Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Astrocytes in cocaine addiction and beyond

Abstract

Drug addiction remains a key biomedical challenge facing current neuroscience research. In addition to neural mechanisms, the focus of the vast majority of studies to date, astrocytes have been increasingly recognized as an “accomplice.” According to the tripartite synapse model, astrocytes critically regulate nearby pre- and postsynaptic neuronal substrates to craft experience-dependent synaptic plasticity, including synapse formation and elimination. Astrocytes within brain regions that are implicated in drug addiction exhibit dynamic changes in activity upon exposure to cocaine and subsequently undergo adaptive changes themselves during chronic drug exposure. Recent results have identified several key astrocytic signaling pathways that are involved in cocaine-induced synaptic and circuit adaptations. In this review, we provide a brief overview of the role of astrocytes in regulating synaptic transmission and neuronal function, and discuss how cocaine influences these astrocyte-mediated mechanisms to induce persistent synaptic and circuit alterations that promote cocaine seeking and relapse. We also consider the therapeutic potential of targeting astrocytic substrates to ameliorate drug-induced neuroplasticity for behavioral benefits. While primarily focusing on cocaine-induced astrocytic responses, we also include brief discussion of other drugs of abuse where data are available.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Astrocyte-mediated regulation of transmission at the tripartite synapse.
Fig. 2: Dysregulation of NAc extracellular glutamate after cocaine experience.
Fig. 3: Astrocyte-mediated synaptogenesis after cocaine self-administration.

References

  1. 1.

    Pfrieger FW, Barres BA. What the fly’s glia tell the fly’s brain. Cell. 1995;83:671–4.

    CAS  PubMed  Article  Google Scholar 

  2. 2.

    Vasile F, Dossi E, Rouach N. Human astrocytes: structure and functions in the healthy brain. Brain Struct Funct. 2017;222:2017–29.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  3. 3.

    Bass NH, Hess HH, Pope A, Thalheimer C. Quantitative cytoarchitectonic distribution of neurons, glia, and DNA in rat cerebral cortex. J Comp Neurol. 1971;143:481–90.

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Pelvig DP, Pakkenberg H, Stark AK, Pakkenberg B. Neocortical glial cell numbers in human brains. Neurobiol Aging. 2008;29:1754–62.

    CAS  PubMed  Article  Google Scholar 

  5. 5.

    Oikonomou G, Shaham S. The glia of Caenorhabditis elegans. Glia. 2011;59:1253–63.

    PubMed  Article  Google Scholar 

  6. 6.

    Oberheim NA, Takano T, Han X, He W, Lin JH, Wang F, et al. Uniquely hominid features of adult human astrocytes. J Neurosci. 2009;29:3276–87.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. 7.

    Oberheim NA, Wang X, Goldman S, Nedergaard M. Astrocytic complexity distinguishes the human brain. Trends Neurosci. 2006;29:547–53.

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Han X, Chen M, Wang F, Windrem M, Wang S, Shanz S, et al. Forebrain engraftment by human glial progenitor cells enhances synaptic plasticity and learning in adult mice. Cell Stem Cell. 2013;12:342–53.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    Perea G, Navarrete M, Araque A. Tripartite synapses: astrocytes process and control synaptic information. Trends Neurosci. 2009;32:421–31.

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    Perea G, Araque A. Properties of synaptically evoked astrocyte calcium signal reveal synaptic information processing by astrocytes. J Neurosci. 2005;25:2192–203.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    Perea G, Araque A. Synaptic information processing by astrocytes. In: Haydon PG, Parpura V, editors. Astrocytes in (patho)physiology of the nervous system. Boston, MA: Springer US; 2009. pp. 287–300.

  12. 12.

    Santello M, Toni N, Volterra A. Astrocyte function from information processing to cognition and cognitive impairment. Nat Neurosci. 2019;22:154–66.

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Zhang Y, Barres BA. A smarter mouse with human astrocytes. Bioessays. 2013;35:876–80.

    PubMed  Article  Google Scholar 

  14. 14.

    Spacek J. Three-dimensional analysis of dendritic spines. III. Glial sheath. Anat Embryol (Berl). 1985;171:245–52.

    CAS  Article  Google Scholar 

  15. 15.

    Octeau JC, Chai H, Jiang R, Bonanno SL, Martin KC, Khakh BS. An optical neuron-astrocyte proximity assay at synaptic distance scales. Neuron. 2018;98:49–66.e49.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. 16.

    Kikuchi T, Gonzalez-Soriano J, Kastanauskaite A, Benavides-Piccione R, Merchan-Perez A, DeFelipe J, et al. Volume electron microscopy study of the relationship between synapses and astrocytes in the developing rat somatosensory cortex. Cereb Cortex. 2020;30:3800–19.

    PubMed  PubMed Central  Article  Google Scholar 

  17. 17.

    Porter JT, McCarthy KD. Astrocytic neurotransmitter receptors in situ and in vivo. Prog Neurobiol. 1997;51:439–55.

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Biber K, Laurie DJ, Berthele A, Sommer B, Tolle TR, Gebicke-Harter PJ, et al. Expression and signaling of group I metabotropic glutamate receptors in astrocytes and microglia. J Neurochem. 1999;72:1671–80.

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    Velez-Fort M, Audinat E, Angulo MC. Central role of GABA in neuron-glia interactions. Neuroscientist. 2012;18:237–50.

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Ribak CE, Tong WM, Brecha NC. GABA plasma membrane transporters, GAT-1 and GAT-3, display different distributions in the rat hippocampus. J Comp Neurol. 1996;367:595–606.

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    Schousboe A. Transport and metabolism of glutamate and GABA in neurons are glial cells. Int Rev Neurobiol. 1981;22:1–45.

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Rothstein JD, Martin L, Levey AI, Dykes-Hoberg M, Jin L, Wu D, et al. Localization of neuronal and glial glutamate transporters. Neuron. 1994;13:713–25.

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Szatkowski M, Barbour B, Attwell D. Non-vesicular release of glutamate from glial cells by reversed electrogenic glutamate uptake. Nature. 1990;348:443–6.

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Cotrina ML, Lin JH, Alves-Rodrigues A, Liu S, Li J, Azmi-Ghadimi H, et al. Connexins regulate calcium signaling by controlling ATP release. Proc Natl Acad Sci USA. 1998;95:15735–40.

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Warr O, Takahashi M, Attwell D. Modulation of extracellular glutamate concentration in rat brain slices by cystine-glutamate exchange. J Physiol. 1999;514(Pt 3):783–93.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. 26.

    Lutter D, Ullrich F, Lueck JC, Kempa S, Jentsch TJ. Selective transport of neurotransmitters and modulators by distinct volume-regulated LRRC8 anion channels. J Cell Sci. 2017;130:1122–33.

    CAS  PubMed  Google Scholar 

  27. 27.

    Bezzi P, Gundersen V, Galbete JL, Seifert G, Steinhauser C, Pilati E, et al. Astrocytes contain a vesicular compartment that is competent for regulated exocytosis of glutamate. Nat Neurosci. 2004;7:613–20.

    CAS  PubMed  Article  Google Scholar 

  28. 28.

    Fiacco TA, McCarthy KD. Multiple lines of evidence indicate that gliotransmission does not occur under physiological conditions. J Neurosci. 2018;38:3–13.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. 29.

    Savtchouk I, Volterra A. Gliotransmission: beyond black-and-white. J Neurosci. 2018;38:14–25.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30.

    Schwarz Y, Zhao N, Kirchhoff F, Bruns D. Astrocytes control synaptic strength by two distinct v-SNARE-dependent release pathways. Nat Neurosci. 2017;20:1529–39.

    CAS  PubMed  Article  Google Scholar 

  31. 31.

    Navarrete M, Cuartero MI, Palenzuela R, Draffin JE, Konomi A, Serra I, et al. Astrocytic p38alpha MAPK drives NMDA receptor-dependent long-term depression and modulates long-term memory. Nat Commun. 2019;10:2968.

    PubMed  PubMed Central  Article  Google Scholar 

  32. 32.

    Takata-Tsuji F, Chounlamountri N, Do LD, Philippot C, Novion Ducassou J, Coute Y, et al. Microglia modulate gliotransmission through the regulation of VAMP2 proteins in astrocytes. Glia. 2021;69:61–72.

    PubMed  Article  Google Scholar 

  33. 33.

    Rajani V, Zhang Y, Jalubula V, Rancic V, SheikhBahaei S, Zwicker JD, et al. Release of ATP by pre-Botzinger complex astrocytes contributes to the hypoxic ventilatory response via a Ca(2+)-dependent P2Y1 receptor mechanism. J Physiol. 2018;596:3245–69.

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Angelova PR, Iversen KZ, Teschemacher AG, Kasparov S, Gourine AV, Abramov AY. Signal transduction in astrocytes: Localization and release of inorganic polyphosphate. Glia. 2018;66:2126–36.

    PubMed  PubMed Central  Article  Google Scholar 

  35. 35.

