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The Adenosinergic System in the Neurobiology of Schizophrenia: Prospective Adenosine Receptor–Based Pharmacotherapy

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Psychiatry and Neuroscience Update - Vol. II

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Abstract

The pharmacotherapy of schizophrenia relies on restoring a dysregulated striatal dopamine and prefrontal cortex glutamate neurotransmission. However, these treatments are usually insufficient to fully cover all the disease symptomatology (i.e., negative and cognitive symptoms). Thus, the search for alternative and/or complementary neurotransmitter systems involved in the etiology of schizophrenia constitutes a big challenge in psychiatry these days. Adenosine, a well known neuromodulator in the central nervous system, has been highlighted because its relationship with both dopaminergic and glutamatergic neurotransmission. Indeed, the disruption of adenosine homeostasis in the adult brain has multiple consequences in the circuitry implicated in the pathophysiology of schizophrenia. Consequently, the “adenosine hypothesis of schizophrenia” foresees that the disruption of adenosine homeostasis within certain brain areas has behavioral consequences resembling schizophrenia symptoms. Thus, it has been postulated that restoring adenosine concentration within the schizophrenia-related brain areas might have beneficial antipsychotic properties. Overall, as adenosine dysfunction can trigger endophenotypes of schizophrenia, the development of drugs targeting the adenosinergic system will definitely constitute a new opportunity for therapeutic intervention in schizophrenia.

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References

  1. Drury AN, Szent-Gyorgyi A. The physiological activity of adenine compounds with especial reference to their action upon the mammalian heart. J Physiol. 1929;68:213–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Jacobson KA, Gao ZG. Adenosine receptors as therapeutic targets. Nat Rev Drug Discov. 2006;5:247–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Abbracchio MP, Burnstock G, Verkhratsky A, Zimmermann H. Purinergic signalling in the nervous system: an overview. Trends Neurosci. 2009;32:19–29.

    Article  CAS  PubMed  Google Scholar 

  4. Boison D. Modulators of nucleoside metabolism in the therapy of brain diseases. Curr Top Med Chem. 2011;11:1068–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  6. Burnstock G. Cotransmission. Curr Opin Pharmacol. 2004;4:47–52.

    Article  CAS  PubMed  Google Scholar 

  7. Zimmermann H. Biochemistry, localization and functional roles of ecto-nucleotidases in the nervous system. Prog Neurobiol. 1996;49:589–618.

    Article  CAS  PubMed  Google Scholar 

  8. Newby AC. Adenosine and the concept of “retaliatory metabolites”. Trends Biotechnol. 1984;9:42–4.

    CAS  Google Scholar 

  9. Brown RA, Spina D, Page CP. Adenosine receptors and asthma. Br J Pharmacol. 2008;153(Suppl):S446–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Burnstock G, Fredholm BB, Verkhratsky A. Adenosine and ATP receptors in the brain. Curr Top Med Chem. 2011;11:973–1011.

    Article  CAS  PubMed  Google Scholar 

  11. Johnston-Cox HA, Ravid K. Adenosine and blood platelets. Purinergic Signal. 2011;7:357–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Barletta KE, Ley K, Mehrad B. Regulation of neutrophil function by adenosine. Arterioscler Thromb Vasc Biol. 2012;32:856–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ernst PB, Garrison JC, Thompson LF. Much ado about adenosine: adenosine synthesis and function in regulatory T cell biology. J Immunol. 2010;185:1993–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Burnstock G. Purinergic regulation of vascular tone and remodelling. Auton Autocoid Pharmacol. 2009;29:63–72.

    Article  CAS  Google Scholar 

  15. Vallon V, Mühlbauer B, Osswald H. Adenosine and kidney function. Physiol Rev. 2006;86:901–40.

    Article  CAS  PubMed  Google Scholar 

  16. Fredholm BB, Sollevi A. Cardiovascular effects of adenosine. Clin Physiol. 1986;6:1–21.

    Article  CAS  PubMed  Google Scholar 

  17. Sebastião AM, Ribeiro JA. Tuning and fine-tuning of synapses with adenosine. Curr Neuropharmacol. 2009;7:180–94.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Fredholm BB. Adenosine and lipolysis. Int J Obes. 1981;5:643–9.

    CAS  PubMed  Google Scholar 

  19. Sebastiao AM, Ribeiro JA. Fine-tuning neuromodulation by adenosine. Trends Pharmacol Sci. 2000;21:341–6.

    Article  CAS  PubMed  Google Scholar 

  20. Latini S, Pedata F. Adenosine in the central nervous system: release mechanisms and extracellular concentrations. J Neurochem. 2001;79:463–84.

