Şizofreni ve Adenozin Reseptörleri
Year 2019,
Volume: 28 Issue: 4, 275 - 284, 31.12.2019
Kübra Akıllıoğlu
,
Zehra Çiçek
,
Meltem Dönmez
Abstract
Şizofreni
hastalığı toplumda yaklaşık %1 oranında görülmekle birlikte kesin tedavisi
olmayan, kronik nöropsikiyatrik bir hastalıktır. Kişinin günlük yaşamını
olumsuz etkileyen bilişsel ve duygusal işlevlerde bozulmaya neden olan
şizofreninin fizyopatolojisi henüz aydınlatılamamıştır. Adenozin, merkezi sinir
sisteminde birçok fonksiyonu etkileyen endojen bir nöromodülatör olarak rol
oynamaktadır. Son yıllarda ise merkezi sinir sisteminde nöromodülatör olarak
işlev gören adenozin ve reseptörlerinin şizofreni fizyopatolojisinde rol
oynayabileceği ileri sürülmektedir. Biz de derlememizde şizofrenide adenozin ve
reseptörlerinin nöromodülatör işlevini son literatür bilgileri ışığında
inceledik.
References
- KAYNAKLAR 1. Black MD, Varty GB, Arad M, et al: Procognitive and antipsychotic efficacy of glycine transport 1 inhibitors (GlyT1) in acute and neurodevelopmental models of schizophrenia: latent inhibition studies in the rat. Psychopharmacology (Berl) 202:385-96, 2009 2. Lara DR, Dall'Igna OP, Ghisolfi ES, et al: Involvement of adenosine in the neurobiology of schizophrenia and its therapeutic implications. Prog Neuropsychopharmacol Biol Psychiatry 30:617-29, 2006 3. Ferre S, O'Connor WT, Snaprud P, et al: Antagonistic interaction between adenosine A2A receptors and dopamine D2 receptors in the ventral striopallidal system. Implications for the treatment of schizophrenia. Neuroscience 63:765-73, 1994 4. Olney JW, Farber NB: Glutamate Receptor Dysfunction and Schizophrenia. Archives of General Psychiatry 52:998-1007, 1995 5. Krystal JH, Karper LP, Seibyl JP, et al: Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 51:199-214, 1994 6. Schwartz TL, Sachdeva S, Stahl SM: Glutamate neurocircuitry: theoretical underpinnings in schizophrenia. Frontiers in Pharmacology 3, 2012 7. Catts VS, Lai YL, Weickert CS, et al: A quantitative review of the postmortem evidence for decreased cortical N-methyl-D-aspartate receptor expression levels in schizophrenia: How can we link molecular abnormalities to mismatch negativity deficits? Biol Psychol 116:57-67, 2016 8. Jadi MP, Behrens MM, Sejnowski TJ: Abnormal Gamma Oscillations in N-Methyl-D-Aspartate Receptor Hypofunction Models of Schizophrenia. Biol Psychiatry 79:716-26, 2016 9. Ellaithy A, Younkin J, Gonzalez-Maeso J, et al: Positive allosteric modulators of metabotropic glutamate 2 receptors in schizophrenia treatment. Trends in Neurosciences 38:506-516, 2015 10. Eggers AE: Extending David Horrobin's membrane phospholipid theory of schizophrenia: Overactivity of cytosolic phospholipase A(2) in the brain is caused by overdrive of coupled serotonergic 5HT(2A/2C) receptors in response to stress. Medical Hypotheses 79:740-743, 2012 11. Yuen EY, Jiang Q, Chen P, et al: Activation of 5-HT2A/C receptors counteracts 5-HT1A regulation of N-methyl-D-aspartate receptor channels in pyramidal neurons of prefrontal cortex. Journal of Biological Chemistry 283:17194-17204, 2008 12. Schubert P, Komp W, Kreutzberg GW: Correlation of 5'-nucleotidase activity and selective transneuronal transfer of adenosine in the hippocampus. Brain Res 168:419-24, 1979 13. Dunwiddie TV, Diao L: Extracellular adenosine concentrations in hippocampal brain slices and the tonic inhibitory modulation of evoked excitatory responses. J Pharmacol Exp Ther 268:537-45, 1994 14. Fredholm BB, Battig K, Holmen J, et al: Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol Rev 51:83-133, 1999 15. Lloyd HG, Lindstrom K, Fredholm BB: Intracellular formation and release of adenosine from rat hippocampal slices evoked by electrical stimulation or energy depletion. Neurochem Int 23:173-85, 1993 16. Fredholm BB, Chen JF, Cunha RA, et al: Adenosine and brain function. Int Rev Neurobiol 63:191-270, 2005 17. Chen JF, Lee CF, Chern YJ: Adenosine. Receptor Neurobiology: Overview. Adenosine Receptors in Neurology and Psychiatry 119:1-49, 2014 18. Sebastiao AM, Ribeiro JA: Adenosine receptors and the central nervous system. Handb Exp Pharmacol:471-534, 2009 19. Eltzschig HK, Eckle T: Ischemia and reperfusion-from mechanism to translation. Nature Medicine 17:1391-1401, 2011 20. Hasko G, Linden J, Cronstein B, et al: Adenosine receptors: therapeutic aspects for inflammatory and immune diseases. Nature Reviews Drug Discovery 7:759-770, 2008 21. Fredholm BB, AP IJ, Jacobson KA, et al: International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol Rev 53:527-52, 2001 22. Fredholm BB, Arslan G, Halldner L, et al: Structure and function of adenosine receptors and their genes. Naunyn