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The mechanism of electrically stimulated adenosine release varies by brain region


Adenosine plays an important role in neuromodulation and neuroprotection. Recent identification of transient changes in adenosine concentration suggests adenosine may have a rapid modulatory role; however, the extent of these changes throughout the brain is not well understood. In this report, transient changes in adenosine evoked by one second, 60 Hz electrical stimulation trains were compared in the caudate–putamen, nucleus accumbens, hippocampus, and cortex. The concentration of evoked adenosine varies between brain regions, but there is less variation in the duration of signaling. The highest concentration of adenosine was evoked in the dorsal caudate–putamen (0.34 ± 0.08 μM), while the lowest concentration was in the secondary motor cortex (0.06 ± 0.02 μM). In all brain regions, adenosine release was activity-dependent. In the nucleus accumbens, hippocampus, and prefrontal cortex, this release was partly due to extracellular ATP breakdown. However, in the caudate–putamen, release was not due to ATP metabolism but was ionotropic glutamate receptor-dependent. The results demonstrate that transient, activity-dependent adenosine can be evoked in many brain regions but that the mechanism of formation and release varies by region.

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fast-scan cyclic voltammetry


artificial cerebrospinal fluid


ethylenediaminetetraacetic acid




α,β-methylene adenosine diphosphate




D(−)-2-amino-5-phosphonopentanoic acid




  1. 1.

    Huston JP, Haas HL, Boix F, Pfister M, Decking U, Schrader J, Schwarting RK (1996) Extracellular adenosine levels in neostriatum and hippocampus during rest and activity periods of rats. Neuroscience 73:99–107

  2. 2.

    Nagel J, Hauber W (2002) Effects of salient environmental stimuli on extracellular adenosine levels in the rat nucleus accumbens measured by in vivo microdialysis. Behav Brain Res 134:485–492

  3. 3.

    Melani A, Turchi D, Vannucchi MG, Cipriani S, Gianfriddo M, Pedata F (2005) ATP extracellular concentrations are increased in the rat striatum during in vivo ischemia. Neurochem Int 47:442–448

  4. 4.

    Bennett HJ, White TD, Semba K (2000) Activation of metabotropic glutamate receptors increases extracellular adenosine in vivo. Neuroreport 11:3489–3492

  5. 5.

    Bennett HJ, White TD, Semba K (2003) Activation of cholinergic and adrenergic receptors increases the concentration of extracellular adenosine in the cerebral cortex of unanesthetized rat. Neuroscience 117:119–127

  6. 6.

    Klyuch BP, Dale N, Wall MJ (2012) Receptor-mediated modulation of activity-dependent adenosine release in rat cerebellum. Neuropharmacology 62:815–824

  7. 7.

    Pajski ML, Venton BJ (2010) Adenosine release evoked by short electrical stimulations in striatal brain slices is primarily activity dependent. ACS Chem Neurosci 1:775–787

  8. 8.

    Cechova S, Venton BJ (2008) Transient adenosine efflux in the rat caudate–putamen. J Neurochem 105:1253–1263

  9. 9.

    Wall M, Eason R, Dale N (2010) Biosensor measurement of purine release from cerebellar cultures and slices. Purinergic Signal 6:339–348

  10. 10.

    Rebola N, Canas PM, Oliveira CR, Cunha RA (2005) Different synaptic and subsynaptic localization of adenosine A2A receptors in the hippocampus and striatum of the rat. Neuroscience 132:893–903

  11. 11.

    Pazzagli M, Corsi C, Fratti S, Pedata F, Pepeu G (1995) Regulation of extracellular adenosine levels in the striatum of aging rats. Brain Res 684:103–106

  12. 12.

    Nelson AM, Battersby AS, Baghdoyan HA, Lydic R (2009) Opioid-induced decreases in rat brain adenosine levels are reversed by inhibiting adenosine deaminase. Anesthesiology 111:1327–1333

  13. 13.

    Dunwiddie TV, Diao L (2000) Regulation of extracellular adenosine in rat hippocampal slices is temperature dependent: role of adenosine transporters. Neuroscience 95:81–88

  14. 14.

    Pankratov Y, Lalo U, Verkhratsky A, North RA (2006) Vesicular release of ATP at central synapses. Pflugers Arch 452:589–597

  15. 15.

    Li A, Banerjee J, Leung CT, Peterson-Yantorno K, Stamer WD, Civan MM (2011) Mechanisms of ATP Release, the enabling step in purinergic dynamics. Cell Physiol Biochem 28:1135–1144

  16. 16.

    Sershen H (2012) Astrocyte origin of activity-dependent release of ATP and glutamate in hippocampal slices: real-time measurement utilizing microelectrode biosensors. Br J Pharmacol 167:1000–1002

  17. 17.

    Klyuch BP, Dale N, Wall MJ (2012) Deletion of ecto-5′-nucleotidase (CD73) reveals direct action potential-dependent adenosine release. J Neurosci 32:3842–3847

  18. 18.

    Huffman ML, Venton BJ (2008) Electrochemical properties of different carbon-fiber microelectrodes using fast-scan cyclic voltammetry. Electroanalysis 20:2422–2428

  19. 19.

    Scholze P, Orr-Urtreger A, Changeux JP, McIntosh JM, Huck S (2007) Catecholamine outflow from mouse and rat brain slice preparations evoked by nicotinic acetylcholine receptor activation and electrical field stimulation. Br J Pharmacol 151:414–422

  20. 20.