    Araque A, Parpura V, Sanzgiri RP, Haydon PG. Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci. 1999;22:208–15.

    CAS  Article  Google Scholar 

  36. 36.

    Haydon PG. GLIA: listening and talking to the synapse. Nat Rev Neurosci. 2001;2:185–93.

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    Khakh BS, Sofroniew MV. Diversity of astrocyte functions and phenotypes in neural circuits. Nat Neurosci. 2015;18:942–52.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    Wise RA. Dopamine, learning and motivation. Nat Rev Neurosci. 2004;5:483–94.

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    Koob GF, Volkow ND. Neurocircuitry of addiction. Neuropsychopharmacology. 2010;35:217–38.

    PubMed  Article  Google Scholar 

  40. 40.

    Adinoff B. Neurobiologic processes in drug reward and addiction. Harv Rev Psychiatry. 2004;12:305–20.

    PubMed  PubMed Central  Article  Google Scholar 

  41. 41.

    Mogenson GJ, Yang CR, Yim CY. Influence of dopamine on limbic inputs to the nucleus accumbens. Ann N Y Acad Sci. 1988;537:86–100.

    CAS  PubMed  Article  Google Scholar 

  42. 42.

    Scofield MD. Exploring the role of astroglial glutamate release and association with synapses in neuronal function and behavior. Biol Psychiatry. 2018;84:778–86.

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Scofield MD, Kalivas PW. Astrocytic dysfunction and addiction: consequences of impaired glutamate homeostasis. Neuroscientist. 2014;20:610–22.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. 44.

    Kim R, Healey KL, Sepulveda-Orengo MT, Reissner KJ. Astroglial correlates of neuropsychiatric disease: from astrocytopathy to astrogliosis. Prog Neuropsychopharmacol Biol Psychiatry. 2018;87(Pt A):126–46.

    PubMed  Article  Google Scholar 

  45. 45.

    Kruyer A, Kalivas PW. Astrocytes as cellular mediators of cue reactivity in addiction. Curr Opin Pharmacol. 2020;56:1–6.

    PubMed  Article  CAS  Google Scholar 

  46. 46.

    Cornell-Bell AH, Finkbeiner SM, Cooper MS, Smith SJ. Glutamate induces calcium waves in cultured astrocytes: long-range glial signaling. Science. 1990;247:470–3.

    CAS  PubMed  Article  Google Scholar 

  47. 47.

    Hille B. Ionic channels: molecular pores of excitable membranes. Harvey Lect. 1986;82:47–69.

    CAS  PubMed  Google Scholar 

  48. 48.

    Sperlagh B, Heinrich A, Csolle C. P2 receptor-mediated modulation of neurotransmitter release-an update. Purinergic Signal. 2007;3:269–84.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. 49.

    Sharp AH, Nucifora FC Jr, Blondel O, Sheppard CA, Zhang C, Snyder SH, et al. Differential cellular expression of isoforms of inositol 1,4,5-triphosphate receptors in neurons and glia in brain. J Comp Neurol. 1999;406:207–20.

    CAS  PubMed  Article  Google Scholar 

  50. 50.

    Hussl S, Boehm S. Functions of neuronal P2Y receptors. Pflug Arch Eur J Physiol. 2006;452:538–51.

    CAS  Article  Google Scholar 

  51. 51.

    Agulhon C, Boyt KM, Xie AX, Friocourt F, Roth BL, McCarthy KD. Modulation of the autonomic nervous system and behaviour by acute glial cell Gq protein-coupled receptor activation in vivo. J Physiol. 2013;591:5599–609.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. 52.

    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  Article  Google Scholar 

  53. 53.

    Verkhratsky A, Rodriguez JJ, Parpura V. Calcium signalling in astroglia. Mol Cell Endocrinol. 2012;353:45–56.

    CAS  PubMed  Article  Google Scholar 

  54. 54.

    Verkhratsky A, Untiet V, Rose CR. Ionic signalling in astroglia beyond calcium. J Physiol. 2020;598:1655–70.

    CAS  PubMed  Article  Google Scholar 

  55. 55.

    Xu G, Wang W, Kimelberg HK, Zhou M. Electrical coupling of astrocytes in rat hippocampal slices under physiological and simulated ischemic conditions. Glia. 2010;58:481–93.

    PubMed  Article  Google Scholar 

  56. 56.

    Verkhratsky A, Nedergaard M. Physiology of Astroglia. Physiol Rev. 2018;98:239–389.

    CAS  PubMed  Article  Google Scholar 

  57. 57.

    Kiyoshi CM, Zhou M. Astrocyte syncytium: a functional reticular system in the brain. Neural Regen Res. 2019;14:595–6.

    PubMed  PubMed Central  Article  Google Scholar 

  58. 58.

    Hanani M, Verkhratsky A. Satellite glial cells and astrocytes, a comparative review. Neurochem Res. 2021 https://doi.org/10.1007/s11064-021-03255-8.

  59. 59.

    Nagai J, Yu X, Papouin T, Cheong E, Freeman MR, Monk KR et al. Behaviorally consequential astrocytic regulation of neural circuits. Neuron 2020;177:1280–92.e20.

    Google Scholar 

  60. 60.

    Agulhon C, Fiacco TA, McCarthy KD. Hippocampal short- and long-term plasticity are not modulated by astrocyte Ca2+ signaling. Science. 2010;327:1250–4.

    CAS  PubMed  Article  Google Scholar 

  61. 61.

    Srinivasan R, Huang BS, Venugopal S, Johnston AD, Chai H, Zeng H, et al. Ca(2+) signaling in astrocytes from Ip3r2(−/−) mice in brain slices and during startle responses in vivo. Nat Neurosci. 2015;18:708–17.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. 62.

    Bindocci E, Savtchouk I, Liaudet N, Becker D, Carriero G, Volterra A. Three-dimensional Ca(2+) imaging advances understanding of astrocyte biology. Science. 2017;356:8185–95.

    Article  CAS  Google Scholar 

  63. 63.

    Agarwal A, Wu PH, Hughes EG, Fukaya M, Tischfield MA, Langseth AJ, et al. Transient opening of the mitochondrial permeability transition pore induces microdomain calcium transients in astrocyte processes. Neuron. 2017;93:587–605. e587.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. 64.

    Kang J, Jiang L, Goldman SA, Nedergaard M. Astrocyte-mediated potentiation of inhibitory synaptic transmission. Nat Neurosci. 1998;1:683–92.

    CAS  PubMed  Article  Google Scholar 

  65. 65.

    Pascual O, Casper KB, Kubera C, Zhang J, Revilla-Sanchez R, Sul JY, et al. Astrocytic purinergic signaling coordinates synaptic networks. Science. 2005;310:113–6.

    CAS  PubMed  Article  Google Scholar 

  66. 66.

    Jourdain P, Bergersen LH, Bhaukaurally K, Bezzi P, Santello M, Domercq M, et al. Glutamate exocytosis from astrocytes controls synaptic strength. Nat Neurosci. 2007;10:331–9.

    CAS  PubMed  Article  Google Scholar 

  67. 67.

    Henneberger C, Papouin T, Oliet SH, Rusakov DA. Long-term potentiation depends on release of D-serine from astrocytes. Nature. 2010;463:232–6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. 68.

    Lee S, Yoon BE, Berglund K, Oh SJ, Park H, Shin HS, et al. Channel-mediated tonic GABA release from glia. Science. 2010;330:790–6.

    CAS  PubMed  Article  Google Scholar 

  69. 69.

    Durkee CA, Covelo A, Lines J, Kofuji P, Aguilar J, Araque A. Gi/o protein-coupled receptors inhibit neurons but activate astrocytes and stimulate gliotransmission. Glia. 2019;67:1076–93.

    PubMed  PubMed Central  Article  Google Scholar 

  70. 70.

    Parpura V, Basarsky TA, Liu F, Jeftinija K, Jeftinija S, Haydon PG. Glutamate-mediated astrocyte-neuron signalling. Nature. 1994;369:744–7.

    CAS  PubMed  Article  Google Scholar 

  71. 71.

    Fiacco TA, Agulhon C, Taves SR, Petravicz J, Casper KB, Dong X, et al. Selective stimulation of astrocyte calcium in situ does not affect neuronal excitatory synaptic activity. Neuron. 2007;54:611–26.

    CAS  PubMed  Article  Google Scholar 

  72. 72.

    Oberheim NA, Goldman SA, Nedergaard M. Heterogeneity of astrocytic form and function. Methods Mol Biol. 2012;814:23–45.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  73. 73.

    Shigetomi E, Bushong EA, Haustein MD, Tong X, Jackson-Weaver O, Kracun S, et al. Imaging calcium microdomains within entire astrocyte territories and endfeet with GCaMPs expressed using adeno-associated viruses. J Gen Physiol. 2013;141:633–47.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. 74.

    Shigetomi E, Kracun S, Sofroniew MV, Khakh BS. A genetically targeted optical sensor to monitor calcium signals in astrocyte processes. Nat Neurosci. 2010;13:759–66.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. 75.

