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Receptor crosstalk: haloperidol treatment enhances A2A adenosine receptor functioning in a transfected cell model

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Abstract

A2A adenosine receptors are considered an excellent target for drug development in several neurological and psychiatric disorders. It is noteworthy that the responses evoked by A2A adenosine receptors are regulated by D2 dopamine receptor ligands. These two receptors are co-expressed at the level of the basal ganglia and interact to form functional heterodimers. In this context, possible changes in A2A adenosine receptor functional responses caused by the chronic blockade/activation of D2 dopamine receptors should be considered to optimise the therapeutic effectiveness of dopaminergic agents and to reduce any possible side effects. In the present paper, we investigated the regulation of A2A adenosine receptors induced by antipsychotic drugs, commonly acting as D2 dopamine receptor antagonists, in a cellular model co-expressing both A2A and D2 receptors. Our data suggest that the treatment of cells with the classical antipsychotic haloperidol increased both the affinity and responsiveness of the A2A receptor and also affected the degree of A2A–D2 receptor heterodimerisation. In contrast, an atypical antipsychotic, clozapine, had no effect on A2A adenosine receptor parameters, suggesting that the two classes of drugs have different effects on adenosine–dopamine receptor interaction. Modifications to A2A adenosine receptors may play a significant role in determining cerebral adenosine effects during the chronic administration of antipsychotics in psychiatric diseases and may account for the efficacy of A2A adenosine receptor ligands in pathologies associated with dopaminergic system dysfunction.

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References

  1. Boison D (2007) Adenosine as a modulator of brain activity. Drug News Perspect 20:607–611

    Article  CAS  PubMed  Google Scholar 

  2. Fiebich BL, Biber K, Lieb K, van Calker D, Berger M, Bauer J, Gebicke-Haerter PJ (1996) Cyclooxygenase-2 expression in rat microglia is induced by adenosine A2a-receptors. Glia 18:152–160

    Article  CAS  PubMed  Google Scholar 

  3. Peterfreund RA, MacCollin M, Gusella J, Fink JS (1996) Characterization and expression of the human A2a adenosine receptor gene. J Neurochem 66:362–368

    Article  CAS  PubMed  Google Scholar 

  4. Brodie C, Blumberg PM, Jacobson KA (1998) Activation of the A2A adenosine receptor inhibits nitric oxide production in glial cells. FEBS Lett 429:139–142

    Article  CAS  PubMed  Google Scholar 

  5. Svenningsson P, Le Moine C, Fisone G, Fredholm BB (1999) Distribution, biochemistry and function of striatal adenosine A2A receptors. Prog Neurobiol 59:355–396

    Article  CAS  PubMed  Google Scholar 

  6. Hettinger BD, Lee A, Linden J, Rosin DL (2001) Ultrastructural localization of adenosine A2A receptors suggests multiple cellular sites for modulation of GABAergic neurons in rat striatum. J Comp Neurol 431:331–346

    Article  CAS  PubMed  Google Scholar 

  7. Yu L, Frith MC, Suzuki Y, Peterfreund RA, Gearan T, Sugano S, Schwarzschild MA, Weng Z, Fink JS, Chen JF (2004) Characterization of genomic organization of the adenosine A(2A) receptor gene by molecular and bioinformatics analyses. Brain Res 1000:156–173

    Article  CAS  PubMed  Google Scholar 

  8. Chen JF, Pedata F (2008) Modulation of ischemic brain injury and neuroinflammation by adenosine A2A receptors. Curr Pharm Des 14:1490–1499

    Article  CAS  PubMed  Google Scholar 

  9. Haskó G, Linden J, Cronstein B, Pacher P (2008) Adenosine receptors: therapeutic aspects for inflammatory and immune diseases. Nat Rev Drug Discov 7:759–770

    Article  PubMed  Google Scholar 

  10. Mayne M, Fotheringham J, Yan HJ, Power C, Del Bigio MR, Peeling J, Geiger JD (2001) Adenosine A2A receptor activation reduces proinflammatory events and decreases cell death following intracerebral hemorrhage. Ann Neurol 49:727–735

    Article  CAS  PubMed  Google Scholar 

  11. Trincavelli ML, Melani A, Guidi S, Cuboni S, Cipriani S, Pedata F, Martini C (2008) Regulation of A(2A) adenosine receptor expression and functioning following permanent focal ischemia in rat brain. J Neurochem 104:479–490

    CAS  PubMed  Google Scholar 

  12. Deckert J, Brenner M, Durany N, Zöchling R, Paulus W, Ransmayr G, Tatschner T, Danielczyk W, Jellinger K, Riederer P (2003) Up-regulation of striatal adenosine A(2A) receptors in schizophrenia. NeuroReport 14:313–316

    Article  CAS  PubMed  Google Scholar 

  13. Martini C, Tuscano D, Trincavelli ML, Cerrai E, Bianchi M, Ciapparelli A, Lucioni A, Novelli L, Catena M, Lucacchini A, Cassano GB, Dell’Osso L (2006) Upregulation of A2A adenosine receptors in platelets from patients affected by bipolar disorders under treatment with classical antipsychotics. J Psychiatr Res 40:81–88