    Article  CAS  PubMed  Google Scholar 

  21. Snyder SH. Adenosine as a neuromodulator. Annu Rev Neurosci. 1985;8:103–24.

    Article  CAS  PubMed  Google Scholar 

  22. Ferre S, Fuxe K. Adenosine as a volume transmission signal. A feedback detector of neuronal activation. Prog Brain Res. 2000;125:353–61.

    Article  CAS  PubMed  Google Scholar 

  23. Fredholm BB. Purinoceptors in the nervous system. Pharmacol Toxicol. 1995;76:228–39.

    Article  CAS  PubMed  Google Scholar 

  24. Pull I, McIlwain H. Adenine derivatives as neurohumoral agents in the brain. The quantities liberated on excitation of superfused cerebral tissues. Biochem J. 1972;130:975–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Sattin A, Rall TW. The effect of adenosine and adenine nucleotides on the cyclic adenosine 3′, 5'-phosphate content of guinea pig cerebral cortex slices. Mol Pharmacol. 1970;6:13–23.

    CAS  PubMed  Google Scholar 

  26. Degubareff T, Sleator Jr W. Effects of caffeine on mammalian atrial muscle, and its interaction with adenosine and calcium. J Pharmacol Exp Ther. 1965;148:202–14.

    CAS  PubMed  Google Scholar 

  27. Trost T, Stock K. Effects of adenosine derivatives on cAMP accumulation and lipolysis in rat adipocytes and on adenylate cyclase in adipocyte plasma membranes. Naunyn Schmiedebergs Arch Pharmacol. 1977;299:33–40.

    Article  CAS  PubMed  Google Scholar 

  28. Londos C, Cooper DM, Wolff J. Subclasses of external adenosine receptors. Proc Natl Acad Sci U S A. 1980;77:2551–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. van Calker D, Muller M, Hamprecht B. Adenosine regulates via two different types of receptors, the accumulation of cyclic AMP in cultured brain cells. J Neurochem. 1979;33:999–1005.

    Article  PubMed  Google Scholar 

  30. Olah ME, Stiles GL. Adenosine receptor subtypes: characterization and therapeutic regulation. Annu Rev Pharmacol Toxicol. 1995;35:581–606.

    Article  CAS  PubMed  Google Scholar 

  31. Murray RD, Churchill PC. Effects of adenosine receptor agonists in the isolated, perfused rat kidney. Am J Phys. 1984;247:H343–8.

    CAS  Google Scholar 

  32. Anderson R, Sheehan MJ, Strong P. Characterization of the adenosine receptors mediating hypothermia in the conscious mouse. Br J Pharmacol. 1994;113:1386–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Yamamoto S, Nakanishi O, Matsui T, Shinohara N, Kinoshita H, Lambert C, et al. Intrathecal adenosine A1 receptor agonist attenuates hyperalgesia without inhibiting spinal glutamate release in the rat. Cell Mol Neurobiol. 2003;23:175–85.

    Article  CAS  PubMed  Google Scholar 

  34. De Lorenzo S, Veggetti M, Muchnik S, Losavio A. Presynaptic inhibition of spontaneous acetylcholine release induced by adenosine at the mouse neuromuscular junction. Br J Pharmacol. 2004;142:113–24.

    Article  CAS  PubMed  Google Scholar 

  35. Scholz KP, Miller RJ. Inhibition of quantal transmitter release in the absence of calcium influx by a G protein-linked adenosine receptor at hippocampal synapses. Neuron. 1992;8:1139–50.

    Article  CAS  PubMed  Google Scholar 

  36. Schnurr M, Toy T, Shin A, Hartmann G, Rothenfusser S, Soellner J, et al. Role of adenosine receptors in regulating chemotaxis and cytokine production of plasmacytoid dendritic cells. Blood. 2004;103:1391–7.

    Article  CAS  PubMed  Google Scholar 

  37. MacGregor DG, Miller WJ, Stone TW. Mediation of the neuroprotective action of R-phenylisopropyl-adenosine through a centrally located adenosine A1 receptor. Br J Pharmacol. 1993;110:470–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Varani K, Portaluppi F, Gessi S, Merighi S, Ongini E, Belardinelli L, et al. Dose and time effects of caffeine intake on human platelet adenosine A(2A) receptors: functional and biochemical aspects. Circulation. 2000;102:285–9.

