers of death. Brain Res Rev. 2009;60:379–407.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Galatro TF, Vainchtein ID, Brouwer N, Boddeke E, Eggen BJL. Isolation of microglia and immune infiltrates from mouse and primate central nervous system. Methods Mol Biol. 2017;1559:333–42.

    CAS  PubMed  Google Scholar 

  30. Socodato R, Portugal CC, Canedo T, Rodrigues A, Almeida TO, Henriques JF, et al. Microglia dysfunction caused by the loss of rhoa disrupts neuronal physiology and leads to neurodegeneration. Cell Rep. 2020;31:107796.

    CAS  PubMed  Google Scholar 

  31. Andrade EB, Magalhaes A, Puga A, Costa M, Bravo J, Portugal CC, et al. A mouse model reproducing the pathophysiology of neonatal group B streptococcal infection. Nat Commun. 2018;9:3138.

    PubMed  PubMed Central  Google Scholar 

  32. Portugal CC, Socodato R, Canedo T, Silva CM, Martins T, Coreixas VS, et al. Caveolin-1-mediated internalization of the vitamin C transporter SVCT2 in microglia triggers an inflammatory phenotype. Sci Signal. 2017;10:eaal2005.

    PubMed  Google Scholar 

  33. Bortell N, Basova L, Semenova S, Fox HS, Ravasi T, Marcondes MC. Astrocyte-specific overexpressed gene signatures in response to methamphetamine exposure in vitro. J Neuroinflammation 2017;14:49.

    PubMed  PubMed Central  Google Scholar 

  34. Socodato R, Portugal CC, Domith I, Oliveira NA, Coreixas VS, Loiola EC, et al. c-Src function is necessary and sufficient for triggering microglial cell activation. Glia 2015;63:497–511.

    PubMed  Google Scholar 

  35. Koenigsknecht J, Landreth G. Microglial phagocytosis of fibrillar beta-amyloid through a beta1 integrin-dependent mechanism. J Neurosci. 2004;24:9838–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Socodato R, Melo P, Ferraz-Nogueira JP, Portugal CC, Relvas JB. A protocol for FRET-based live-cell imaging in microglia. STAR Protocols. 2020;1:100147.

    PubMed  PubMed Central  Google Scholar 

  37. Mateus-Pinheiro A, Alves ND, Patrício P, Machado-Santos AR, Loureiro-Campos E, Silva JM, et al. AP2γ controls adult hippocampal neurogenesis and modulates cognitive, but not anxiety or depressive-like behavior. Mol Psychiatry. 2017;22:1725–34.

    CAS  PubMed  Google Scholar 

  38. Ayata P, Badimon A, Strasburger HJ, Duff MK, Montgomery SE, Loh Y-HE, et al. Epigenetic regulation of brain region-specific microglia clearance activity. Nat Neurosci. 2018;21:1049–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Butovsky O, Jedrychowski MP, Moore CS, Cialic R, Lanser AJ, Gabriely G, et al. Identification of a unique TGF-β–dependent molecular and functional signature in microglia. Nat Neurosci. 2014;17:131–43.

    CAS  PubMed  Google Scholar 

  40. Hammond TR, Dufort C, Dissing-Olesen L, Giera S, Young A, Wysoker A, et al. Single-cell RNA sequencing of microglia throughout the mouse lifespan and in the injured brain reveals complex cell-state changes. Immunity. 2019;50:253–71.e6.

    CAS  PubMed  Google Scholar 

  41. Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, et al. a unique microglia type associated with restricting development of Alzheimer’s disease. Cell. 2017;169:1276–90.e17.

    CAS  PubMed  Google Scholar 

  42. Najera JA, Bustamante EA, Bortell N, Morsey B, Fox HS, Ravasi T, et al. Methamphetamine abuse affects gene expression in brain-derived microglia of SIV-infected macaques to enhance inflammation and promote virus targets. BMC Immunol. 2016;17:7–7.

    PubMed  PubMed Central  Google Scholar 

  43. Savell KE, Tuscher JJ, Zipperly ME, Duke CG, Phillips RA, Bauman AJ, et al. A dopamine-induced gene expression signature regulates neuronal function and cocaine response. Sci Adv. 2020;6:eaba4221.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Astarita G, Avanesian A, Grimaldi B, Realini N, Justinova Z, Panlilio LV, et al. Methamphetamine accelerates cellular senescence through stimulation of de novo ceramide biosynthesis. PLoS One. 2015;10:e0116961.