    Haustein MD, Kracun S, Lu XH, Shih T, Jackson-Weaver O, Tong X, et al. Conditions and constraints for astrocyte calcium signaling in the hippocampal mossy fiber pathway. Neuron. 2014;82:413–29.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. 76.

    Duan S, Anderson CM, Keung EC, Chen Y, Chen Y, Swanson RA. P2X7 receptor-mediated release of excitatory amino acids from astrocytes. J Neurosci. 2003;23:1320–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. 77.

    Ye ZC, Wyeth MS, Baltan-Tekkok S, Ransom BR. Functional hemichannels in astrocytes: a novel mechanism of glutamate release. J Neurosci. 2003;23:3588–96.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. 78.

    Covelo A, Araque A. Neuronal activity determines distinct gliotransmitter release from a single astrocyte. Elife 2018;7:e32237–55.

    PubMed  PubMed Central  Article  Google Scholar 

  79. 79.

    Bushong EA, Martone ME, Jones YZ, Ellisman MH. Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains. J Neurosci. 2002;22:183–92.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  80. 80.

    Halassa MM, Fellin T, Takano H, Dong JH, Haydon PG. Synaptic islands defined by the territory of a single astrocyte. J Neurosci. 2007;27:6473–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. 81.

    Pirttimaki TM, Sims RE, Saunders G, Antonio SA, Codadu NK, Parri HR. Astrocyte-mediated neuronal synchronization properties revealed by false gliotransmitter release. J Neurosci. 2017;37:9859–70.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. 82.

    Parpura V, Scemes E, Spray DC. Mechanisms of glutamate release from astrocytes: gap junction “hemichannels”, purinergic receptors and exocytotic release. Neurochemistry Int. 2004;45:259–64.

    CAS  Article  Google Scholar 

  83. 83.

    Woo DH, Han KS, Shim JW, Yoon BE, Kim E, Bae JY, et al. TREK-1 and Best1 channels mediate fast and slow glutamate release in astrocytes upon GPCR activation. Cell. 2012;151:25–40.

    CAS  PubMed  Article  Google Scholar 

  84. 84.

    Park H, Han KS, Seo J, Lee J, Dravid SM, Woo J, et al. Channel-mediated astrocytic glutamate modulates hippocampal synaptic plasticity by activating postsynaptic NMDA receptors. Mol Brain. 2015;8:7.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  85. 85.

    Baker DA, McFarland K, Lake RW, Shen H, Tang XC, Toda S, et al. Neuroadaptations in cystine-glutamate exchange underlie cocaine relapse. Nat Neurosci. 2003;6:743–9.

    CAS  PubMed  Article  Google Scholar 

  86. 86.

    Fellin T, Pascual O, Gobbo S, Pozzan T, Haydon PG, Carmignoto G. Neuronal synchrony mediated by astrocytic glutamate through activation of extrasynaptic NMDA receptors. Neuron. 2004;43:729–43.

    CAS  PubMed  Article  Google Scholar 

  87. 87.

    Bardoni R, Ghirri A, Zonta M, Betelli C, Vitale G, Ruggieri V, et al. Glutamate-mediated astrocyte-to-neuron signalling in the rat dorsal horn. J Physiol. 2010;588:831–46.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. 88.

    Santello M, Bezzi P, Volterra A. TNFalpha controls glutamatergic gliotransmission in the hippocampal dentate gyrus. Neuron. 2011;69:988–1001.

    CAS  PubMed  Article  Google Scholar 

  89. 89.

    Vance KM, Rogers RC, Hermann GE. PAR1-activated astrocytes in the nucleus of the solitary tract stimulate adjacent neurons via NMDA receptors. J Neurosci. 2015;35:776–85.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  90. 90.

    Testa CM, Catania MV, Young AB. Anatomical Distribution of Metabotropic Glutamate Receptors in Mammalian Brain. The Metabotropic Glutamate Receptors, 1 edn. Totowa, NJ: Humana Press; 1994, pp 99–123.

  91. 91.

    Schools GP, Kimelberg HK. mGluR3 and mGluR5 are the predominant metabotropic glutamate receptor mRNAs expressed in hippocampal astrocytes acutely isolated from young rats. J Neurosci Res. 1999;58:533–43.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  92. 92.

    Sun W, McConnell E, Pare J-F, Xu Q, Chen M, Peng W, et al. Glutamate-dependent neuroglial calcium signaling differs between young and adult brain. Science. 2013;339:197–200.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  93. 93.

    Chai H, Diaz-Castro B, Shigetomi E, Monte E, Octeau JC, Yu X, et al. Neural circuit-specialized astrocytes: transcriptomic, proteomic, morphological, and functional evidence. Neuron. 2017;95:531–49. e539.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  94. 94.

    Nakahara K, Okada M, Nakanishi S. The metabotropic glutamate receptor mGluR5 induces calcium oscillations in cultured astrocytes via protein kinase C phosphorylation. J Neurochem. 1997;69:1467–75.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  95. 95.

    D’Ascenzo M, Fellin T, Terunuma M, Revilla-Sanchez R, Meaney DF, Auberson YP, et al. mGluR5 stimulates gliotransmission in the nucleus accumbens. Proc Natl Acad Sci USA. 2007;104:1995–2000.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  96. 96.

    Balazs R, Miller S, Chun Y, Cotman CW. Receptor-coupled phospholipase C and adenylyl cyclase function with different calcium pools in astrocytes. Neuroreport. 1998;9:1397–401.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  97. 97.

    Li X, Peng XQ, Jordan CJ, Li J, Bi GH, He Y, et al. mGluR5 antagonism inhibits cocaine reinforcement and relapse by elevation of extracellular glutamate in the nucleus accumbens via a CB1 receptor mechanism. Sci Rep. 2018;8:3686.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  98. 98.

    Kenny PJ, Boutrel B, Gasparini F, Koob GF, Markou A. Metabotropic glutamate 5 receptor blockade may attenuate cocaine self-administration by decreasing brain reward function in rats. Psychopharmacol (Berl). 2005;179:247–54.

    CAS  Article  Google Scholar 

  99. 99.

    Paterson NE, Markou A. The metabotropic glutamate receptor 5 antagonist MPEP decreased break points for nicotine, cocaine and food in rats. Psychopharmacol (Berl). 2005;179:255–61.

    CAS  Article  Google Scholar 

  100. 100.

    Benneyworth MA, Hearing MC, Asp AJ, Madayag A, Ingebretson AE, Schmidt CE, et al. Synaptic depotentiation and mGluR5 activity in the nucleus accumbens drive cocaine-primed reinstatement of place preference. J Neurosci. 2019;39:4785–96.

    PubMed  PubMed Central  Article  Google Scholar 

  101. 101.

    Burnstock G. Purinergic nerves. Pharmacol Rev. 1972;24:509–81.

    CAS  PubMed  Google Scholar 

  102. 102.

    Hepp R, Perraut M, Chasserot-Golaz S, Galli T, Aunis D, Langley K, et al. Cultured glial cells express the SNAP-25 analogue SNAP-23. Glia. 1999;27:181–7.

    CAS  PubMed  Article  Google Scholar 

  103. 103.

    Wilhelm A, Volknandt W, Langer D, Nolte C, Kettenmann H, Zimmermann H. Localization of SNARE proteins and secretory organelle proteins in astrocytes in vitro and in situ. Neurosci Res. 2004;48:249–57.

    CAS  PubMed  Article  Google Scholar 

  104. 104.

    Koizumi S, Fujishita K, Tsuda M, Shigemoto-Mogami Y, Inoue K. Dynamic inhibition of excitatory synaptic transmission by astrocyte-derived ATP in hippocampal cultures. Proc Natl Acad Sci USA. 2003;100:11023–8.

    CAS  PubMed  Article  Google Scholar 

  105. 105.

    Guthrie PB, Knappenberger J, Segal M, Bennett MV, Charles AC, Kater SB. ATP released from astrocytes mediates glial calcium waves. J Neurosci. 1999;19:520–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  106. 106.

    Lalo U, Pankratov Y, Kirchhoff F, North RA, Verkhratsky A. NMDA receptors mediate neuron-to-glia signaling in mouse cortical astrocytes. J Neurosci. 2006;26:2673–83.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  107. 107.

    Hamilton N, Vayro S, Kirchhoff F, Verkhratsky A, Robbins J, Gorecki DC, et al. Mechanisms of ATP- and glutamate-mediated calcium signaling in white matter astrocytes. Glia. 2008;56:734–49.

    PubMed  Article  Google Scholar 

  108. 108.

    Queiroz G, Meyer DK, Meyer A, Starke K, von Kugelgen I. A study of the mechanism of the release of ATP from rat cortical astroglial cells evoked by activation of glutamate receptors. Neuroscience. 1999;91:1171–81.

    CAS  PubMed  Article  Google Scholar 

  109. 109.

    Abdipranoto A, Liu GJ, Werry EL, Bennett MR. Mechanisms of secretion of ATP from cortical astrocytes triggered by uridine triphosphate. Neuroreport. 2003;14:2177–81.