    Article  CAS  PubMed  Google Scholar 

  39. Carroll MA, Doumad AB, Li J, Cheng MK, Falck JR, McGiff JC. Adenosine2A receptor vasodilation of rat preglomerular microvessels is mediated by EETs that activate the cAMP/PKA pathway. Am J Physiol Ren Physiol. 2006;291:F155–61.

    Article  CAS  Google Scholar 

  40. Popoli P, Betto P, Reggio R, Ricciarello G. Adenosine A2A receptor stimulation enhances striatal extracellular glutamate levels in rats. Eur J Pharmacol. 1995;287:215–7.

    Article  CAS  PubMed  Google Scholar 

  41. Nagel J, Schladebach H, Koch M, Schwienbacher I, Müller CE, Hauber W. Effects of an adenosine A2A receptor blockade in the nucleus accumbens on locomotion, feeding, and prepulse inhibition in rats. Synapse. 2003;49:279–86.

    Article  CAS  PubMed  Google Scholar 

  42. Scammell TE, Gerashchenko DY, Mochizuki T, McCarthy MT, Estabrooke IV, Sears CA, et al. An adenosine A2a agonist increases sleep and induces Fos in ventrolateral preoptic neurons. Neuroscience. 2001;107:653–63.

    Article  CAS  PubMed  Google Scholar 

  43. Kemp BK, Cocks TM. Adenosine mediates relaxation of human small resistance-like coronary arteries via A2B receptors. Br J Pharmacol. 1999;126:1796–800.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Donoso MV, López R, Miranda R, Briones R, Huidobro-Toro JP. A2B adenosine receptor mediates human chorionic vasoconstriction and signals through arachidonic acid cascade. Am J Physiol Heart Circ Physiol. 2005;288:H2439–49.

    Article  CAS  PubMed  Google Scholar 

  45. Zhong H, Belardinelli L, Maa T, Feoktistov I, Biaggioni I, Zeng D. A(2B) adenosine receptors increase cytokine release by bronchial smooth muscle cells. Am J Respir Cell Mol Biol. 2004;30:118–25.

    Article  CAS  PubMed  Google Scholar 

  46. Dubey RK, Gillespie DG, Mi Z, Jackson EK. Adenosine inhibits PDGF-induced growth of human glomerular mesangial cells via A(2B) receptors. Hypertension. 2005;46:628–34.

    Article  CAS  PubMed  Google Scholar 

  47. Zhong H, Shlykov SG, Molina JG, Sanborn BM, Jacobson MA, Tilley SL, et al. Activation of murine lung mast cells by the adenosine A3 receptor. J Immunol. 2003;171:338–45.

    Article  CAS  PubMed  Google Scholar 

  48. Das S, Cordis GA, Maulik N, Das DK. Pharmacological preconditioning with resveratrol: role of CREB-dependent Bcl-2 signaling via adenosine A3 receptor activation. Am J Physiol Heart Circ Physiol. 2005;288:H328–35.

    Article  CAS  PubMed  Google Scholar 

  49. Hinschen AK, Rose’Meyer RB, Headrick JP. Adenosine receptor subtypes mediating coronary vasodilation in rat hearts. J Cardiovasc Pharmacol. 2003;41:73–80.

    Article  CAS  PubMed  Google Scholar 

  50. Avila MY, Stone RA, Civan MM. Knockout of A3 adenosine receptors reduces mouse intraocular pressure. Invest Ophthalmol Vis Sci. 2002;43:3021–6.

    PubMed  Google Scholar 

  51. Stella L, de Novellis V, Marabese I, Berrino L, Maione S, Filippelli A, et al. The role of A3 adenosine receptors in central regulation of arterial blood pressure. Br J Pharmacol. 1998;125:437–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kolakowski Jr LF. GCRDb: a G-protein-coupled receptor database. Recept Channels. 1994;2:1–7.

    CAS  PubMed  Google Scholar 

  53. Fritze O, Filipek S, Kuksa V, Palczewski K, Hofmann KP, Ernst OP. Role of the conserved NPxxY(x)5,6F motif in the rhodopsin ground state and during activation. Proc Natl Acad Sci U S A. 2003;100:2290–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Rovati GE, Capra V, Neubig RR. The highly conserved DRY motif of class A G protein-coupled receptors: beyond the ground state. Mol Pharmacol. 2007;71:959–64.

    Article  CAS  PubMed  Google Scholar 

  55. Dunwiddie TV, Masino SA. The role and regulation of adenosine in the central nervous system. Annu Rev Neurosci. 2001;24:31–55.