    PubMed  PubMed Central  Google Scholar 

  45. Liddelow SA, Marsh SE, Stevens B. Microglia and astrocytes in disease: dynamic duo or partners in crime? Trends Immunol. 2020;41:820–35.

    CAS  PubMed  Google Scholar 

  46. Socodato R, Portugal CC, Canedo T, Domith I, Oliveira NA, Paes-de-Carvalho R, et al. c-Src deactivation by the polyphenol 3-O-caffeoylquinic acid abrogates reactive oxygen species-mediated glutamate release from microglia and neuronal excitotoxicity. Free Radic Biol Med. 2015;79:45–55.

    CAS  PubMed  Google Scholar 

  47. Goncalves J, Martins T, Ferreira R, Milhazes N, Borges F, Ribeiro CF, et al. Methamphetamine-induced early increase of IL-6 and TNF-alpha mRNA expression in the mouse brain. Ann NY Acad Sci. 2008;1139:103–11.

    CAS  PubMed  Google Scholar 

  48. Bezzi P, Domercq M, Brambilla L, Galli R, Schols D, De Clercq E, et al. CXCR4-activated astrocyte glutamate release via TNFalpha: amplification by microglia triggers neurotoxicity. Nat Neurosci. 2001;4:702–10.

    CAS  PubMed  Google Scholar 

  49. Okumoto S, Looger LL, Micheva KD, Reimer RJ, Smith SJ, Frommer WB. Detection of glutamate release from neurons by genetically encoded surface-displayed FRET nanosensors. Proc Natl Acad Sci USA. 2005;102:8740–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Harada K, Kamiya T, Tsuboi T. Gliotransmitter release from astrocytes: functional, developmental, and pathological implications in the brain. Front Neurosci. 2015;9:499.

    PubMed  Google Scholar 

  51. Parpura V, Grubisic V, Verkhratsky A. Ca(2+) sources for the exocytotic release of glutamate from astrocytes. Biochim Biophys Acta. 2011;1813:984–91.

    CAS  PubMed  Google Scholar 

  52. Palmer AE, Jin C, Reed JC, Tsien RY. Bcl-2-mediated alterations in endoplasmic reticulum Ca2+ analyzed with an improved genetically encoded fluorescent sensor. Proc Natl Acad Sci USA. 2004;101:17404–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Gafni J, Munsch JA, Lam TH, Catlin MC, Costa LG, Molinski TF, et al. Xestospongins: potent membrane permeable blockers of the inositol 1,4,5-trisphosphate receptor. Neuron. 1997;19:723–33.

    CAS  PubMed  Google Scholar 

  54. Verkhratsky A, Matteoli M, Parpura V, Mothet JP, Zorec R. Astrocytes as secretory cells of the central nervous system: idiosyncrasies of vesicular secretion. EMBO J. 2016;35:239–57.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Schiavo G, Matteoli M, Montecucco C. Neurotoxins affecting neuroexocytosis. Physiol Rev. 2000;80:717–66.

    CAS  PubMed  Google Scholar 

  56. Petravicz J, Fiacco TA, McCarthy KD. Loss of IP3 receptor-dependent Ca2+ increases in hippocampal astrocytes does not affect baseline CA1 pyramidal neuron synaptic activity. J Neurosci. 2008;28:4967–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Blank T, Prinz M. Microglia as modulators of cognition and neuropsychiatric disorders. Glia. 2013;61:62–70.

    PubMed  Google Scholar 

  58. Rooney S, Sah A, Unger MS, Kharitonova M, Sartori SB, Schwarzer C, et al. Neuroinflammatory alterations in trait anxiety: modulatory effects of minocycline. Transl Psychiatry. 2020;10:256.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Sekine Y, Ouchi Y, Sugihara G, Takei N, Yoshikawa E, Nakamura K, et al. Methamphetamine causes microglial activation in the brains of human abusers. J Neurosci. 2008;28:5756–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Buchanan JB, Sparkman NL, Johnson RW. A neurotoxic regimen of methamphetamine exacerbates the febrile and neuroinflammatory response to a subsequent peripheral immune stimulus. J Neuroinflammation. 2010;7:82.