    Article  PubMed  Google Scholar 

  14. Baldessarini RJ (2002) Treatment research in bipolar disorder: issues and recommendations. CNS Drugs 16:721–729

    Article  PubMed  Google Scholar 

  15. Brambilla P, Barale F, Soares JC (2003) Atypical antipsychotics and mood stabilization in bipolar disorder. Psychopharmacology 166:315–332

    CAS  PubMed  Google Scholar 

  16. Sundram S, Joyce PR, Kennedy MA (2003) Schizophrenia and bipolar affective disorder: perspectives for the development of therapeutics. Curr Mol Med 3:393–407

    Article  CAS  PubMed  Google Scholar 

  17. Ferré S, O’Connor WT, Snaprud P, Ungerstedt U, Fuxe K (1994) Antagonistic interaction between adenosine A2A receptors and dopamine D2 receptors in the ventral striopallidal system. Implications for the treatment of schizophrenia. Neurosci 63:765–773

    Article  Google Scholar 

  18. Ferré S, Quiroz C, Woods AS, Cunha R, Popoli P, Ciruela F, Lluis C, Franco R, Azdad K, Schiffmann SN (2008) An update on adenosine A2A–dopamine D2 receptor interactions: implications for the function of G protein-coupled receptors. Curr Pharm Des 14:1468–1474

    Article  PubMed  Google Scholar 

  19. Azdad K, Gall D, Woods AS, Ledent C, Ferré S, Schiffmann SN (2009) Dopamine D2 and adenosine A2A receptors regulate NMDA-mediated excitation in accumbens neurons through A2A–D2 receptor heteromerization. Neuropsychopharmacology 34:972–986

    Article  CAS  PubMed  Google Scholar 

  20. Fink JS, Weaver DR, Rivkees SA, Peterfreund RA, Pollack AE, Adler EM, Reppert SM (1992) Molecular cloning of the rat A2 adenosine receptor: selective co-expression with D2 dopamine receptors in rat striatum. Brain Res Mol Brain Res 14:186–195

    Article  CAS  PubMed  Google Scholar 

  21. Canals M, Marcellino D, Fanelli F, Ciruela F, de Benedetti P, Goldberg SR, Neve K, Fuxe K, Agnati LF, Woods AS, Ferré S, Lluis C, Bouvier M, Franco R (2003) Adenosine A2A-dopamine D2 receptor–receptor heteromerization: qualitative and quantitative assessment by fluorescence and bioluminescence energy transfer. J Biol Chem 278:46741–46749

    Article  CAS  PubMed  Google Scholar 

  22. Fuxe K, Ferré S, Canals M, Torvinen M, Terasmaa A, Marcellino D, Goldberg SR, Staines W, Jacobsen KX, Lluis C, Woods AS, Agnati LF, Franco R (2005) Adenosine A2A and dopamine D2 heteromeric receptor complexes and their function. J Mol Neurosci 26:209–220

    Article  CAS  PubMed  Google Scholar 

  23. Tsai SJ (2005) Adenosine A2a receptor/dopamine D2 receptor hetero-oligomerization: a hypothesis that may explain behavioral sensitization to psychostimulants and schizophrenia. Med Hypotheses 64:197–200

    Article  CAS  PubMed  Google Scholar 

  24. Navarro G, Carriba P, Gandía J, Ciruela F, Casadó V, Cortés A, Mallol J, Canela EI, Lluis C, Franco R (2008) Detection of heteromers formed by cannabinoid CB1, dopamine D2, and adenosine A2A G-protein-coupled receptors by combining bimolecular fluorescence complementation and bioluminescence energy transfer. Scientific World Journal 8:1088–1097

    CAS  PubMed  Google Scholar 

  25. Vidi PA, Chemel BR, Hu CD, Watts VJ (2008) Ligand-dependent oligomerization of dopamine D(2) and adenosine A(2A) receptors in living neuronal cells. Mol Pharmacol 74:544–751

    Article  CAS  PubMed  Google Scholar 

  26. Dixon DA, Fenix LA, Kim DM, Raffa RB (1999) Indirect modulation of dopamine D2 receptors as potential pharmacotherapy for schizophrenia: I. Adenosine agonists. Ann Pharmacother 33:480–488

    Article  CAS  PubMed  Google Scholar 

  27. Wardas J (2008) Potential role of adenosine A2A receptors in the treatment of schizophrenia. Front Biosci 13:4071–4096

    Article  CAS  PubMed  Google Scholar 

  28. Klotz KN, Hessling J, Hegler J, Owman C, Kull B, Fredholm BB, Lohse MJ (1998) Comparative pharmacology of human adenosine receptor subtypes—characterization of stably transfected receptors in CHO cells. Naunyn Schmiedebergs Arch Pharmacol 357:1–9