    CAS  PubMed  Article  Google Scholar 

  110. 110.

    Gourine AV, Kasymov V, Marina N, Tang F, Figueiredo MF, Lane S, et al. Astrocytes control breathing through pH-dependent release of ATP. Science. 2010;329:571–5.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  111. 111.

    Anderson CM, Bergher JP, Swanson RA. ATP-induced ATP release from astrocytes. J Neurochem. 2004;88:246–56.

    CAS  PubMed  Article  Google Scholar 

  112. 112.

    Koizumi S. Synchronization of Ca2+ oscillations: involvement of ATP release in astrocytes. FEBS J. 2010;277:286–92.

    CAS  PubMed  Article  Google Scholar 

  113. 113.

    Fellin T, Pozzan T, Carmignoto G. Purinergic receptors mediate two distinct glutamate release pathways in hippocampal astrocytes. J Biol Chem. 2006;281:4274–84.

    CAS  PubMed  Article  Google Scholar 

  114. 114.

    Zimmermann H, Braun N. Extracellular metabolism of nucleotides in the nervous system. J Auton Pharm. 1996;16:397–400.

    CAS  Article  Google Scholar 

  115. 115.

    Deng Q, Terunuma M, Fellin T, Moss SJ, Haydon PG. Astrocytic activation of A1 receptors regulates the surface expression of NMDA receptors through a Src kinase dependent pathway. Glia. 2011;59:1084–93.

    PubMed  PubMed Central  Article  Google Scholar 

  116. 116.

    Nutt DJ, Lingford-Hughes A, Erritzoe D, Stokes PR. The dopamine theory of addiction: 40 years of highs and lows. Nat Rev Neurosci. 2015;16:305–12.

    CAS  PubMed  Article  Google Scholar 

  117. 117.

    Del Campo N, Chamberlain SR, Sahakian BJ, Robbins TW. The roles of dopamine and noradrenaline in the pathophysiology and treatment of attention-deficit/hyperactivity disorder. Biol Psychiatry. 2011;69:e145–57.

    PubMed  Article  CAS  Google Scholar 

  118. 118.

    Tye KM, Mirzabekov JJ, Warden MR, Ferenczi EA, Tsai HC, Finkelstein J, et al. Dopamine neurons modulate neural encoding and expression of depression-related behaviour. Nature. 2013;493:537–41.

    CAS  PubMed  Article  Google Scholar 

  119. 119.

    Howes OD, Kambeitz J, Kim E, Stahl D, Slifstein M, Abi-Dargham A, et al. The nature of dopamine dysfunction in schizophrenia and what this means for treatment. Arch Gen psychiatry. 2012;69:776–86.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  120. 120.

    Beaulieu JM, Gainetdinov RR. The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol Rev. 2011;63:182–217.

    CAS  PubMed  Article  Google Scholar 

  121. 121.

    Karakaya S, Kipp M, Beyer C. Oestrogen regulates the expression and function of dopamine transporters in astrocytes of the nigrostriatal system. J Neuroendocrinol. 2007;19:682–90.

    CAS  PubMed  Article  Google Scholar 

  122. 122.

    Zanassi P, Paolillo M, Montecucco A, Avvedimento EV, Schinelli S. Pharmacological and molecular evidence for dopamine D(1) receptor expression by striatal astrocytes in culture. J Neurosci Res. 1999;58:544–52.

    CAS  PubMed  Article  Google Scholar 

  123. 123.

    Khan ZU, Koulen P, Rubinstein M, Grandy DK, Goldman-Rakic PS. An astroglia-linked dopamine D2-receptor action in prefrontal cortex. Proc Natl Acad Sci USA. 2001;98:1964–9.

    CAS  PubMed  Article  Google Scholar 

  124. 124.

    Shao W, Zhang SZ, Tang M, Zhang XH, Zhou Z, Yin YQ, et al. Suppression of neuroinflammation by astrocytic dopamine D2 receptors via alphaB-crystallin. Nature. 2013;494:90–94.

    CAS  PubMed  Article  Google Scholar 

  125. 125.

    Requardt RP, Hirrlinger PG, Wilhelm F, Winkler U, Besser S, Hirrlinger J. Ca(2)(+) signals of astrocytes are modulated by the NAD(+)/NADH redox state. J Neurochem. 2012;120:1014–25.

    CAS  PubMed  Google Scholar 

  126. 126.

    Fischer T, Scheffler P, Lohr C. Dopamine-induced calcium signaling in olfactory bulb astrocytes. Sci Rep. 2020;10:631.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  127. 127.

    Kebabian JW, Petzold GL, Greengard P. Dopamine-sensitive adenylate cyclase in caudate nucleus of rat brain, and its similarity to the “dopamine receptor”. Proc Natl Acad Sci USA. 1972;69:2145–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  128. 128.

    Miller RJ, Horn AS, Iversen LL. The action of neuroleptic drugs on dopamine-stimulated adenosine cyclic 3’,5’-monophosphate production in rat neostriatum and limbic forebrain. Mol Pharmacol. 1974;10:759–66.

    CAS  Google Scholar 

  129. 129.

    Galloway A, Adeluyi A, O’Donovan B, Fisher ML, Rao CN, Critchfield P, et al. Dopamine triggers CTCF-dependent morphological and genomic remodeling of astrocytes. J Neurosci. 2018;38:4846–58.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  130. 130.

    Jennings A, Tyurikova O, Bard L, Zheng K, Semyanov A, Henneberger C, et al. Dopamine elevates and lowers astroglial Ca(2+) through distinct pathways depending on local synaptic circuitry. Glia. 2017;65:447–59.

    PubMed  Article  Google Scholar 

  131. 131.

    Inazu M, Kubota N, Takeda H, Zhang J, Kiuchi Y, Oguchi K, et al. Pharmacological characterization of dopamine transport in cultured rat astrocytes. Life Sci. 1999;64:2239–45.

    CAS  PubMed  Article  Google Scholar 

  132. 132.

    Pelton EW II, Kimelberg HK, Shipherd SV, Bourke RS. Dopamine and norepinephrine uptake and metabolism by astroglial cells in culture. Life Sci. 1981;28:1655–63.

    CAS  PubMed  Article  Google Scholar 

  133. 133.

    Asanuma M, Miyazaki I, Murakami S, Diaz-Corrales FJ, Ogawa N. Striatal astrocytes act as a reservoir for L-DOPA. PloS One. 2014;9:e106362.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  134. 134.

    Schomig E, Russ H, Staudt K, Martel F, Gliese M, Grundemann D. The extraneuronal monoamine transporter exists in human central nervous system glia. Adv Pharm. 1998;42:356–9.

    CAS  Article  Google Scholar 

  135. 135.

    Vaarmann A, Gandhi S, Abramov AY. Dopamine induces Ca2+ signaling in astrocytes through reactive oxygen species generated by monoamine oxidase. J Biol Chem. 2010;285:25018–23.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  136. 136.

    Zhang Y, Sloan SA, Clarke LE, Caneda C, Plaza CA, Blumenthal PD, et al. Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse. Neuron. 2016;89:37–53.

    CAS  PubMed  Article  Google Scholar 

  137. 137.

    Petrelli F, Dallerac G, Pucci L, Cali C, Zehnder T, Sultan S, et al. Dysfunction of homeostatic control of dopamine by astrocytes in the developing prefrontal cortex leads to cognitive impairments. Mol Psychiatry. 2020;25:732–49.

    CAS  PubMed  Article  Google Scholar 

  138. 138.

    Bliss TV, Lomo T. Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J Physiol. 1973;232:331–56.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  139. 139.

    Hebb DO. The organization of behavior: a neuropsychological theory. New York, NY: Wiley, 1949.

  140. 140.

    Lichtman JW, Purves D. Activity-mediated neural change. Nature. 1983;301:563.

    CAS  PubMed  Article  Google Scholar 

  141. 141.

    Morris RG, Anderson E, Lynch GS, Baudry M. Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5. Nature. 1986;319:774–6.

    CAS  PubMed  Article  Google Scholar 

  142. 142.

    Cajal SRY. Estructura de los centros nerviosos de las aves. Rev Trim Histol Norm Patol. 1888;1–10.

  143. 143.

    Lushnikova I, Skibo G, Muller D, Nikonenko I. Synaptic potentiation induces increased glial coverage of excitatory synapses in CA1 hippocampus. Hippocampus. 2009;19:753–62.

    PubMed  Article  Google Scholar 

  144. 144.

    Perea G, Araque A. Astrocytes potentiate transmitter release at single hippocampal synapses. Science. 2007;317:1083–6.

    CAS  PubMed  Article  Google Scholar 

  145. 145.

    Henneberger C, Bard L, Panatier A, Reynolds JP, Kopach O, Medvedev NI et al. LTP Induction Boosts Glutamate Spillover by Driving Withdrawal of Perisynaptic Astroglia. Neuron 2020;108:919–36.e911.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  146. 146.