    PubMed  PubMed Central  Google Scholar 

  61. Loftis JM, Choi D, Hoffman W, Huckans MS. Methamphetamine causes persistent immune dysregulation: a cross-species, translational report. Neurotox Res. 2011;20:59–68.

    CAS  PubMed  Google Scholar 

  62. Block ML, Zecca L, Hong JS. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci. 2007;8:57–69.

    CAS  PubMed  Google Scholar 

  63. Coelho-Santos V, Goncalves J, Fontes-Ribeiro C, Silva AP. Prevention of methamphetamine-induced microglial cell death by TNF-alpha and IL-6 through activation of the JAK-STAT pathway. J Neuroinflammation. 2012;9:103.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Frank MG, Adhikary S, Sobesky JL, Weber MD, Watkins LR, Maier SF. The danger-associated molecular pattern HMGB1 mediates the neuroinflammatory effects of methamphetamine. Brain Behav Immun. 2016;51:99–108.

    CAS  PubMed  Google Scholar 

  65. Lewitus GM, Konefal SC, Greenhalgh AD, Pribiag H, Augereau K, Stellwagen D. Microglial TNF-alpha suppresses cocaine-induced plasticity and behavioral sensitization. Neuron. 2016;90:483–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Escartin C, Galea E, Lakatos A, O’Callaghan JP, Petzold GC, Serrano-Pozo A, et al. Reactive astrocyte nomenclature, definitions, and future directions. Nat Neurosci. 2021;24:312–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Narita M, Miyatake M, Narita M, Shibasaki M, Shindo K, Nakamura A, et al. Direct evidence of astrocytic modulation in the development of rewarding effects induced by drugs of abuse. Neuropsychopharmacology. 2006;31:2476–88.

    CAS  PubMed  Google Scholar 

  68. Du SH, Qiao DF, Chen CX, Chen S, Liu C, Lin Z, et al. Toll-like receptor 4 mediates methamphetamine-induced neuroinflammation through caspase-11 signaling pathway in astrocytes. Front Mol Neurosci. 2017;10:409.

    PubMed  PubMed Central  Google Scholar 

  69. Dang J, Tiwari SK, Agrawal K, Hui H, Qin Y, Rana TM. Glial cell diversity and methamphetamine-induced neuroinflammation in human cerebral organoids. Mol Psychiatry. 2021;26:1194–207.

    CAS  Google Scholar 

  70. Dong Y, Benveniste EN. Immune function of astrocytes. Glia 2001;36:180–90.

    CAS  PubMed  Google Scholar 

  71. Farina C, Aloisi F, Meinl E. Astrocytes are active players in cerebral innate immunity. Trends Immunol. 2007;28:138–45.

    CAS  PubMed  Google Scholar 

  72. Rossi D. Astrocyte physiopathology: at the crossroads of intercellular networking, inflammation and cell death. Prog Neurobiol. 2015;130:86–120.

    CAS  PubMed  Google Scholar 

  73. Domercq M, Brambilla L, Pilati E, Marchaland J, Volterra A, Bezzi P. P2Y1 receptor-evoked glutamate exocytosis from astrocytes: control by tumor necrosis factor-alpha and prostaglandins. J Biol Chem. 2006;281:30684–96.

    CAS  PubMed  Google Scholar 

  74. Sitcheran R, Gupta P, Fisher PB, Baldwin AS. Positive and negative regulation of EAAT2 by NF-kappaB: a role for N-myc in TNFalpha-controlled repression. EMBO J. 2005;24:510–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Wang Z, Pekarskaya O, Bencheikh M, Chao W, Gelbard HA, Ghorpade A, et al. Reduced expression of glutamate transporter EAAT2 and impaired glutamate transport in human primary astrocytes exposed to HIV-1 or gp120. Virology. 2003;312:60–73.

    CAS  PubMed  Google Scholar 

  76. Doble A. The role of excitotoxicity in neurodegenerative disease: implications for therapy. Pharm Ther. 1999;81:163–221.