    Article  CAS  PubMed  Google Scholar 

  56. Palmer TM, Stiles GL. Adenosine receptors. Neuropharmacology. 1995;34:683–94.

    Article  CAS  PubMed  Google Scholar 

  57. Rosin DL, Hettinger BD, Lee A, Linden J. Anatomy of adenosine A2A receptors in brain: morphological substrates for integration of striatal function. Neurology. 2003;61:S12–8.

    Article  CAS  PubMed  Google Scholar 

  58. Marala RB, Mustafa SJ. Direct evidence for the coupling of A2-adenosine receptor to stimulatory guanine nucleotide-binding-protein in bovine brain striatum. J Pharmacol Exp Ther. 1993;266:294–300.

    CAS  PubMed  Google Scholar 

  59. Ferre S, Karcz-Kubicha M, Hope BT, Popoli P, Burgueno J, Gutierrez MA, et al. Synergistic interaction between adenosine A2A and glutamate mGlu5 receptors: implications for striatal neuronal function. Proc Natl Acad Sci U S A. 2002;99:11940–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Feoktistov I, Biaggioni I. Adenosine A2B receptors. Pharmacol Rev. 1997;49:381–402.

    CAS  PubMed  Google Scholar 

  61. Patel V. Universal health coverage for schizophrenia: a global mental health priority. Schizophr Bull. 2016;42:885–90.

    Article  PubMed  Google Scholar 

  62. Haahr U, Friis S, Larsen TK, Melle I, Johannessen JO, Opjordsmoen S, et al. First-episode psychosis: diagnostic stability over one and two years. Psychopathology. 2008;41:322–9.

    Article  PubMed  Google Scholar 

  63. Bromet EJ, Kotov R, Fochtmann LJ, Carlson GA, Tanenberg-Karant M, Ruggero C, et al. Diagnostic shifts during the decade following first admission for psychosis. Am J Psychiatry. 2011;168:1186–94.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Tandon R, Gaebel W, Barch DM, Bustillo J, Gur RE, Heckers S, et al. Definition and description of schizophrenia in the DSM-5. Schizophr Res. 2013;150:3–10.

    Article  PubMed  Google Scholar 

  65. Laruelle M, Kegeles LS, Abi-Dargham A. Glutamate, dopamine, and schizophrenia: from pathophysiology to treatment. Ann N Y Acad Sci. 2003;1003:138–58.

    Article  CAS  PubMed  Google Scholar 

  66. Javitt DC. Glutamatergic theories of schizophrenia. Isr J Psychiatry Relat Sci. 2010;47:4–16.

    PubMed  Google Scholar 

  67. Carlsson A. The current status of the dopamine hypothesis of schizophrenia. Neuropsychopharmacology. 1988;1:179–86.

    Article  CAS  PubMed  Google Scholar 

  68. Leucht S, Heres S, Kissling W, Davis JM. Evidence-based pharmacotherapy of schizophrenia. Int J Neuropsychopharmacol. 2011;14:269–84.

    Article  CAS  PubMed  Google Scholar 

  69. Citrome L. Unmet needs in the treatment of schizophrenia: new targets to help different symptom domains. J Clin Psychiatry. 2014;74(Suppl 2):21–6.

    Article  CAS  Google Scholar 

  70. Ferre S, Agnati LF, Ciruela F, Lluis C, Woods AS, Fuxe K, et al. Neurotransmitter receptor heteromers and their integrative role in “local modules”: the striatal spine module. Brain Res Rev. 2007;55:55–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Fuxe K, Ferre S, Genedani S, Franco R, Agnati LF. Adenosine receptor-dopamine receptor interactions in the basal ganglia and their relevance for brain function. Physiol Behav. 2007;92:210–7.

    Article  CAS  PubMed  Google Scholar 

  72. Ferré S. Adenosine-dopamine interactions in the ventral striatum. Implications for the treatment of schizophrenia. Psychopharmacology. 1997;133:107–20.

    Article  PubMed  Google Scholar 

  73. Ferre S, Ciruela F, Quiroz C, Lujan R, Popoli P, Cunha RA, et al. Adenosine receptor heteromers and their integrative role in striatal function. ScientificWorldJournal. 2007;7:74–85.

    Article  PubMed  Google Scholar 

  74. Ferre S, Borycz J, Goldberg SR, Hope BT, Morales M, Lluis C, et al. Role of adenosine in the control of homosynaptic plasticity in striatal excitatory synapses. J Integr Neurosci. 2005;4:445–64.