    Masuoka T, Ikeda R, Konishi S. Persistent activation of histamine H1 receptors in the hippocampal CA1 region enhances NMDA receptor-mediated synaptic excitation and long-term potentiation in astrocyte- and D-serine-dependent manner. Neuropharmacology. 2019;151:64–73.

    CAS  PubMed  Article  Google Scholar 

  147. 147.

    Min R, Nevian T. Astrocyte signaling controls spike timing-dependent depression at neocortical synapses. Nat Neurosci. 2012;15:746–53.

    CAS  PubMed  Article  Google Scholar 

  148. 148.

    Ichtchenko K, Hata Y, Nguyen T, Ullrich B, Missler M, Moomaw C, et al. Neuroligin 1: a splice site-specific ligand for beta-neurexins. Cell. 1995;81:435–43.

    CAS  PubMed  Article  Google Scholar 

  149. 149.

    Song JY, Ichtchenko K, Sudhof TC, Brose N. Neuroligin 1 is a postsynaptic cell-adhesion molecule of excitatory synapses. Proc Natl Acad Sci USA. 1999;96:1100–5.

    CAS  PubMed  Article  Google Scholar 

  150. 150.

    Ullian EM, Christopherson KS, Barres BA. Role for glia in synaptogenesis. Glia. 2004;47:209–16.

    PubMed  Article  Google Scholar 

  151. 151.

    Miller FD, Gauthier AS. Timing is everything: making neurons versus glia in the developing cortex. Neuron. 2007;54:357–69.

    CAS  PubMed  Article  Google Scholar 

  152. 152.

    Gotz M, Barde YA. Radial glial cells defined and major intermediates between embryonic stem cells and CNS neurons. Neuron. 2005;46:369–72.

    PubMed  Article  CAS  Google Scholar 

  153. 153.

    Bayer SA, Altman J. Neocortical development. New York, Raven Press; 1991.

  154. 154.

    Allen NJ, Eroglu C. Cell biology of astrocyte-synapse interactions. Neuron. 2017;96:697–708.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  155. 155.

    Ullian EM, Sapperstein SK, Christopherson KS, Barres BA. Control of synapse number by glia. Science. 2001;291:657–61.

    CAS  PubMed  Article  Google Scholar 

  156. 156.

    Pfrieger FW, Barres BA. Synaptic efficacy enhanced by glial cells in vitro. Science. 1997;277:1684–7.

    CAS  PubMed  Article  Google Scholar 

  157. 157.

    Christopherson KS, Ullian EM, Stokes CC, Mullowney CE, Hell JW, Agah A, et al. Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell. 2005;120:421–33.

    CAS  PubMed  Article  Google Scholar 

  158. 158.

    Stellwagen D, Beattie EC, Seo JY, Malenka RC. Differential regulation of AMPA receptor and GABA receptor trafficking by tumor necrosis factor-alpha. J Neurosci. 2005;25:3219–28.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  159. 159.

    Kucukdereli H, Allen NJ, Lee AT, Feng A, Ozlu MI, Conatser LM, et al. Control of excitatory CNS synaptogenesis by astrocyte-secreted proteins Hevin and SPARC. Proc Natl Acad Sci USA. 2011;108:E440–449.

    CAS  PubMed  Article  Google Scholar 

  160. 160.

    Allen NJ, Bennett ML, Foo LC, Wang GX, Chakraborty C, Smith SJ, et al. Astrocyte glypicans 4 and 6 promote formation of excitatory synapses via GluA1 AMPA receptors. Nature. 2012;486:410–4.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  161. 161.

    Nagler K, Mauch DH, Pfrieger FW. Glia-derived signals induce synapse formation in neurones of the rat central nervous system. J Physiol. 2001;533(Pt 3):665–79.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  162. 162.

    Eroglu C, Allen NJ, Susman MW, O’Rourke NA, Park CY, Ozkan E, et al. Gabapentin receptor alpha2delta-1 is a neuronal thrombospondin receptor responsible for excitatory CNS synaptogenesis. Cell. 2009;139:380–92.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  163. 163.

    Adams JC. Thrombospondins: multifunctional regulators of cell interactions. Annu Rev Cell Dev Biol. 2001;17:25–51.

    CAS  PubMed  Article  Google Scholar 

  164. 164.

    Bornstein P, Agah A, Kyriakides TR. The role of thrombospondins 1 and 2 in the regulation of cell-matrix interactions, collagen fibril formation, and the response to injury. Int J Biochem Cell Biol. 2004;36:1115–25.

    CAS  PubMed  Article  Google Scholar 

  165. 165.

    Liao D, Hessler NA, Malinow R. Activation of postsynaptically silent synapses during pairing-induced LTP in CA1 region of hippocampal slice. Nature. 1995;375:400–4.

    CAS  PubMed  Article  Google Scholar 

  166. 166.

    Isaac JT, Nicoll RA, Malenka RC. Evidence for silent synapses: implications for the expression of LTP. Neuron. 1995;15:427–34.

    CAS  PubMed  Article  Google Scholar 

  167. 167.

    Ashby MC, Isaac JT. Maturation of a recurrent excitatory neocortical circuit by experience-dependent unsilencing of newly formed dendritic spines. Neuron. 2011;70:510–21.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  168. 168.

    Isaac JT, Crair MC, Nicoll RA, Malenka RC. Silent synapses during development of thalamocortical inputs. Neuron. 1997;18:269–80.

    CAS  PubMed  Article  Google Scholar 

  169. 169.

    Dolphin AC. Calcium channel auxiliary alpha2delta and beta subunits: trafficking and one step beyond. Nat Rev Neurosci. 2012;13:542–55.

    CAS  PubMed  Article  Google Scholar 

  170. 170.

    Dolphin AC. Voltage-gated calcium channels and their auxiliary subunits: physiology and pathophysiology and pharmacology. J Physiol. 2016;594:5369–90.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  171. 171.

    Dolphin AC, Lee A. Presynaptic calcium channels: specialized control of synaptic neurotransmitter release. Nat Rev Neurosci. 2020;21:213–29.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  172. 172.

    Brown JP, Gee NS. Cloning and deletion mutagenesis of the alpha2 delta calcium channel subunit from porcine cerebral cortex. Expression of a soluble form of the protein that retains [3H]gabapentin binding activity. J Biol Chem. 1998;273:25458–65.

    CAS  PubMed  Article  Google Scholar 

  173. 173.

    Dooley DJ, Taylor CP, Donevan S, Feltner D. Ca2+ channel alpha2delta ligands: novel modulators of neurotransmission. Trends Pharm Sci. 2007;28:75–82.

    CAS  PubMed  Article  Google Scholar 

  174. 174.

    van Hooft JA, Dougherty JJ, Endeman D, Nichols RA, Wadman WJ. Gabapentin inhibits presynaptic Ca(2+) influx and synaptic transmission in rat hippocampus and neocortex. Eur J Pharmacol. 2002;449:221–8.

    PubMed  Article  Google Scholar 

  175. 175.

    Risher WC, Eroglu C. Thrombospondins as key regulators of synaptogenesis in the central nervous system. Matrix Biol. 2012;31:170–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  176. 176.

    Risher WC, Kim N, Koh S, Choi JE, Mitev P, Spence EF, et al. Thrombospondin receptor alpha2delta-1 promotes synaptogenesis and spinogenesis via postsynaptic Rac1. J cell Biol. 2018;217:3747–65.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  177. 177.

    Dietz DM, Sun H, Lobo MK, Cahill ME, Chadwick B, Gao V, et al. Rac1 is essential in cocaine-induced structural plasticity of nucleus accumbens neurons. Nat Neurosci. 2012;15:891–6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  178. 178.

    Wright WJ, Graziane NM, Neumann PA, Hamilton PJ, Cates HM, Fuerst L, et al. Silent synapses dictate cocaine memory destabilization and reconsolidation. Nat Neurosci. 2020;23:32–46.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  179. 179.

    Xu J, Xiao N, Xia J. Thrombospondin 1 accelerates synaptogenesis in hippocampal neurons through neuroligin 1. Nat Neurosci. 2010;13:22–24.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  180. 180.

    Singh SK, Stogsdill JA, Pulimood NS, Dingsdale H, Kim YH, Pilaz LJ, et al. Astrocytes assemble thalamocortical synapses by bridging NRX1alpha and NL1 via Hevin. Cell. 2016;164:183–96.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  181. 181.

    Takano T, Wallace JT, Baldwin KT, Purkey AM, Uezu A, Courtland JL et al. Chemico-genetic discovery of astrocytic control of inhibition in vivo. Nature 2020;588:296–302.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  182. 182.

    Bosworth AP, Allen NJ. The diverse actions of astrocytes during synaptic development. Curr Opin Neurobiol. 2017;47:38–43.

    CAS  PubMed  Article  Google Scholar 

  183. 183.

    Jung YJ, Chung WS. Phagocytic roles of glial cells in healthy and diseased brains. Biomol Ther (Seoul). 2018;26:350–7.