Schmiedebergs Arch Pharmacol 362:364-74, 2000 23. Fredholm BB, AP IJ, Jacobson KA, et al: International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and classification of adenosine receptors--an update. Pharmacol Rev 63:1-34, 2011 24. Goodman RR, Snyder SH: Autoradiographic Localization of Adenosine Receptors in Rat-Brain Using [H-3]Cyclohexyladenosine. Journal of Neuroscience 2:1230-1241, 1982 25. Rebola N, Pinheiro PC, Oliveira CR, et al: Subcellular localization of adenosine A(1) receptors in nerve terminals and synapses of the rat hippocampus. Brain Res 987:49-58, 2003 26. Fredholm BB, Dunwiddie TV: How Does Adenosine Inhibit Transmitter Release. Trends in Pharmacological Sciences 9:130-134, 1988 27. Johnston JB, Silva C, Gonzalez G, et al: Diminished adenosine A1 receptor expression on macrophages in brain and blood of patients with multiple sclerosis. Annals of Neurology 49:650-658, 2001 28. Rosin DL, Robeva A, Woodard RL, et al: Immunohistochemical localization of adenosine A2A receptors in the rat central nervous system. J Comp Neurol 401:163-86, 1998 29. Rosin DL, Hettinger BD, Lee A, et al: Anatomy of adenosine A2A receptors in brain: morphological substrates for integration of striatal function. Neurology 61:S12-8, 2003 30. Navarro G, Borroto-Escuela DO, Fuxe K, et al: Purinergic signaling in Parkinson's disease. Relevance for treatment. Neuropharmacology 104:161-168, 2016 31. Svenningsson P, Hall H, Sedvall G, et al: Distribution of adenosine receptors in the postmortem human brain: an extended autoradiographic study. Synapse 27:322-35, 1997 32. Rebola N, Canas PM, Oliveira CR, et al: Different synaptic and subsynaptic localization of adenosine A2A receptors in the hippocampus and striatum of the rat. Neuroscience 132:893-903, 2005 33. Ciruela F, Gomez-Soler M, Guidolin D, et al: Adenosine receptor containing oligomers: their role in the control of dopamine and glutamate neurotransmission in the brain. Biochim Biophys Acta 1808:1245-55, 2011 34. Fredholm BB, Arslan G, Halldner L, et al: Structure and function of adenosine receptors and their genes. Naunyn-Schmiedebergs Archives of Pharmacology 362:364-374, 2000 35. Ballarin M, Fredholm BB, Ambrosio S, et al: Extracellular Levels of Adenosine and Its Metabolites in the Striatum of Awake Rats - Inhibition of Uptake and Metabolism. Acta Physiologica Scandinavica 142:97-103, 1991 36. Fisone G, Borgkvist A, Usiello A: Caffeine as a psychomotor stimulant: mechanism of action. Cellular and Molecular Life Sciences 61:857-872, 2004 37. Goncalves FQ, Pires J, Pliassova A, et al: Adenosine A2b receptors control A1 receptor-mediated inhibition of synaptic transmission in the mouse hippocampus. Eur J Neurosci 41:878-88, 2015 38. Muller CE, Stein B: Adenosine receptor antagonists: Structures and potential therapeutic applications. Current Pharmaceutical Design 2:501-530, 1996 39. Hinz S, Navarro G, Borroto-Escuela D, et al: Adenosine A2A receptor ligand recognition and signaling is blocked by A2B receptors. Oncotarget 9:13593-13611, 2018 40. Lopes LV, Rebola N, Pinheiro PC, et al: Adenosine A3 receptors are located in neurons of the rat hippocampus. Neuroreport 14:1645-8, 2003 41. Fishman P, Bar-Yehuda S, Liang BT, et al: Pharmacological and therapeutic effects of A3 adenosine receptor agonists. Drug Discov Today 17:359-66, 2012 42. Boison D: Adenosine dysfunction and adenosine kinase in epileptogenesis. Open Neurosci J 4:93-101, 2010 43. Little JW, Ford A, Symons-Liguori AM, et al: Endogenous adenosine A3 receptor activation selectively alleviates persistent pain states. Brain 138:28-35, 2015 44. Dunwiddie TV, Fredholm BB: Adenosine Receptors Mediating Inhibitory Electrophysiological Responses in Rat Hippocampus Are Different from Receptors Mediating Cyclic-Amp Accumulation. Naunyn-Schmiedebergs Archives of Pharmacology 326:294-301, 1984 45. Ciruela F, Casado V, Rodrigues RJ, et al: Presynaptic control of striatal glutamatergic neurotransmission by adenosine A1-A2A receptor heteromers. Journal of Neurochemistry 102:97-97, 2007 46. Yin DM, Chen YJ, Sathyamurthy A, et al: Synaptic dysfunction in schizophrenia. Adv Exp Med Biol 970:493-516, 2012 47. Canas PM, Porciuncula LO, Cunha GM, et al: Adenosine A2A receptor blockade prevents synaptotoxicity and memory dysfunction caused by beta-amyloid peptides via p38 mitogen-activated protein kinase pathway. J Neurosci 29:14741-51, 2009 48. Gomes CV, Kaster MP, Tome AR, et al: Adenosine receptors and brain diseases: neuroprotection and neurodegeneration. Biochim Biophys Acta 1808:1380-99, 2011 49. Abbracchio MP, Cattabeni F: Brain adenosine receptors as targets for therapeutic intervention in neurodegenerative