    Article  PubMed  Google Scholar 

  75. Ciruela F, Casado V, Rodrigues RJ, Lujan R, Burgueno J, Canals M, et al. Presynaptic control of striatal glutamatergic neurotransmission by adenosine A1-A2A receptor heteromers. J Neurosci. 2006;26:2080–7.

    Article  CAS  PubMed  Google Scholar 

  76. Lara DR, Souza DO. Schizophrenia: a purinergic hypothesis. Med Hypotheses. 2000;54:157–66.

    Article  CAS  PubMed  Google Scholar 

  77. Lara DR, Dall’Igna OP, Ghisolfi ES, Brunstein MG. Involvement of adenosine in the neurobiology of schizophrenia and its therapeutic implications. Prog Neuro-Psychopharmacol Biol Psychiatry. 2006;30:617–29.

    Article  CAS  Google Scholar 

  78. Moscoso-Castro M, Gracia-Rubio I, Ciruela F, Valverde O. Genetic blockade of adenosine A2A receptors induces cognitive impairments and anatomical changes related to psychotic symptoms in mice. Eur Neuropsychopharmacol. 2016;26:1227–40.

    Article  CAS  PubMed  Google Scholar 

  79. Boison D, Singer P, Shen H-Y, Feldon J, Yee BK. Adenosine hypothesis of schizophrenia — opportunities for pharmacotherapy. Neuropharmacology. 2012;62:1527–43.

    Article  CAS  PubMed  Google Scholar 

  80. Luby ED, Cohen BD, Rosenbaum G, Gottlieb JS, Kelley R. Study of a new schizophrenomimetic drug; sernyl. AMA Arch Neurol Psychiatry. 1959;81:363–9.

    Article  CAS  PubMed  Google Scholar 

  81. Lodge D, Anis NA. Effects of phencyclidine on excitatory amino acid activation of spinal interneurones in the cat. Eur J Pharmacol. 1982;77:203–4.

    Article  CAS  PubMed  Google Scholar 

  82. Moghaddam B, Adams B, Verma A, Daly D. Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J Neurosci. 1997;17:2921–7.

    CAS  PubMed  Google Scholar 

  83. Olney JW, Sharpe LG. Brain lesions in an infant rhesus monkey treated with monsodium glutamate. Science. 1969;166:386–8.

    Article  CAS  PubMed  Google Scholar 

  84. Adams B, Moghaddam B. Corticolimbic dopamine neurotransmission is temporally dissociated from the cognitive and locomotor effects of phencyclidine. J Neurosci. 1998;18:5545–54.

    CAS  PubMed  Google Scholar 

  85. Ikonomidou C, Bosch F, Miksa M, Bittigau P, Vöckler J, Dikranian K, et al. Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science. 1999;283:70–4.

    Article  CAS  PubMed  Google Scholar 

  86. Olney JW, Labruyere J, Wang G, Wozniak DF, Price MT, Sesma MA. NMDA antagonist neurotoxicity: mechanism and prevention. Science. 1991;254:1515–8.

    Article  CAS  PubMed  Google Scholar 

  87. Weinberger DR. On the plausibility of “the neurodevelopmental hypothesis” of schizophrenia. Neuropsychopharmacology. 1996;14:1S–11S.

    Article  CAS  PubMed  Google Scholar 

  88. Javitt DC, Zukin SR. Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry. 1991;148:1301–8.

    Article  CAS  PubMed  Google Scholar 

  89. Kalinichev M, Robbins MJ, Hartfield EM, Maycox PR, Moore SH, Savage KM, et al. Comparison between intraperitoneal and subcutaneous phencyclidine administration in Sprague-Dawley rats: a locomotor activity and gene induction study. Prog Neuro-Psychopharmacol Biol Psychiatry. 2008;32:414–22.

    Article  CAS  Google Scholar 

  90. Sams-Dodd F. Distinct effects of d-amphetamine and phencyclidine on the social behaviour of rats. Behav Pharmacol. 1995;6:55–65.

    CAS  PubMed  Google Scholar 

  91. Egerton A, Reid L, McKerchar CE, Morris BJ, Pratt JA. Impairment in perceptual attentional set-shifting following PCP administration: a rodent model of set-shifting deficits in schizophrenia. Psychopharmacology. 2005;179:77–84.

    Article  CAS  PubMed  Google Scholar 

  92. Mansbach RS, Geyer MA. Effects of phencyclidine and phencyclidine biologs on sensorimotor gating in the rat. Neuropsychopharmacology. 1989;2:299–308.