    CAS  Article  Google Scholar 

  184. 184.

    Chung WS, Clarke LE, Wang GX, Stafford BK, Sher A, Chakraborty C, et al. Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways. Nature. 2013;504:394–400.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  185. 185.

    Tung TT, Nagaosa K, Fujita Y, Kita A, Mori H, Okada R, et al. Phosphatidylserine recognition and induction of apoptotic cell clearance by Drosophila engulfment receptor Draper. J Biochem. 2013;153:483–91.

    CAS  PubMed  Article  Google Scholar 

  186. 186.

    Lee JH, Kim JY, Noh S, Lee H, Lee SY, Mun JY et al. Astrocytes phagocytose adult hippocampal synapses for circuit homeostasis. Nature 2021;590:612–7.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  187. 187.

    Bialas AR, Stevens B. TGF-beta signaling regulates neuronal C1q expression and developmental synaptic refinement. Nat Neurosci. 2013;16:1773–82.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  188. 188.

    Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R, et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron. 2012;74:691–705.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  189. 189.

    Chung WS, Allen NJ, Eroglu C. Astrocytes control synapse formation, function, and elimination. Cold Spring Harb Perspect Biol. 2015;7:a020370.

    PubMed  PubMed Central  Article  Google Scholar 

  190. 190.

    Schultz W. Predictive reward signal of dopamine neurons. J Neurophysiol. 1998;80:1–27.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  191. 191.

    Fiorino DF, Coury A, Fibiger HC, Phillips AG. Electrical stimulation of reward sites in the ventral tegmental area increases dopamine transmission in the nucleus accumbens of the rat. Behav Brain Res. 1993;55:131–41.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  192. 192.

    Solinas M, Ferre S, You ZB, Karcz-Kubicha M, Popoli P, Goldberg SR. Caffeine induces dopamine and glutamate release in the shell of the nucleus accumbens. J Neurosci. 2002;22:6321–4.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  193. 193.

    Pontieri FE, Tanda G, Di Chiara G. Intravenous cocaine, morphine, and amphetamine preferentially increase extracellular dopamine in the “shell” as compared with the “core” of the rat nucleus accumbens. Proc Natl Acad Sci USA. 1995;92:12304–8.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  194. 194.

    Wise RA, Bozarth MA. A psychomotor stimulant theory of addiction. Psychological Rev. 1987;94:469–92.

    CAS  Article  Google Scholar 

  195. 195.

    Weiss F, Markou A, Lorang MT, Koob GF. Basal extracellular dopamine levels in the nucleus accumbens are decreased during cocaine withdrawal after unlimited-access self-administration. Brain Res. 1992;593:314–8.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  196. 196.

    Gerrits MA, Petromilli P, Westenberg HG, Di Chiara G, van Ree JM. Decrease in basal dopamine levels in the nucleus accumbens shell during daily drug-seeking behaviour in rats. Brain Res. 2002;924:141–50.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  197. 197.

    Parsons LH, Smith AD, Justice JB Jr. Basal extracellular dopamine is decreased in the rat nucleus accumbens during abstinence from chronic cocaine. Synapse. 1991;9:60–5.

    CAS  PubMed  Article  Google Scholar 

  198. 198.

    Robertson MW, Leslie CA, Bennett JP Jr. Apparent synaptic dopamine deficiency induced by withdrawal from chronic cocaine treatment. Brain Res. 1991;538:337–9.

    CAS  PubMed  Article  Google Scholar 

  199. 199.

    Fontana DJ, Post RM, Pert A. Conditioned increases in mesolimbic dopamine overflow by stimuli associated with cocaine. Brain Res. 1993;629:31–39.

    CAS  PubMed  Article  Google Scholar 

  200. 200.

    Di Ciano P, Blaha CD, Phillips AG. Conditioned changes in dopamine oxidation currents in the nucleus accumbens of rats by stimuli paired with self-administration or yoked-administration of d-amphetamine. Eur J Neurosci. 1998;10:1121–7.

    PubMed  Article  Google Scholar 

  201. 201.

    Duvauchelle CL, Ikegami A, Asami S, Robens J, Kressin K, Castaneda E. Effects of cocaine context on NAcc dopamine and behavioral activity after repeated intravenous cocaine administration. Brain Res. 2000;862:49–58.

    CAS  PubMed  Article  Google Scholar 

  202. 202.

    Weiss F, Maldonado-Vlaar CS, Parsons LH, Kerr TM, Smith DL, Ben-Shahar O. Control of cocaine-seeking behavior by drug-associated stimuli in rats: effects on recovery of extinguished operant-responding and extracellular dopamine levels in amygdala and nucleus accumbens. Proc Natl Acad Sci USA. 2000;97:4321–6.

    CAS  PubMed  Article  Google Scholar 

  203. 203.

    Ito R, Dalley JW, Howes SR, Robbins TW, Everitt BJ. Dissociation in conditioned dopamine release in the nucleus accumbens core and shell in response to cocaine cues and during cocaine-seeking behavior in rats. J Neurosci. 2000;20:7489–95.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  204. 204.

    Neisewander JL, O’Dell LE, Tran-Nguyen LT, Castaneda E, Fuchs RA. Dopamine overflow in the nucleus accumbens during extinction and reinstatement of cocaine self-administration behavior. Neuropsychopharmacology. 1996;15:506–14.

    CAS  PubMed  Article  Google Scholar 

  205. 205.

    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. e1035.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  206. 206.

    Pan HT, Menacherry S, Justice JB Jr. Differences in the pharmacokinetics of cocaine in naive and cocaine-experienced rats. J Neurochem. 1991;56:1299–306.

    CAS  PubMed  Article  Google Scholar 

  207. 207.

    Pettit HO, Pan HT, Parsons LH, Justice JB Jr. Extracellular concentrations of cocaine and dopamine are enhanced during chronic cocaine administration. J Neurochem. 1990;55:798–804.

    CAS  PubMed  Article  Google Scholar 

  208. 208.

    Wang J, Li KL, Shukla A, Beroun A, Ishikawa M, Huang X, et al. Cocaine triggers astrocyte-mediated synaptogenesis. Biol Psychiatry. 2021;89:386–97.

    CAS  PubMed  Article  Google Scholar 

  209. 209.

    Xin W, Schuebel KE, Jair KW, Cimbro R, De Biase LM, Goldman D, et al. Ventral midbrain astrocytes display unique physiological features and sensitivity to dopamine D2 receptor signaling. Neuropsychopharmacology. 2019;44:344–55.

    CAS  PubMed  Article  Google Scholar 

  210. 210.

    Sanz E, Yang L, Su T, Morris DR, McKnight GS, Amieux PS. Cell-type-specific isolation of ribosome-associated mRNA from complex tissues. Proc Natl Acad Sci USA. 2009;106:13939–44.

    CAS  PubMed  Article  Google Scholar 

  211. 211.

    Jiang R, Diaz-Castro B, Looger LL, Khakh BS. Dysfunctional calcium and glutamate signaling in striatal astrocytes from huntington’s disease model mice. J Neurosci. 2016;36:3453–70.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  212. 212.

    Tong X, Ao Y, Faas GC, Nwaobi SE, Xu J, Haustein MD, et al. Astrocyte Kir4.1 ion channel deficits contribute to neuronal dysfunction in Huntington’s disease model mice. Nat Neurosci. 2014;17:694–703.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  213. 213.

    Adermark L, Lovinger DM. Electrophysiological properties and gap junction coupling of striatal astrocytes. Neurochemistry Int. 2008;52:1365–72.

    CAS  Article  Google Scholar 

  214. 214.

    Kemp JM, Powell TP. The connexions of the striatum and globus pallidus: synthesis and speculation. Philos Trans R Soc Lond Ser B Biol Sci. 1971;262:441–57.

    CAS  Google Scholar 

  215. 215.

    Salgado S, Kaplitt MG. The nucleus accumbens: a comprehensive review. Stereotact Funct Neurosurg. 2015;93:75–93.

    PubMed  PubMed Central  Article  Google Scholar 

  216. 216.

    Martin R, Bajo-Graneras R, Moratalla R, Perea G, Araque A. Circuit-specific signaling in astrocyte-neuron networks in basal ganglia pathways. Science. 2015;349:730–4.

    CAS  PubMed  Article  Google Scholar 

  217. 217.

    Graziane NM, Sun S, Wright WJ, Jang D, Liu Z, Huang YH, et al. Opposing mechanisms mediate morphine- and cocaine-induced generation of silent synapses. Nat Neurosci. 2016;19:915–25.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  218. 218.

    Knackstedt LA, Moussawi K, Lalumiere R, Schwendt M, Klugmann M, Kalivas PW. Extinction training after cocaine self-administration induces glutamatergic plasticity to inhibit cocaine seeking. J Neurosci. 2010;30:7984–92.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  219. 219.