diseases. Ann N Y Acad Sci 890:79-92, 1999 50. Tebano MT, Martire A, Pepponi R, et al: Is the functional interaction between adenosine A(2A) receptors and metabotropic glutamate 5 receptors a general mechanism in the brain? Differences and similarities between the striatum and the hippocampus. Purinergic Signal 2:619-25, 2006 51. Chen HH, Liao PF, Chan MH: mGluR5 positive modulators both potentiate activation and restore inhibition in NMDA receptors by PKC dependent pathway. Journal of Biomedical Science 18, 2011 52. Sarantis K, Tsiamaki E, Kouvaros S, et al: Adenosine A(2)A receptors permit mGluR5-evoked tyrosine phosphorylation of NR2B (Tyr1472) in rat hippocampus: a possible key mechanism in NMDA receptor modulation. J Neurochem 135:714-26, 2015 53. Schiffmann SN, Fisone G, Moresco R, et al: Adenosine A2A receptors and basal ganglia physiology. Prog Neurobiol 83:277-92, 2007 54. Borycz J, Pereira MF, Melani A, et al: Differential glutamate-dependent and glutamate-independent adenosine A1 receptor-mediated modulation of dopamine release in different striatal compartments. J Neurochem 101:355-63, 2007 55. Fuxe K, Stromberg I, Popoli P, et al: Adenosine receptors and Parkinson's disease. Relevance of antagonistic adenosine and dopamine receptor interactions in the striatum. Adv Neurol 86:345-53, 2001 56. Agnati LF, Fuxe K, Zini I, et al: Aspects on receptor regulation and isoreceptor identification. Med Biol 58:182-7, 1980 57. Fuxe K, Ferre S, Zoli M, et al: Integrated events in central dopamine transmission as analyzed at multiple levels. Evidence for intramembrane adenosine A(2A) dopamine D-2 and adenosine A(1) dopamine D-1 receptor interactions in the basal ganglia. Brain Research Reviews 26:258-273, 1998 58. Fuxe K, Ferre S, Genedani S, et al: Adenosine receptor-dopamine receptor interactions in the basal ganglia and their relevance for brain function. Physiol Behav 92:210-7, 2007 59. Ferre S, Voneuler G, Johansson B, et al: Stimulation of High-Affinity Adenosine-A2 Receptors Decreases the Affinity of Dopamine D2 Receptors in Rat Striatal Membranes. Proceedings of the National Academy of Sciences of the United States of America 88:7238-7241, 1991 60. Al-Hasani R, Foster JD, Metaxas A, et al: Increased desensitization of dopamine D(2) receptor-mediated response in the ventral tegmental area in the absence of adenosine A(2A) receptors. Neuroscience 190:103-11, 2011 61. Higley MJ, Sabatini BL: Competitive regulation of synaptic Ca2+ influx by D2 dopamine and A2A adenosine receptors. Nat Neurosci 13:958-66, 2010 62. Azdad K, Gall D, Woods AS, et al: Dopamine D2 and adenosine A2A receptors regulate NMDA-mediated excitation in accumbens neurons through A2A-D2 receptor heteromerization. Neuropsychopharmacology 34:972-86, 2009 63. Borroto-Escuela DO, Romero-Fernandez W, Tarakanov AO, et al: On the existence of a possible A2A-D2-beta-Arrestin2 complex: A2A agonist modulation of D2 agonist-induced beta-arrestin2 recruitment. J Mol Biol 406:687-99, 2011 64. Akhondzadeh S, Shasavand E, Jamilian H, et al: Dipyridamole in the treatment of schizophrenia: adenosine-dopamine receptor interactions. J Clin Pharm Ther 25:131-7, 2000 65. Wonodi I, Gopinath HV, Liu J, et al: Dipyridamole monotherapy in schizophrenia: pilot of a novel treatment approach by modulation of purinergic signaling. Psychopharmacology (Berl) 218:341-5, 2011 66. Sebastiao AM, Ribeiro JA: Neuromodulation and metamodulation by adenosine: Impact and subtleties upon synaptic plasticity regulation. Brain Research 1621:102-113, 2015 67. Ginsborg BL, Hirst GD: The effect of adenosine on the release of the transmitter from the phrenic nerve of the rat. J Physiol 224:629-45, 1972 68. Jackisch R, Strittmatter H, Kasakov L, et al: Endogenous Adenosine as a Modulator of Hippocampal Acetylcholine-Release. Naunyn-Schmiedebergs Archives of Pharmacology 327:319-325, 1984 69. Brown SJ, James S, Reddington M, et al: Both A1 and A2a Purine Receptors Regulate Striatal Acetylcholine-Release. Journal of Neurochemistry 55:31-38, 1990 70. Correiadesa P, Sebastiao AM, Ribeiro JA: Inhibitory and Excitatory Effects of Adenosine Receptor Agonists on Evoked Transmitter Release from Phrenic-Nerve Endings of the Rat. British Journal of Pharmacology 103:1614-1620, 1991 71. Cunha RA, Johansson B, van der Ploeg I, et al: Evidence for functionally important adenosine A2a receptors in the rat hippocampus. Brain Res 649:208-16, 1994 72. Kamiya H: Some Pharmacological Differences between Hippocampal Excitatory and Inhibitory Synapses in Transmitter Release - an Invitro Study. Synapse 8:229-235, 1991 73. Ochiishi T, Chen L, Yukawa A, et al: Cellular localization of adenosine A1 receptors in