    CAS  Google Scholar 

  77. Cisneros IE, Ghorpade A. Methamphetamine and HIV-1-induced neurotoxicity: role of trace amine associated receptor 1 cAMP signaling in astrocytes. Neuropharmacology. 2014;85:499–507.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Yan Y, Nitta A, Koseki T, Yamada K, Nabeshima T. Dissociable role of tumor necrosis factor alpha gene deletion in methamphetamine self-administration and cue-induced relapsing behavior in mice. Psychopharmacol. 2012;221:427–36.

    CAS  Google Scholar 

  79. Volterra A, Liaudet N, Savtchouk I. Astrocyte Ca(2)(+) signalling: an unexpected complexity. Nat Rev Neurosci. 2014;15:327–35.

    CAS  PubMed  Google Scholar 

  80. Corkrum M, Covelo A, Lines J, Bellocchio L, Pisansky M, Loke K, et al. Dopamine-evoked synaptic regulation in the nucleus accumbens requires astrocyte activity. Neuron. 2020;105:1036–47 e5.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We acknowledge the support of the following i3S Scientific Platforms: Animal Facility, Cell Culture and Genotyping (CCGen), Translational Cytometry Unit (TraCy), and the assistance of Mafalda Rocha (Genomics platform) and Maria Azevedo (ALM platform) and André Maia (BioSciences screening). We also acknowledge our late colleague Rui Applelberg for kindly make TNF KO mice available to us, and the designer Maria Summavielle for her contribution in assembling the figures that illustrate this publication. RS has contributed as first author.

Funding

This work was financed by FEDER—Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020 - Operational Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, and by Portuguese funds through FCT—Fundação para a Ciência e a Tecnologia/Ministério da Ciência (FCT), Tecnologia e Ensino Superior in the framework of the project POCI-01-0145-FEDER-030647 (PTDC/SAU-TOX/30647/2017) in TS lab. FEDER Portugal (Norte-01-0145-FEDER-000008000008—Porto Neurosciences and Neurologic Disease Research Initiative at I3S, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF); FCOMP-01-0124-FEDER-021333). CCP and RS hold employment contracts financed by national funds through FCT –in the context of the program-contract described in paragraphs 4, 5, and 6 of art. 23 of Law no. 57/2016, of August 29, as amended by Law no. 57/2017 of July 2019. TC, TOA, AFT, JB, AIS and AM were supported by FCT (SFRH/BD/117148/2016, SFRH/BD/147981/2019, 2020.07188.BD, PD/BD/135450/2017, SFRH/BD/144324/2019, and IF/00753/2014). Work in JBR lab was supported by the FCT project PTDC/ MED-NEU/31318/2017. JFO was also supported by FCT projects PTDC/MED-NEU/31417/2017 and POCI-01-0145-FEDER-016818; Bial Foundation Grants 207/14 and 037/18, by National funds, through FCT - project UIDB/50026/2020; and by the projects NORTE-01-0145-FEDER-000013 and NORTE-01-0145-FEDER-000023, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). Funding of i3S Scientific Platforms: Advanced Light Microscopy (ALM), a member of the national infrastructure PPBI-Portuguese Platform of BioImaging (POCI-01–0145-FEDER-022122); and Genomics through GenomePT project (POCI-01-0145-FEDER-022184), supported by COMPETE 2020—Operational Programme for Competitiveness and Internationalization (POCI), Lisboa Portugal Regional Operational Programme (Lisboa2020), Algarve Portugal Regional Operational Programme (CRESC Algarve2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF), and by FCT.

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Conception of the work—TC, CCP, RS, JBR, TS; Acquisition, analysis, or interpretation of data for the work—TC, CCP, RS, TOA, AFT, JB, AIS, JDM, SGG, JFO, AM, JBR, TS; Drafting the work or revising it critically—TC, CCP, RS, NS, JFO, JBR, TS; Final approval of the version to be published- TC, CCP, TS. Agreement to be accountable for all aspects of the work in ensuring accuracy and integrity—CCP and TS.

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Correspondence to Camila Cabral Portugal or Teresa Summavielle.

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Canedo, T., Portugal, C.C., Socodato, R. et al. Astrocyte-derived TNF and glutamate critically modulate microglia activation by methamphetamine. Neuropsychopharmacol. 46, 2358–2370 (2021). https://doi.org/10.1038/s41386-021-01139-7

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