    Ghasemzadeh MB, Vasudevan P, Mueller C, Seubert C, Mantsch JR. Neuroadaptations in the cellular and postsynaptic group 1 metabotropic glutamate receptor mGluR5 and Homer proteins following extinction of cocaine self-administration. Neurosci Lett. 2009;452:167–71.

    CAS  PubMed  Article  Google Scholar 

  220. 220.

    Ghasemzadeh MB, Vasudevan P, Mueller CR, Seubert C, Mantsch JR. Region-specific alterations in glutamate receptor expression and subcellular distribution following extinction of cocaine self-administration. Brain Res. 2009;1267:89–102.

    CAS  PubMed  Article  Google Scholar 

  221. 221.

    Ebner SR, Larson EB, Hearing MC, Ingebretson AE, Thomas MJ. Extinction and reinstatement of cocaine-seeking in self-administering mice is associated with bidirectional AMPAR-mediated plasticity in the nucleus accumbens shell. Neuroscience. 2018;384:340–9.

    CAS  PubMed  Article  Google Scholar 

  222. 222.

    Sutton MA, Schmidt EF, Choi KH, Schad CA, Whisler K, Simmons D, et al. Extinction-induced upregulation in AMPA receptors reduces cocaine-seeking behaviour. Nature. 2003;421:70–75.

    CAS  PubMed  Article  Google Scholar 

  223. 223.

    Scofield MD, Li H, Siemsen BM, Healey KL, Tran PK, Woronoff N, et al. Cocaine self-administration and extinction leads to reduced glial fibrillary acidic protein expression and morphometric features of astrocytes in the nucleus accumbens core. Biol Psychiatry. 2016;80:207–15.

    CAS  PubMed  Article  Google Scholar 

  224. 224.

    Testen A, Sepulveda-Orengo MT, Gaines CH, Reissner KJ. Region-specific reductions in morphometric properties and synaptic colocalization of astrocytes following cocaine self-administration and extinction. Front Cell Neurosci. 2018;12:246.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  225. 225.

    Siemsen BM, Reichel CM, Leong KC, Garcia-Keller C, Gipson CD, Spencer S, et al. Effects of methamphetamine self-administration and extinction on astrocyte structure and function in the nucleus accumbens core. Neuroscience. 2019;406:528–41.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  226. 226.

    Kruyer A, Scofield MD, Wood D, Reissner KJ, Kalivas PW. Heroin cue-evoked astrocytic structural plasticity at nucleus accumbens synapses inhibits heroin seeking. Biol Psychiatry. 2019;86:811–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  227. 227.

    Scofield MD, Boger HA, Smith RJ, Li H, Haydon PG, Kalivas PW. Gq-DREADD selectively initiates glial glutamate release and inhibits cue-induced cocaine seeking. Biol Psychiatry. 2015;78:441–51.

    CAS  PubMed  Article  Google Scholar 

  228. 228.

    Le Merrer J, Becker JA, Befort K, Kieffer BL. Reward processing by the opioid system in the brain. Physiol Rev. 2009;89:1379–412.

    PubMed  PubMed Central  Article  Google Scholar 

  229. 229.

    Nam MH, Han KS, Lee J, Bae JY, An H, Park S, et al. Expression of micro-opioid receptor in CA1 hippocampal astrocytes. Exp Neurobiol. 2018;27:120–8.

    PubMed  PubMed Central  Article  Google Scholar 

  230. 230.

    Corkrum M, Rothwell PE, Thomas MJ, Kofuji P, Araque A. Opioid-Mediated Astrocyte-Neuron Signaling in the Nucleus Accumbens. Cells 2019;8:586–97.

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  231. 231.

    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  Article  Google Scholar 

  232. 232.

    McFarland K, Lapish CC, Kalivas PW. Prefrontal glutamate release into the core of the nucleus accumbens mediates cocaine-induced reinstatement of drug-seeking behavior. J Neurosci. 2003;23:3531–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  233. 233.

    Kalivas PW, Volkow N, Seamans J. Unmanageable motivation in addiction: a pathology in prefrontal-accumbens glutamate transmission. Neuron. 2005;45:647–50.

    CAS  PubMed  Article  Google Scholar 

  234. 234.

    Ma YY, Lee BR, Wang X, Guo C, Liu L, Cui R, et al. Bidirectional modulation of incubation of cocaine craving by silent synapse-based remodeling of prefrontal cortex to accumbens projections. Neuron. 2014;83:1453–67.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  235. 235.

    Kalivas PW. The glutamate homeostasis hypothesis of addiction. Nat Rev Neurosci. 2009;10:561–72.

    CAS  PubMed  Article  Google Scholar 

  236. 236.

    Danbolt NC. Glutamate uptake. Prog Neurobiol. 2001;65:1–105.

    CAS  PubMed  Article  Google Scholar 

  237. 237.

    Bergles DE, Jahr CE. Synaptic activation of glutamate transporters in hippocampal astrocytes. Neuron. 1997;19:1297–308.

    CAS  PubMed  Article  Google Scholar 

  238. 238.

    Bergles DE, Jahr CE. Glial contribution to glutamate uptake at Schaffer collateral-commissural synapses in the hippocampus. J Neurosci. 1998;18:7709–16.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  239. 239.

    Rothstein JD, Dykes-Hoberg M, Pardo CA, Bristol LA, Jin L, Kuncl RW, et al. Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron. 1996;16:675–86.

    CAS  PubMed  Article  Google Scholar 

  240. 240.

    Tanaka K, Watase K, Manabe T, Yamada K, Watanabe M, Takahashi K, et al. Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1. Science. 1997;276:1699–702.

    CAS  PubMed  Article  Google Scholar 

  241. 241.

    Lehre KP, Danbolt NC. The number of glutamate transporter subtype molecules at glutamatergic synapses: chemical and stereological quantification in young adult rat brain. J Neurosci. 1998;18:8751–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  242. 242.

    Reissner KJ, Gipson CD, Tran PK, Knackstedt LA, Scofield MD, Kalivas PW. Glutamate transporter GLT-1 mediates N-acetylcysteine inhibition of cocaine reinstatement. Addiction Biol. 2015;20:316–23.

    CAS  Article  Google Scholar 

  243. 243.

    Roberts-Wolfe DJ, Kalivas PW. Glutamate transporter GLT-1 as a therapeutic target for substance use disorders. CNS Neurol Disord Drug Targets. 2015;14:745–56.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  244. 244.

    Piet R, Vargova L, Sykova E, Poulain DA, Oliet SH. Physiological contribution of the astrocytic environment of neurons to intersynaptic crosstalk. Proc Natl Acad Sci USA. 2004;101:2151–5.

    CAS  PubMed  Article  Google Scholar 

  245. 245.

    Mitchell SJ, Silver RA. Glutamate spillover suppresses inhibition by activating presynaptic mGluRs. Nature. 2000;404:498–502.

    CAS  PubMed  Article  Google Scholar 

  246. 246.

    Vogt KE, Nicoll RA. Glutamate and gamma-aminobutyric acid mediate a heterosynaptic depression at mossy fiber synapses in the hippocampus. Proc Natl Acad Sci USA. 1999;96:1118–22.

    CAS  PubMed  Article  Google Scholar 

  247. 247.

    Min MY, Melyan Z, Kullmann DM. Synaptically released glutamate reduces gamma-aminobutyric acid (GABA)ergic inhibition in the hippocampus via kainate receptors. Proc Natl Acad Sci USA. 1999;96:9932–7.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  248. 248.

    LaLumiere RT, Kalivas PW. Glutamate release in the nucleus accumbens core is necessary for heroin seeking. J Neurosci. 2008;28:3170–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  249. 249.

    Boudreau AC, Reimers JM, Milovanovic M, Wolf ME. Cell surface AMPA receptors in the rat nucleus accumbens increase during cocaine withdrawal but internalize after cocaine challenge in association with altered activation of mitogen-activated protein kinases. J Neurosci. 2007;27:10621–35.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  250. 250.

    McCutcheon JE, Wang X, Tseng KY, Wolf ME, Marinelli M. Calcium-permeable AMPA receptors are present in nucleus accumbens synapses after prolonged withdrawal from cocaine self-administration but not experimenter-administered cocaine. J Neurosci. 2011;31:5737–43.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  251. 251.

    Smith ACW, Scofield MD, Heinsbroek JA, Gipson CD, Neuhofer D, Roberts-Wolfe DJ, et al. Accumbens nNOS interneurons regulate cocaine relapse. J Neurosci. 2017;37:742–56.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  252. 252.

    Chalifoux JR, Carter AG. Glutamate spillover promotes the generation of NMDA spikes. J Neurosci. 2011;31:16435–46.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  253. 253.

    Knackstedt LA, Melendez RI, Kalivas PW. Ceftriaxone restores glutamate homeostasis and prevents relapse to cocaine seeking. Biol Psychiatry. 2010;67:81–84.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  254. 254.

    Reissner KJ, Brown RM, Spencer S, Tran PK, Thomas CA, Kalivas PW. Chronic administration of the methylxanthine propentofylline impairs reinstatement to cocaine by a GLT-1-dependent mechanism. Neuropsychopharmacology. 2014;39:499–506.