rat forebrain: Immunohistochemical analysis using adenosine A1 receptor-specific monoclonal antibody. Journal of Comparative Neurology 411:301-316, 1999 74. Rombo DM, Dias RB, Duarte ST, et al: Adenosine A1 Receptor Suppresses Tonic GABAA Receptor Currents in Hippocampal Pyramidal Cells and in a Defined Subpopulation of Interneurons. Cereb Cortex 26:1081-95, 2016 75. Rombo DM, Newton K, Nissen W, et al: Synaptic mechanisms of adenosine A2A receptor-mediated hyperexcitability in the hippocampus. Hippocampus 25:566-80, 2015 76. Cristovao-Ferreira S, Vaz SH, Ribeiro JA, et al: Adenosine A2A receptors enhance GABA transport into nerve terminals by restraining PKC inhibition of GAT-1. Journal of Neurochemistry 109:336-347, 2009 77. Arai A, Kessler M, Lynch G: The Effects of Adenosine on the Development of Long-Term Potentiation. Neuroscience Letters 119:41-44, 1990 78. Demendonca A, Ribeiro JA: 2-Chloroadenosine Decreases Long-Term Potentiation in the Hippocampal Ca1 Area of the Rat. Neuroscience Letters 118:107-111, 1990 79. Flajolet M, Wang ZF, Futter M, et al: FGF acts as a co-transmitter through adenosine A(2A) receptor to regulate synaptic plasticity. Nature Neuroscience 11:1402-1409, 2008 80. Shen HY, Coelho JE, Ohtsuka N, et al: A critical role of the adenosine A(2A) receptor in extrastriatal neurons in modulating psychomotor activity as revealed by opposite phenotypes of striatum and forebrain A2A receptor knock-outs. Journal of Neuroscience 28:2970-2975, 2008 81. Liang YC, Huang CC, Hsu KS: A role of p38 mitogen-activated protein kinase in adenosine A(1) receptor-mediated synaptic depotentiation in area CA1 of the rat hippocampus. Molecular Brain 1, 2008 82. Huang CC, Liang YC, Hsu KS: A role for extracellular adenosine in time-dependent reversal of long-term potentiation by low-frequency stimulation at hippocampal CA1 synapses. Journal of Neuroscience 19:9728-9738, 1999 83. Huang CC, Liang YC, Hsu KS: Characterization of the mechanism underlying the reversal of long term potentiation by low frequency stimulation at hippocampal CA1 synapses. Journal of Biological Chemistry 276:48108-48117, 2001 84. Costenla AR, Lopes LV, de Mendonca A, et al: A functional role for adenosine A3 receptors: modulation of synaptic plasticity in the rat hippocampus. Neurosci Lett 302:53-7, 2001 85. Costenla AR, Diogenes MJ, Canas PM, et al: Enhanced role of adenosine A(2A) receptors in the modulation of LTP in the rat hippocampus upon ageing. European Journal of Neuroscience 34:12-21, 2011 86. Lopes LV, Cunha RA, Ribeiro JA: Increase in the number, G protein coupling, and efficiency of facilitatory adenosine A2A receptors in the limbic cortex, but not striatum, of aged rats. J Neurochem 73:1733-8, 1999 87. Batalha VL, Pego JM, Fontinha BM, et al: Adenosine A(2A) receptor blockade reverts hippocampal stress-induced deficits and restores corticosterone circadian oscillation. Molecular Psychiatry 18:320-331, 2013 88. Lara DR, Souza DO: Schizophrenia: a purinergic hypothesis. Med Hypotheses 54:157-66, 2000 89. Akhondzadeh S, Safarcherati A, Amini H: Beneficial antipsychotic effects of allopurinol as add-on therapy for schizophrenia: a double blind, randomized and placebo controlled trial. Progress in Neuro-Psychopharmacology & Biological Psychiatry 29:253-259, 2005 90. Kurumaji A, Toru M: An increase in [3H] CGS21680 binding in the striatum of postmortem brains of chronic schizophrenics. Brain Res 808:320-3, 1998 91. Rial D, Lara DR, Cunha RA: The Adenosine Neuromodulation System in Schizophrenia. Adenosine Receptors in Neurology and Psychiatry 119:395-449, 2014 92. Ning YL, Yang N, Chen X, et al: Adenosine A2A receptor deficiency alleviates blast-induced cognitive dysfunction. Journal of Cerebral Blood Flow and Metabolism 33:1789-1798, 2013 93. Haller S, Rodriguez C, Moser D, et al: Acute Caffeine Administration Impact on Working Memory-Related Brain Activation and Functional Connectivity in the Elderly: A Bold and Perfusion Mri Study. Neuroscience 250:364-371, 2013 94. Pereira GS, Rossato JI, Sarkis JJF, et al: Activation of adenosine receptors in the posterior cingulate cortex impairs memory retrieval in the rat. Neurobiology of Learning and Memory 83:217-223, 2005 95. Augusto E, Matos M, Sevigny J, et al: Ecto-5'-nucleotidase (CD73)-mediated formation of adenosine is critical for the striatal adenosine A2A receptor functions. J Neurosci 33:11390-9, 2013 96. Waldeck B: Effect of caffeine on locomotor activity and central catecholamine mechanisms: a study with special reference to drug interaction. Acta Pharmacol Toxicol (Copenh) 36:1-23, 1975 97. El Yacoubi M, Ledent C, Menard JF, et al: The stimulant effects of caffeine on locomotor behaviour in mice are mediated through its blockade of adenosine A(2A) receptors. British Journal of Pharmacology 129:1465-1473, 2000 98. Shen HY, Canas PM, Garcia-Sanz P, et al: Adenosine A(2)A receptors in striatal glutamatergic terminals and GABAergic neurons oppositely modulate psychostimulant action and DARPP-32 phosphorylation. PLoS One 8:e80902, 2013