    Article  CAS  PubMed  Google Scholar 

  93. Mouri A, Noda Y, Enomoto T, Nabeshima T. Phencyclidine animal models of schizophrenia: approaches from abnormality of glutamatergic neurotransmission and neurodevelopment. Neurochem Int. 2007;51:173–84.

    Article  CAS  PubMed  Google Scholar 

  94. Rainey JM, Crowder MK. Prolonged psychosis attributed to phencyclidine: report of three cases. Am J Psychiatry. 1975;132:1076–8.

    Article  PubMed  Google Scholar 

  95. Allen RM, Young SJ. Phencyclidine-induced psychosis. Am J Psychiatry. 1978;135:1081–4.

    Article  CAS  PubMed  Google Scholar 

  96. Gotoh L, Kawanami N, Nakahara T, Hondo H, Motomura K, Ohta E, et al. Effects of the adenosine A(1) receptor agonist N(6)-cyclopentyladenosine on phencyclidine-induced behavior and expression of the immediate-early genes in the discrete brain regions of rats. Brain Res Mol Brain Res. 2002;100:1–12.

    Article  CAS  PubMed  Google Scholar 

  97. Rimondini R, Ferre S, Ogren SO, Fuxe K. Adenosine A2A agonists: a potential new type of atypical antipsychotic. Neuropsychopharmacology. 1997;17:82–91.

    Article  CAS  PubMed  Google Scholar 

  98. Malec D, Poleszak E. Involvement of adenosine receptors in dizocilpine-induced motor activity in mice. Pharmacol Rep. 2006;58:101–6.

    CAS  PubMed  Google Scholar 

  99. Shen H-Y, Coelho JE, Ohtsuka N, Canas PM, Day Y-J, Huang Q-Y, et al. A critical role of the adenosine A2A receptor in extrastriatal neurons in modulating psychomotor activity as revealed by opposite phenotypes of striatum and forebrain A2A receptor knock-outs. J Neurosci. 2008;28:2970–5.

    Article  CAS  PubMed  Google Scholar 

  100. Howes OD, Kapur S. The dopamine hypothesis of schizophrenia: version III — the final common pathway. Schizophr Bull. 2009;35:549–62.

    Article  PubMed  PubMed Central  Google Scholar 

  101. Edeleanu L. Uber einige Derivate der Phenylmethacrylsäure und der Phenylisobuttersäure. Ber Dtsch Chem Ges. 1887;20:616.

    Article  Google Scholar 

  102. Heal DJ, Smith SL, Gosden J, Nutt DJ. Amphetamine, past and present — a pharmacological and clinical perspective. J Psychopharmacol. 2013;27:479–96.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Deller T, Sarter M. Effects of repeated administration of amphetamine on behavioral vigilance: evidence for “sensitized” attentional impairments. Psychopharmacology. 1998;137:410–4.

    Article  CAS  PubMed  Google Scholar 

  104. Kondrad RL, Burk JA. Transient disruption of attentional performance following escalating amphetamine administration in rats. Psychopharmacology. 2004;175:436–42.

    CAS  PubMed  Google Scholar 

  105. Castner SA, Vosler PS, Goldman-Rakic PS. Amphetamine sensitization impairs cognition and reduces dopamine turnover in primate prefrontal cortex. Biol Psychiatry. 2005;57:743–51.

    Article  CAS  PubMed  Google Scholar 

  106. Kolb B, Gorny G, Li Y, Samaha A-N, Robinson TE. Amphetamine or cocaine limits the ability of later experience to promote structural plasticity in the neocortex and nucleus accumbens. Proc Natl Acad Sci U S A. 2003;100:10523–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Selemon LD, Begović A, Goldman-Rakic PS, Castner SA. Amphetamine sensitization alters dendritic morphology in prefrontal cortical pyramidal neurons in the non-human primate. Neuropsychopharmacology. 2007;32:919–31.

    Article  CAS  PubMed  Google Scholar 

  108. Wolf ME, Mangiavacchi S, Sun X. Mechanisms by which dopamine receptors may influence synaptic plasticity. Ann N Y Acad Sci. 2003;1003:241–9.

    Article  CAS  PubMed  Google Scholar 

  109. Durieux PF, Schiffmann SN, de Kerchove d’Exaerde A. Differential regulation of motor control and response to dopaminergic drugs by D1R and D2R neurons in distinct dorsal striatum subregions. EMBO J. 2012;31:640–53.