    Gallo V, Giovannini C, Levi G (1990) Modulation of non-N-methyl-D-aspartate receptors in cultured cerebellar granule cells. J Neurochem 54:1619–1625

  21. 21.

    Wall MJ, Dale N (2007) Auto-inhibition of rat parallel fibre-Purkinje cell synapses by activity-dependent adenosine release. J Physiol 581:553–565

  22. 22.

    Christie JM, Jane DE, Monaghan DT (2000) Native N-methyl-D-aspartate receptors containing NR2A and NR2B subunits have pharmacologically distinct competitive antagonist binding sites. J Pharmacol Exp Ther 292:1169–1174

  23. 23.

    Sperlagh B, Zsilla G, Baranyi M, Illes P, Vizi ES (2007) Purinergic modulation of glutamate release under ischemic-like conditions in the hippocampus. Neuroscience 149:99–111

  24. 24.

    Naito Y, Lowenstein JM (1985) 5'-Nucleotidase from rat heart membranes. Inhibition by adenine nucleotides and related compounds. Biochem J 226:645–651

  25. 25.

    Kovacs Z, Dobolyi A, Juhasz G, Kekesi KA (2010) Nucleoside map of the human central nervous system. Neurochem Res 35:452–464

  26. 26.

    Akula KK, Kaur M, Kulkarni SK (2008) Estimation of adenosine and its major metabolites in brain tissues of rats using high-performance thin-layer chromatography-densitometry. J Chromatogr A 1209:230–237

  27. 27.

    Kobayashi T, Yamada T, Okada Y (1998) The levels of adenosine and its metabolites in the guinea pig and rat brain during complete ischemia-in vivo study. Brain Res 787:211–219

  28. 28.

    Pascual O, Casper KB, Kubera C, Zhang J, Revilla-Sanchez R, Sul JY, Takano H, Moss SJ, McCarthy K, Haydon PG (2005) Astrocytic purinergic signaling coordinates synaptic networks. Science 310:113–116

  29. 29.

    Wall M, Dale N (2008) Activity-dependent release of adenosine: a critical re-evaluation of mechanism. Curr Neuropharmacol 6:329–337

  30. 30.

    Dunwiddie TV, Diao LH, Proctor WR (1997) Adenine nucleotides undergo rapid, quantitative conversion to adenosine in the extracellular space in rat hippocampus. J Neurosci 17:7673–7682

  31. 31.

    Wall MJ, Atterbury A, Dale N (2007) Control of basal extracellular adenosine concentration in rat cerebellum. J Physiol 582:137–151

  32. 32.

    Kolachana BS, Saunders RC, Weinberger DR (1997) In vivo characterization of extracellular GABA release in the caudate nucleus and prefrontal cortex of the rhesus monkey. Synapse 25:285–292

  33. 33.

    Tanganelli S, O’Connor WT, Ferraro L, Bianchi C, Beani L, Ungerstedt U, Fuxe K (1994) Facilitation of GABA release by neurotensin is associated with a reduction of dopamine release in rat nucleus accumbens. Neuroscience 60:649–657

  34. 34.

    Jarvis MF, Murphy DE, Williams M (1987) Quantitative autoradiographic localization of NMDA receptors in rat brain using [3H]CPP: comparison with [3H]TCP binding sites. Eur J Pharmacol 141:149–152

  35. 35.

    Rainbow TC, Wieczorek CM, Halpain S (1984) Quantitative autoradiography of binding sites for [3H]AMPA, a structural analogue of glutamic acid. Brain Res 309:173–177

  36. 36.

    Rivkees SA, Price SL, Zhou FC (1995) Immunohistochemical detection of A1 adenosine receptors in rat brain with emphasis on localization in the hippocampal formation, cerebral cortex, cerebellum, and basal ganglia. Brain Res 677:193–203

  37. 37.

    Fastbom J, Pazos A, Probst A, Palacios JM (1986) Adenosine-A1-receptors in human-brain—characterization and autoradiographic visualization. Neurosci Lett 65:127–132

  38. 38.

    Moreau JL, Huber G (1999) Central adenosine A(2A) receptors: an overview. Brain Res Brain Res Rev 31:65–82

  39. 39.

    Cechova S, Elsobky AM, Venton BJ (2010) A1 receptors self-regulate adenosine release in the striatum: evidence of autoreceptor characteristics. Neuroscience 171:1006–1015

  40. 40.

    Brand A, Vissiennon Z, Eschke D, Nieber K (2001) Adenosine A(1) and A(3) receptors mediate inhibition of synaptic transmission in rat cortical neurons. Neuropharmacology 40:85–95

  41. 41.

    Paxinos G, Watson C (2005) The rat brain in stereotaxic coordinates. Elsevier Academic Press, New York

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The authors have no conflict of interest related to this research. Funding for this research was provided by the National Institute of Health R01NS076875 and the University of Virginia.

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Correspondence to B. Jill Venton.

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Pajski, M.L., Venton, B.J. The mechanism of electrically stimulated adenosine release varies by brain region. Purinergic Signalling 9, 167–174 (2013).

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  • Carbon-fiber microelectrode
  • Striatum
  • Hippocampus
  • Cortex
  • Electrical stimulation
  • Fast-scan cyclic voltammetry