Year 2019,
Volume: 28 Issue: 4, 275 - 284, 31.12.2019
Kübra Akıllıoğlu
,
Zehra Çiçek
,
Meltem Dönmez
References
- KAYNAKLAR 1. Black MD, Varty GB, Arad M, et al: Procognitive and antipsychotic efficacy of glycine transport 1 inhibitors (GlyT1) in acute and neurodevelopmental models of schizophrenia: latent inhibition studies in the rat. Psychopharmacology (Berl) 202:385-96, 2009 2. Lara DR, Dall'Igna OP, Ghisolfi ES, et al: Involvement of adenosine in the neurobiology of schizophrenia and its therapeutic implications. Prog Neuropsychopharmacol Biol Psychiatry 30:617-29, 2006 3. Ferre S, O'Connor WT, Snaprud P, et al: Antagonistic interaction between adenosine A2A receptors and dopamine D2 receptors in the ventral striopallidal system. Implications for the treatment of schizophrenia. Neuroscience 63:765-73, 1994 4. Olney JW, Farber NB: Glutamate Receptor Dysfunction and Schizophrenia. Archives of General Psychiatry 52:998-1007, 1995 5. Krystal JH, Karper LP, Seibyl JP, et al: Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 51:199-214, 1994 6. Schwartz TL, Sachdeva S, Stahl SM: Glutamate neurocircuitry: theoretical underpinnings in schizophrenia. Frontiers in Pharmacology 3, 2012 7. Catts VS, Lai YL, Weickert CS, et al: A quantitative review of the postmortem evidence for decreased cortical N-methyl-D-aspartate receptor expression levels in schizophrenia: How can we link molecular abnormalities to mismatch negativity deficits? Biol Psychol 116:57-67, 2016 8. Jadi MP, Behrens MM, Sejnowski TJ: Abnormal Gamma Oscillations in N-Methyl-D-Aspartate Receptor Hypofunction Models of Schizophrenia. Biol Psychiatry 79:716-26, 2016 9. Ellaithy A, Younkin J, Gonzalez-Maeso J, et al: Positive allosteric modulators of metabotropic glutamate 2 receptors in schizophrenia treatment. Trends in Neurosciences 38:506-516, 2015 10. Eggers AE: Extending David Horrobin's membrane phospholipid theory of schizophrenia: Overactivity of cytosolic phospholipase A(2) in the brain is caused by overdrive of coupled serotonergic 5HT(2A/2C) receptors in response to stress. Medical Hypotheses 79:740-743, 2012 11. Yuen EY, Jiang Q, Chen P, et al: Activation of 5-HT2A/C receptors counteracts 5-HT1A regulation of N-methyl-D-aspartate receptor channels in pyramidal neurons of prefrontal cortex. Journal of Biological Chemistry 283:17194-17204, 2008 12. Schubert P, Komp W, Kreutzberg GW: Correlation of 5'-nucleotidase activity and selective transneuronal transfer of adenosine in the hippocampus. Brain Res 168:419-24, 1979 13. Dunwiddie TV, Diao L: Extracellular adenosine concentrations in hippocampal brain slices and the tonic inhibitory modulation of evoked excitatory responses. J Pharmacol Exp Ther 268:537-45, 1994 14. Fredholm BB, Battig K, Holmen J, et al: Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol Rev 51:83-133, 1999 15. Lloyd HG, Lindstrom K, Fredholm BB: Intracellular formation and release of adenosine from rat hippocampal slices evoked by electrical stimulation or energy depletion. Neurochem Int 23:173-85, 1993 16. Fredholm BB, Chen JF, Cunha RA, et al: Adenosine and brain function. Int Rev Neurobiol 63:191-270, 2005 17. Chen JF, Lee CF, Chern YJ: Adenosine. Receptor Neurobiology: Overview. Adenosine Receptors in Neurology and Psychiatry 119:1-49, 2014 18. Sebastiao AM, Ribeiro JA: Adenosine receptors and the central nervous system. Handb Exp Pharmacol:471-534, 2009 19. Eltzschig HK, Eckle T: Ischemia and reperfusion-from mechanism to translation. Nature Medicine 17:1391-1401, 2011 20. Hasko G, Linden J, Cronstein B, et al: Adenosine receptors: therapeutic aspects for inflammatory and immune diseases. Nature Reviews Drug Discovery 7:759-770, 2008 21. Fredholm BB, AP IJ, Jacobson KA, et al: International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol Rev 53:527-52, 2001 22. Fredholm BB, Arslan G, Halldner L, et al: Structure and function of adenosine receptors and their genes. Naunyn Schmiedebergs Arch Pharmacol 362:364-74, 2000 23. Fredholm BB, AP IJ, Jacobson KA, et al: International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and classification of adenosine receptors--an update. Pharmacol Rev 63:1-34, 2011 24. Goodman RR, Snyder SH: Autoradiographic Localization of Adenosine Receptors in Rat-Brain Using [H-3]Cyclohexyladenosine. Journal of