    Article  CAS  PubMed  Google Scholar 

  110. Seeman P. Dopamine D2 receptors as treatment targets in schizophrenia. Clin Schizophr Relat Psychoses. 2010;4:56–73.

    Article  PubMed  Google Scholar 

  111. Ferre S, Fredholm BB, Morelli M, Popoli P, Fuxe K. Adenosine–dopamine receptor–receptor interactions as an integrative mechanism in the basal ganglia. Trends Neurosci. 1997;20:482–7.

    Article  CAS  PubMed  Google Scholar 

  112. Ferre S, Ciruela F, Canals M, Marcellino D, Burgueno J, Casado V, et al. Adenosine A2A–dopamine D2 receptor–receptor heteromers. Targets for neuro-psychiatric disorders. Parkinsonism Relat Disord. 2004;10:265–71.

    Article  PubMed  Google Scholar 

  113. Shen H-Y, Singer P, Lytle N, Wei CJ, Lan J-Q, Williams-Karnesky RL, et al. Adenosine augmentation ameliorates psychotic and cognitive endophenotypes of schizophrenia. J Clin Invest. 2012;122:2567–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Kurumaji A, Toru M. An increase in [3H] CGS21680 binding in the striatum of postmortem brains of chronic schizophrenics. Brain Res. 1998;808:320–3.

    Article  CAS  PubMed  Google Scholar 

  115. Deckert J, Brenner M, Durany N, Zöchling R, Paulus W, Ransmayr G, et al. Up-regulation of striatal adenosine A(2A) receptors in schizophrenia. Neuroreport. 2003;14:313–6.

    Article  CAS  PubMed  Google Scholar 

  116. Hwang Y, Kim J, Shin JY, Kim JI, Seo JS, Webster MJ, et al. Gene expression profiling by mRNA sequencing reveals increased expression of immune/inflammation-related genes in the hippocampus of individuals with schizophrenia. Transl Psychiatry. 2013;3:e321.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Villar-Menéndez I, Díaz-Sánchez S, Blanch M, Albasanz JL, Pereira-Veiga T, Monje A, et al. Reduced striatal adenosine A2A receptor levels define a molecular subgroup in schizophrenia. J Psychiatr Res. 2014;51:49–59.

    Article  PubMed  Google Scholar 

  118. Hong C-J, Liu H-C, Liu T-Y, Liao D-L, Tsai S-J. Association studies of the adenosine A2a receptor (1976T>C) genetic polymorphism in Parkinson’s disease and schizophrenia. J Neural Transm. 2005;112:1503–10.

    Article  CAS  PubMed  Google Scholar 

  119. Gotoh L, Mitsuyasu H, Kobayashi Y, Oribe N, Takata A, Ninomiya H, et al. Association analysis of adenosine A1 receptor gene (ADORA1) polymorphisms with schizophrenia in a Japanese population. Psychiatr Genet. 2009;19:328–35.

    Article  PubMed  Google Scholar 

  120. Dutra GP, Ottoni GL, Lara DR, Bogo MR. Lower frequency of the low activity adenosine deaminase allelic variant (ADA1*2) in schizophrenic patients. Rev Bras Psiquiatr. 2010;32:275–8.

    Article  PubMed  Google Scholar 

  121. 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. Prog Neuro-Psychopharmacol Biol Psychiatry. 2005;29:253–9.

    Article  CAS  Google Scholar 

  122. Brunstein MG, Ghisolfi ES, Ramos FLP, Lara DR. A clinical trial of adjuvant allopurinol therapy for moderately refractory schizophrenia. J Clin Psychiatry. 2005;66:213–9.

    Article  CAS  PubMed  Google Scholar 

  123. Dickerson FB, Stallings CR, Origoni AE, Sullens A, Khushalani S, Sandson N, et al. A double-blind trial of adjunctive allopurinol for schizophrenia. Schizophr Res. 2009;109:66–9.

    Article  PubMed  Google Scholar 

  124. Linden N, Onwuanibe A, Sandson N. Rapid resolution of psychotic symptoms in a patient with schizophrenia using allopurinol as an adjuvant: a case report. Clin Schizophr Relat Psychoses. 2014;7:231–4.

    Article  PubMed  Google Scholar 

  125. Weiser M, Gershon AA, Rubinstein K, Petcu C, Ladea M, Sima D, et al. A randomized controlled trial of allopurinol vs. placebo added on to antipsychotics in patients with schizophrenia or schizoaffective disorder. Schizophr Res. 2012;138:35–8.