    CAS  PubMed  Article  Google Scholar 

  255. 255.

    Baker DA, Xi ZX, Shen H, Swanson CJ, Kalivas PW. The origin and neuronal function of in vivo nonsynaptic glutamate. J Neurosci. 2002;22:9134–41.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  256. 256.

    Bridges RJ, Natale NR, Patel SA. System xc(-) cystine/glutamate antiporter: an update on molecular pharmacology and roles within the CNS. Br J Pharm. 2012;165:20–34.

    CAS  Article  Google Scholar 

  257. 257.

    Madayag A, Lobner D, Kau KS, Mantsch JR, Abdulhameed O, Hearing M, et al. Repeated N-acetylcysteine administration alters plasticity-dependent effects of cocaine. J Neurosci. 2007;27:13968–76.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  258. 258.

    Miguens M, Del Olmo N, Higuera-Matas A, Torres I, Garcia-Lecumberri C, Ambrosio E. Glutamate and aspartate levels in the nucleus accumbens during cocaine self-administration and extinction: a time course microdialysis study. Psychopharmacol (Berl). 2008;196:303–13.

    CAS  Article  Google Scholar 

  259. 259.

    Knackstedt LA, LaRowe S, Mardikian P, Malcolm R, Upadhyaya H, Hedden S, et al. The role of cystine-glutamate exchange in nicotine dependence in rats and humans. Biol Psychiatry. 2009;65:841–5.

    CAS  PubMed  Article  Google Scholar 

  260. 260.

    Kupferschmidt DA, Lovinger DM. Inhibition of presynaptic calcium transients in cortical inputs to the dorsolateral striatum by metabotropic GABA(B) and mGlu2/3 receptors. J Physiol. 2015;593:2295–310.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  261. 261.

    Moran MM, McFarland K, Melendez RI, Kalivas PW, Seamans JK. Cystine/glutamate exchange regulates metabotropic glutamate receptor presynaptic inhibition of excitatory transmission and vulnerability to cocaine seeking. J Neurosci. 2005;25:6389–93.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  262. 262.

    Moussawi K, Pacchioni A, Moran M, Olive MF, Gass JT, Lavin A, et al. N-Acetylcysteine reverses cocaine-induced metaplasticity. Nat Neurosci. 2009;12:182–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  263. 263.

    Ducret E, Puaud M, Lacoste J, Belin-Rauscent A, Fouyssac M, Dugast E, et al. N-acetylcysteine facilitates self-imposed abstinence after escalation of cocaine intake. Biol Psychiatry. 2016;80:226–34.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  264. 264.

    LaRowe SD, Kalivas PW, Nicholas JS, Randall PK, Mardikian PN, Malcolm RJ. A double-blind placebo-controlled trial of N-acetylcysteine in the treatment of cocaine dependence. Am J Addict. 2013;22:443–52.

    PubMed  PubMed Central  Article  Google Scholar 

  265. 265.

    Back SE, McCauley JL, Korte KJ, Gros DF, Leavitt V, Gray KM, et al. A double-blind, randomized, controlled pilot trial of N-acetylcysteine in veterans with posttraumatic stress disorder and substance use disorders. J Clin psychiatry. 2016;77:e1439–46.

    PubMed  PubMed Central  Article  Google Scholar 

  266. 266.

    Back SE, Gray K, Santa Ana E, Jones JL, Jarnecke AM, Joseph JE, et al. N-acetylcysteine for the treatment of comorbid alcohol use disorder and posttraumatic stress disorder: design and methodology of a randomized clinical trial. Contemp Clin Trials. 2020;91:105961.

    PubMed  PubMed Central  Article  Google Scholar 

  267. 267.

    Xi ZX, Baker DA, Shen H, Carson DS, Kalivas PW. Group II metabotropic glutamate receptors modulate extracellular glutamate in the nucleus accumbens. J Pharm Exp Ther. 2002;300:162–71.

    CAS  Article  Google Scholar 

  268. 268.

    Hu G, Duffy P, Swanson C, Ghasemzadeh MB, Kalivas PW. The regulation of dopamine transmission by metabotropic glutamate receptors. J Pharm Exp Ther. 1999;289:412–6.

    CAS  Google Scholar 

  269. 269.

    Di Castro MA, Chuquet J, Liaudet N, Bhaukaurally K, Santello M, Bouvier D, et al. Local Ca2+ detection and modulation of synaptic release by astrocytes. Nat Neurosci. 2011;14:1276–84.

    PubMed  Article  CAS  Google Scholar 

  270. 270.

    Rusakov DA, Bard L, Stewart MG, Henneberger C. Diversity of astroglial functions alludes to subcellular specialisation. Trends Neurosci. 2014;37:228–42.

    CAS  PubMed  Article  Google Scholar 

  271. 271.

    Scofield MD, Heinsbroek JA, Gipson CD, Kupchik YM, Spencer S, Smith AC, et al. The nucleus accumbens: mechanisms of addiction across drug classes reflect the importance of glutamate homeostasis. Pharmacol Rev. 2016;68:816–71.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  272. 272.

    Smaga I, Gawlinska K, Frankowska M, Wydra K, Sadakierska-Chudy A, Suder A, et al. Extinction training after cocaine self-administration influences the epigenetic and genetic machinery responsible for glutamatergic transporter gene expression in male rat brain. Neuroscience. 2020;451:99–110.

    CAS  PubMed  Article  Google Scholar 

  273. 273.

    Dong Y, Nestler EJ. The neural rejuvenation hypothesis of cocaine addiction. Trends Pharm Sci. 2014;35:374–83.

    CAS  PubMed  Article  Google Scholar 

  274. 274.

    Farhy-Tselnicker I, Allen NJ. Astrocytes, neurons, synapses: a tripartite view on cortical circuit development. Neural Dev. 2018;13:7.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  275. 275.

    Huang YH, Lin Y, Mu P, Lee BR, Brown TE, Wayman G, et al. In vivo cocaine experience generates silent synapses. Neuron. 2009;63:40–47.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  276. 276.

    Brown TE, Lee BR, Mu P, Ferguson D, Dietz D, Ohnishi YN, et al. A silent synapse-based mechanism for cocaine-induced locomotor sensitization. J Neurosci. 2011;31:8163–74.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  277. 277.

    Iruela-Arispe ML, Liska DJ, Sage EH, Bornstein P. Differential expression of thrombospondin 1, 2, and 3 during murine development. Dev Dyn. 1993;197:40–56.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  278. 278.

    Spencer S, Brown RM, Quintero GC, Kupchik YM, Thomas CA, Reissner KJ, et al. alpha2delta-1 signaling in nucleus accumbens is necessary for cocaine-induced relapse. J Neurosci. 2014;34:8605–11.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  279. 279.

    Nagai J, Rajbhandari AK, Gangwani MR, Hachisuka A, Coppola G, Masmanidis SC, et al. Hyperactivity with disrupted attention by activation of an astrocyte synaptogenic cue. Cell. 2019;177:1280–92.e1220.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  280. 280.

    Lee BR, Ma YY, Huang YH, Wang X, Otaka M, Ishikawa M, et al. Maturation of silent synapses in amygdala-accumbens projection contributes to incubation of cocaine craving. Nat Neurosci. 2013;16:1644–51.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  281. 281.

    Lee BR, Dong Y. Cocaine-induced metaplasticity in the nucleus accumbens: silent synapse and beyond. Neuropharmacology. 2011;61:1060–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  282. 282.

    Neumann PA, Wang Y, Yan Y, Wang Y, Ishikawa M, Cui R, et al. Cocaine-induced synaptic alterations in thalamus to nucleus accumbens projection. Neuropsychopharmacology. 2016;41:2399–410.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  283. 283.

    Wright WJ, Dong Y. Psychostimulant-induced adaptations in nucleus accumbens glutamatergic transmission. Cold Spring Harb Perspect Med. 2020;10:a039255.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  284. 284.

    Robinson TE, Kolb B. Alterations in the morphology of dendrites and dendritic spines in the nucleus accumbens and prefrontal cortex following repeated treatment with amphetamine or cocaine. Eur J Neurosci. 1999;11:1598–604.

    CAS  PubMed  Article  Google Scholar 

  285. 285.

    Robinson TE, Gorny G, Mitton E, Kolb B. Cocaine self-administration alters the morphology of dendrites and dendritic spines in the nucleus accumbens and neocortex. Synapse. 2001;39:257–66.

    CAS  PubMed  Article  Google Scholar 

Download references

Funding

Preparation of this review was supported by NIH grants R01DA014133 (EJN), R01DA040620 (EJN, YD), R21DA047861 (YD), R37DA023206 (YD), and R21DA051010 (YD).

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Eric J. Nestler or Yan Dong.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wang, J., Holt, L.M., Huang, H.H. et al. Astrocytes in cocaine addiction and beyond. Mol Psychiatry (2021). https://doi.org/10.1038/s41380-021-01080-7

Download citation

Search

Quick links