Neuroscience 2:1230-1241, 1982 25. Rebola N, Pinheiro PC, Oliveira CR, et al: Subcellular localization of adenosine A(1) receptors in nerve terminals and synapses of the rat hippocampus. Brain Res 987:49-58, 2003 26. Fredholm BB, Dunwiddie TV: How Does Adenosine Inhibit Transmitter Release. Trends in Pharmacological Sciences 9:130-134, 1988 27. Johnston JB, Silva C, Gonzalez G, et al: Diminished adenosine A1 receptor expression on macrophages in brain and blood of patients with multiple sclerosis. Annals of Neurology 49:650-658, 2001 28. Rosin DL, Robeva A, Woodard RL, et al: Immunohistochemical localization of adenosine A2A receptors in the rat central nervous system. J Comp Neurol 401:163-86, 1998 29. Rosin DL, Hettinger BD, Lee A, et al: Anatomy of adenosine A2A receptors in brain: morphological substrates for integration of striatal function. Neurology 61:S12-8, 2003 30. Navarro G, Borroto-Escuela DO, Fuxe K, et al: Purinergic signaling in Parkinson's disease. Relevance for treatment. Neuropharmacology 104:161-168, 2016 31. Svenningsson P, Hall H, Sedvall G, et al: Distribution of adenosine receptors in the postmortem human brain: an extended autoradiographic study. Synapse 27:322-35, 1997 32. Rebola N, Canas PM, Oliveira CR, et al: Different synaptic and subsynaptic localization of adenosine A2A receptors in the hippocampus and striatum of the rat. Neuroscience 132:893-903, 2005 33. Ciruela F, Gomez-Soler M, Guidolin D, et al: Adenosine receptor containing oligomers: their role in the control of dopamine and glutamate neurotransmission in the brain. Biochim Biophys Acta 1808:1245-55, 2011 34. Fredholm BB, Arslan G, Halldner L, et al: Structure and function of adenosine receptors and their genes. Naunyn-Schmiedebergs Archives of Pharmacology 362:364-374, 2000 35. Ballarin M, Fredholm BB, Ambrosio S, et al: Extracellular Levels of Adenosine and Its Metabolites in the Striatum of Awake Rats - Inhibition of Uptake and Metabolism. Acta Physiologica Scandinavica 142:97-103, 1991 36. Fisone G, Borgkvist A, Usiello A: Caffeine as a psychomotor stimulant: mechanism of action. Cellular and Molecular Life Sciences 61:857-872, 2004 37. Goncalves FQ, Pires J, Pliassova A, et al: Adenosine A2b receptors control A1 receptor-mediated inhibition of synaptic transmission in the mouse hippocampus. Eur J Neurosci 41:878-88, 2015 38. Muller CE, Stein B: Adenosine receptor antagonists: Structures and potential therapeutic applications. Current Pharmaceutical Design 2:501-530, 1996 39. Hinz S, Navarro G, Borroto-Escuela D, et al: Adenosine A2A receptor ligand recognition and signaling is blocked by A2B receptors. Oncotarget 9:13593-13611, 2018 40. Lopes LV, Rebola N, Pinheiro PC, et al: Adenosine A3 receptors are located in neurons of the rat hippocampus. Neuroreport 14:1645-8, 2003 41. Fishman P, Bar-Yehuda S, Liang BT, et al: Pharmacological and therapeutic effects of A3 adenosine receptor agonists. Drug Discov Today 17:359-66, 2012 42. Boison D: Adenosine dysfunction and adenosine kinase in epileptogenesis. Open Neurosci J 4:93-101, 2010 43. Little JW, Ford A, Symons-Liguori AM, et al: Endogenous adenosine A3 receptor activation selectively alleviates persistent pain states. Brain 138:28-35, 2015 44. Dunwiddie TV, Fredholm BB: Adenosine Receptors Mediating Inhibitory Electrophysiological Responses in Rat Hippocampus Are Different from Receptors Mediating Cyclic-Amp Accumulation. Naunyn-Schmiedebergs Archives of Pharmacology 326:294-301, 1984 45. Ciruela F, Casado V, Rodrigues RJ, et al: Presynaptic control of striatal glutamatergic neurotransmission by adenosine A1-A2A receptor heteromers. Journal of Neurochemistry 102:97-97, 2007 46. Yin DM, Chen YJ, Sathyamurthy A, et al: Synaptic dysfunction in schizophrenia. Adv Exp Med Biol 970:493-516, 2012 47. Canas PM, Porciuncula LO, Cunha GM, et al: Adenosine A2A receptor blockade prevents synaptotoxicity and memory dysfunction caused by beta-amyloid peptides via p38 mitogen-activated protein kinase pathway. J Neurosci 29:14741-51, 2009 48. Gomes CV, Kaster MP, Tome AR, et al: Adenosine receptors and brain diseases: neuroprotection and neurodegeneration. Biochim Biophys Acta 1808:1380-99, 2011 49. Abbracchio MP, Cattabeni F: Brain adenosine receptors as targets for therapeutic intervention in neurodegenerative diseases. Ann N Y Acad Sci 890:79-92, 1999 50. Tebano MT, Martire A, Pepponi R, et al: Is the functional interaction between adenosine A(2A) receptors and metabotropic glutamate 5 receptors a general mechanism in the brain? Differences and similarities between the striatum and the hippocampus. Purinergic Signal 2:619-25, 2006 51. Chen HH, Liao PF, Chan MH: mGluR5 positive