    Article  PubMed  Google Scholar 

  126. Hirota T, Kishi T. Adenosine hypothesis in schizophrenia and bipolar disorder: a systematic review and meta-analysis of randomized controlled trial of adjuvant purinergic modulators. Schizophr Res. 2013;149:88–95.

    Article  PubMed  Google Scholar 

  127. Buie LW, Oertel MD, Cala SO. Allopurinol as adjuvant therapy in poorly responsive or treatment refractory schizophrenia. Ann Pharmacother. 2006;40:2200–4.

    Article  CAS  PubMed  Google Scholar 

  128. Akhondzadeh S, Shasavand E, Jamilian H, Shabestari O, Kamalipour A. Dipyridamole in the treatment of schizophrenia: adenosine-dopamine receptor interactions. J Clin Pharm Ther. 2000;25:131–7.

    Article  CAS  PubMed  Google Scholar 

  129. Machado-Vieira R, Soares JC, Lara DR, Luckenbaugh DA, Busnello JV, Marca G, et al. A double-blind, randomized, placebo-controlled 4-week study on the efficacy and safety of the purinergic agents allopurinol and dipyridamole adjunctive to lithium in acute bipolar mania. J Clin Psychiatry. 2008;69:1237–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Svenningsson P, Le Moine C, Fisone G, Fredholm BB. Distribution, biochemistry and function of striatal adenosine A2A receptors. Prog Neurobiol. 1999;59:355–96.

    Article  CAS  PubMed  Google Scholar 

  131. Fredholm BB, Chen JF, Cunha RA, Svenningsson P, Vaugeois JM. Adenosine and brain function. Int Rev Neurobiol. 2005;63:191–270.

    Article  CAS  PubMed  Google Scholar 

  132. Gomes CV, Kaster MP, Tomé AR, Agostinho PM, Cunha RA. Adenosine receptors and brain diseases: neuroprotection and neurodegeneration. Biochim Biophys Acta. 1808;2011:1380–99.

    Google Scholar 

  133. Kaiser S, Quinn R. Adenosine receptors as potential therapeutic targets. Drug Discov Today. 1999;4:542–51.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by grants SAF2011-24779, Consolider-Ingenio CSD2008-00005 and PCIN-2013-019-C03-03 from Ministerio de Economía y Competitividad and ICREA Academia-2010 from the Catalan Institution for Research and Advanced Studies to F.C. Also, the authors belong to the “Neuropharmacology and Pain” accredited research group (Generalitat de Catalunya, 2009 SGR 232).

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Authors and Affiliations

  1. Francisco Ciruela Pharmacology Unit, Department of Pharmacology, Faculty of Medicine, University of Barcelona, Government Pavilion, Llobregat Hospital, Barcelona, Spain

    Francisco Ciruela, Víctor Fernández-Dueñas & Xavier Altafaj

  2. Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain

    Francisco Ciruela, Víctor Fernández-Dueñas & Xavier Altafaj

  3. Servei de Psiquitria, Hospital Universitari de Bellvitge-IDIBELL, Universitat de Barcelona, CIBERSAM, L’Hospitalet de Llobregat, 08907, Barcelona, Spain

    Fernando Contreras & José Manuel Menchón

  4. Unitat de Farmacologia, Departament Patologia i Terapèutica Experimental, Facultat de Medicina, IDIBELL, Universitat de Barcelona, L’Hospitalet de Llobregat, 08907, Barcelona, Spain

    Antoni Vallano & Marta Valle-León

  5. Servei de Farmacologia Clínica, Hospital Universitari de Bellvitge-IDIBELL, L’Hospitalet de Llobregat, 08907, Barcelona, Spain

    Antoni Vallano

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  1. Francisco Ciruela
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Correspondence to Francisco Ciruela .

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  1. National University of Cuyo, Catholic University of Argentina, Guaymallen Mendoza, Argentina

    Pascual Ángel Gargiulo

  2. Institute of Neurobiology Foundation, National Academy of Medicine, Buenos Aires, Argentina

    Humberto Luis Mesones-Arroyo

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Ciruela, F. et al. (2017). The Adenosinergic System in the Neurobiology of Schizophrenia: Prospective Adenosine Receptor–Based Pharmacotherapy. In: Gargiulo, P., Mesones-Arroyo, H. (eds) Psychiatry and Neuroscience Update - Vol. II. Springer, Cham. https://doi.org/10.1007/978-3-319-53126-7_29

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