modulators both potentiate activation and restore inhibition in NMDA receptors by PKC dependent pathway. Journal of Biomedical Science 18, 2011 52. Sarantis K, Tsiamaki E, Kouvaros S, et al: Adenosine A(2)A receptors permit mGluR5-evoked tyrosine phosphorylation of NR2B (Tyr1472) in rat hippocampus: a possible key mechanism in NMDA receptor modulation. J Neurochem 135:714-26, 2015 53. Schiffmann SN, Fisone G, Moresco R, et al: Adenosine A2A receptors and basal ganglia physiology. Prog Neurobiol 83:277-92, 2007 54. Borycz J, Pereira MF, Melani A, et al: Differential glutamate-dependent and glutamate-independent adenosine A1 receptor-mediated modulation of dopamine release in different striatal compartments. J Neurochem 101:355-63, 2007 55. Fuxe K, Stromberg I, Popoli P, et al: Adenosine receptors and Parkinson's disease. Relevance of antagonistic adenosine and dopamine receptor interactions in the striatum. Adv Neurol 86:345-53, 2001 56. Agnati LF, Fuxe K, Zini I, et al: Aspects on receptor regulation and isoreceptor identification. Med Biol 58:182-7, 1980 57. Fuxe K, Ferre S, Zoli M, et al: Integrated events in central dopamine transmission as analyzed at multiple levels. Evidence for intramembrane adenosine A(2A) dopamine D-2 and adenosine A(1) dopamine D-1 receptor interactions in the basal ganglia. Brain Research Reviews 26:258-273, 1998 58. Fuxe K, Ferre S, Genedani S, et al: Adenosine receptor-dopamine receptor interactions in the basal ganglia and their relevance for brain function. Physiol Behav 92:210-7, 2007 59. Ferre S, Voneuler G, Johansson B, et al: Stimulation of High-Affinity Adenosine-A2 Receptors Decreases the Affinity of Dopamine D2 Receptors in Rat Striatal Membranes. Proceedings of the National Academy of Sciences of the United States of America 88:7238-7241, 1991 60. Al-Hasani R, Foster JD, Metaxas A, et al: Increased desensitization of dopamine D(2) receptor-mediated response in the ventral tegmental area in the absence of adenosine A(2A) receptors. Neuroscience 190:103-11, 2011 61. Higley MJ, Sabatini BL: Competitive regulation of synaptic Ca2+ influx by D2 dopamine and A2A adenosine receptors. Nat Neurosci 13:958-66, 2010 62. Azdad K, Gall D, Woods AS, et al: Dopamine D2 and adenosine A2A receptors regulate NMDA-mediated excitation in accumbens neurons through A2A-D2 receptor heteromerization. Neuropsychopharmacology 34:972-86, 2009 63. Borroto-Escuela DO, Romero-Fernandez W, Tarakanov AO, et al: On the existence of a possible A2A-D2-beta-Arrestin2 complex: A2A agonist modulation of D2 agonist-induced beta-arrestin2 recruitment. J Mol Biol 406:687-99, 2011 64. Akhondzadeh S, Shasavand E, Jamilian H, et al: Dipyridamole in the treatment of schizophrenia: adenosine-dopamine receptor interactions. J Clin Pharm Ther 25:131-7, 2000 65. Wonodi I, Gopinath HV, Liu J, et al: Dipyridamole monotherapy in schizophrenia: pilot of a novel treatment approach by modulation of purinergic signaling. Psychopharmacology (Berl) 218:341-5, 2011 66. Sebastiao AM, Ribeiro JA: Neuromodulation and metamodulation by adenosine: Impact and subtleties upon synaptic plasticity regulation. Brain Research 1621:102-113, 2015 67. Ginsborg BL, Hirst GD: The effect of adenosine on the release of the transmitter from the phrenic nerve of the rat. J Physiol 224:629-45, 1972 68. Jackisch R, Strittmatter H, Kasakov L, et al: Endogenous Adenosine as a Modulator of Hippocampal Acetylcholine-Release. Naunyn-Schmiedebergs Archives of Pharmacology 327:319-325, 1984 69. Brown SJ, James S, Reddington M, et al: Both A1 and A2a Purine Receptors Regulate Striatal Acetylcholine-Release. Journal of Neurochemistry 55:31-38, 1990 70. Correiadesa P, Sebastiao AM, Ribeiro JA: Inhibitory and Excitatory Effects of Adenosine Receptor Agonists on Evoked Transmitter Release from Phrenic-Nerve Endings of the Rat. British Journal of Pharmacology 103:1614-1620, 1991 71. Cunha RA, Johansson B, van der Ploeg I, et al: Evidence for functionally important adenosine A2a receptors in the rat hippocampus. Brain Res 649:208-16, 1994 72. Kamiya H: Some Pharmacological Differences between Hippocampal Excitatory and Inhibitory Synapses in Transmitter Release - an Invitro Study. Synapse 8:229-235, 1991 73. Ochiishi T, Chen L, Yukawa A, et al: Cellular localization of adenosine A1 receptors in rat forebrain: Immunohistochemical analysis using adenosine A1 receptor-specific monoclonal antibody. Journal of Comparative Neurology 411:301-316, 1999 74. Rombo DM, Dias RB, Duarte ST, et al: Adenosine A1 Receptor Suppresses Tonic GABAA Receptor Currents in Hippocampal Pyramidal Cells and in a Defined Subpopulation of Interneurons. Cereb Cortex 26:1081-95, 2016 75. Rombo DM, Newton K, Nissen W, et al: Synaptic mechanisms of adenosine A2A receptor-mediated hyperexcitability in the hippocampus. Hippocampus 25:566-80, 2015 76. Cristovao-Ferreira S, Vaz SH, Ribeiro JA, et al: Adenosine A2A receptors enhance GABA transport into nerve terminals by restraining PKC inhibition of GAT-1. Journal of Neurochemistry 109:336-347, 2009 77. Arai A, Kessler M, Lynch G: The Effects of Adenosine on the Development of Long-Term Potentiation. Neuroscience Letters 119:41-44, 1990 78. Demendonca A, Ribeiro JA: 2-Chloroadenosine Decreases Long-Term Potentiation in the Hippocampal Ca1 Area of the Rat. Neuroscience Letters 118:107-111, 1990 79. Flajolet M, Wang ZF, Futter M, et al: FGF acts as a co-transmitter through adenosine A(2A) receptor to regulate synaptic plasticity. Nature Neuroscience 11:1402-1409, 2008 80. Shen HY, Coelho JE, Ohtsuka N, et al: A critical role of the adenosine A(2A) receptor in extrastriatal neurons in modulating psychomotor activity as revealed by opposite phenotypes of striatum and forebrain A2A receptor knock-outs. Journal of Neuroscience 28:2970-2975, 2008 81. Liang YC, Huang CC, Hsu KS: A role of p38 mitogen-activated protein kinase in adenosine A(1) receptor-mediated synaptic depotentiation in area CA1 of the rat hippocampus. Molecular Brain 1, 2008 82. Huang CC, Liang YC, Hsu KS: A role for extracellular adenosine in time-dependent reversal of long-term potentiation by low-frequency stimulation at hippocampal CA1 synapses. Journal of Neuroscience 19:9728-9738, 1999 83. Huang CC, Liang YC, Hsu KS: Characterization of the mechanism underlying the reversal of long term potentiation by low frequency stimulation at hippocampal CA1 synapses. Journal of Biological Chemistry 276:48108-48117, 2001 84. Costenla AR, Lopes LV, de Mendonca A, et al: A functional role for adenosine A3 receptors: modulation of synaptic plasticity in the rat hippocampus. Neurosci Lett 302:53-7, 2001 85. Costenla AR, Diogenes MJ, Canas PM, et al: Enhanced role of adenosine A(2A) receptors in the modulation of LTP in the rat hippocampus upon ageing. European Journal of Neuroscience 34:12-21, 2011 86. Lopes LV, Cunha RA, Ribeiro JA: Increase in the number, G protein coupling, and efficiency of facilitatory adenosine A2A receptors in the limbic cortex, but not striatum, of aged rats. J Neurochem 73:1733-8, 1999 87. Batalha VL, Pego JM, Fontinha BM, et al: Adenosine A(2A) receptor blockade reverts hippocampal stress-induced deficits and restores corticosterone circadian oscillation. Molecular Psychiatry 18:320-331, 2013 88. Lara DR, Souza DO: Schizophrenia: a purinergic hypothesis. Med Hypotheses 54:157-66, 2000 89. Akhondzadeh S, Safarcherati A, Amini H: Beneficial antipsychotic effects of allopurinol as add-on therapy for schizophrenia: a double blind, randomized and placebo controlled trial. Progress in Neuro-Psychopharmacology & Biological Psychiatry 29:253-259, 2005 90. Kurumaji A, Toru M: An increase in [3H] CGS21680 binding in the striatum of postmortem brains of chronic schizophrenics. Brain Res 808:320-3, 1998 91. Rial D, Lara DR, Cunha RA: The Adenosine Neuromodulation System in Schizophrenia. Adenosine Receptors in Neurology and Psychiatry 119:395-449, 2014 92. Ning YL, Yang N, Chen X, et al: Adenosine A2A receptor deficiency alleviates blast-induced cognitive dysfunction. Journal of Cerebral Blood Flow and Metabolism 33:1789-1798, 2013 93. Haller S, Rodriguez C, Moser D, et al: Acute Caffeine Administration Impact on Working Memory-Related Brain Activation and Functional Connectivity in the Elderly: A Bold and Perfusion Mri Study. Neuroscience 250:364-371, 2013 94. Pereira GS, Rossato JI, Sarkis JJF, et al: Activation of adenosine receptors in the posterior cingulate cortex impairs memory retrieval in the rat. Neurobiology of Learning and Memory 83:217-223, 2005 95. Augusto E, Matos M, Sevigny J, et al: Ecto-5'-nucleotidase (CD73)-mediated formation of adenosine is critical for the striatal adenosine A2A receptor functions. J Neurosci 33:11390-9, 2013 96. Waldeck B: Effect of caffeine on locomotor activity and central catecholamine mechanisms: a study with special reference to drug interaction. Acta Pharmacol Toxicol (Copenh) 36:1-23, 1975 97. El Yacoubi M, Ledent C, Menard JF, et al: The stimulant effects of caffeine on locomotor behaviour in mice are mediated through its blockade of adenosine A(2A) receptors. British Journal of Pharmacology 129:1465-1473, 2000 98. Shen HY, Canas PM, Garcia-Sanz P, et al: Adenosine A(2)A receptors in striatal glutamatergic terminals and GABAergic neurons oppositely modulate psychostimulant action and DARPP-32 phosphorylation. PLoS One 8:e80902, 2013