    Article  CAS  PubMed  Google Scholar 

  29. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    Article  CAS  PubMed  Google Scholar 

  30. Klotz KN, Cristalli G, Grifantini M, Vittori S, Lohse MJ (1985) Photoaffinity labeling of A1-adenosine receptors. J Biol Chem 260:14659–14664

    CAS  PubMed  Google Scholar 

  31. Albasanz JL, Rodríguez A, Ferrer I, Martín M (2006) Adenosine A2A receptors are up-regulated in Pick’s disease frontal cortex. Brain Pathol 16:249–255

    Article  CAS  PubMed  Google Scholar 

  32. Hillion J, Canals M, Torvinen M, Casado V, Scott R, Terasmaa A, Hansson A, Watson S, Olah ME, Mallol J, Canela EI, Zoli M, Agnati LF, Ibanez CF, Lluis C, Franco R, Ferre S, Fuxe K (2002) Coaggregation, cointernalization, and codesensitization of adenosine A2A receptors and dopamine D2 receptors. J Biol Chem 277:18091–18097

    Article  CAS  PubMed  Google Scholar 

  33. Kapur S, Seeman P (2001) Does fast dissociation from the dopamine D(2) receptor explain the action of atypical antipsychotics? A new hypothesis. Am J Psych 158:360–369

    Article  CAS  Google Scholar 

  34. Baron JC, Martinot JL, Cambon H, Boulenger JP, Poirier MF, Caillard V, Blin J, Huret JD, Loc’h C, Maziere B (1989) Striatal dopamine receptor occupancy during and following withdrawal from neuroleptic treatment: correlative evaluation by positron emission tomography and plasma prolactin levels. Psychopharmacology 99:463–472

    Article  CAS  PubMed  Google Scholar 

  35. Schlegel S, Schlösser R, Hiemke C, Nickel O, Bockisch A, Hahn K (1996) Prolactin plasma levels and D2-dopamine receptor occupancy measured with IBZM-SPECT. Psychopharmacology 124:285–287

    Article  CAS  PubMed  Google Scholar 

  36. Kessler RM, Ansari MS, Riccardi P, Li R, Jayathilake K, Dawant B, Meltzer HY (2006) Occupancy of striatal and extrastriatal dopamine D2 receptors by clozapine and quetiapine. Neuropsychopharmacology 31:1991–2001

    Article  CAS  PubMed  Google Scholar 

  37. Catafau AM, Penengo MM, Nucci G, Bullich S, Corripio I, Parellada E, García-Ribera C, Gomeni R, Merlo-Pich E (2008) Pharmacokinetics and time-course of D(2) receptor occupancy induced by atypical antipsychotics in stabilized schizophrenic patients. J Psychopharmacol 22:882–894

    Article  CAS  PubMed  Google Scholar 

  38. Ritter LM, Meador-Woodruff JH (1997) Antipsychotic regulation of hippocampal dopamine receptor messenger RNA expression. Biol Psychiatry 42:155–164

    Article  CAS  PubMed  Google Scholar 

  39. Florijn WJ, Tarazi FI, Creese I (1997) Dopamine receptor subtypes: differential regulation after 8 months treatment with antipsychotic drugs. J Pharmacol Exp Ther 280:561–569

    CAS  PubMed  Google Scholar 

  40. Reuss B, Unsicker K (2001) Atypical neuroleptic drugs downregulate dopamine sensitivity in rat cortical and striatal astrocytes. Mol Cell Neurosci 18:197–209

    Article  CAS  PubMed  Google Scholar 

  41. Rimondini R, Ferré S, Ogren SO, Fuxe K (1997) Adenosine A2A agonists: a potential new type of atypical antipsychotic. Neuropsychopharmacology 17:82–91

    Article  CAS  PubMed  Google Scholar 

  42. Ferré S, Ciruela F, Canals M, Marcellino D, Burgueno J, Casadó V, Hillion J, Torvinen M, Fanelli F, Benedetti Pd P, Goldberg SR, Bouvier M, Fuxe K, Agnati LF, Lluis C, Franco R, Woods A (2004) Adenosine A2A–dopamine D2 receptor–receptor heteromers. Targets for neuro-psychiatric disorders. Parkinsonism Relat Disord 10:265–271

    Article  PubMed  Google Scholar 

  43. Ikeda K, Kurokawa M, Aoyama S, Kuwana Y (2002) Neuroprotection by adenosine A2A receptor blockade in experimental models of Parkinson’s disease. J Neurochem 80:262–270

    Article  CAS  PubMed  Google Scholar 

  44. Chen JF, Sonsalla PK, Pedata F, Melani A, Domenici MR, Popoli P, Geiger J, Lopes LV, de Mendonça A (2007) Adenosine A2A receptors and brain injury: broad spectrum of neuroprotection, multifaceted actions and “fine tuning” modulation. Prog Neurobiol 83:310–331

    Article  CAS  PubMed  Google Scholar 

  45. Genovese T, Melani A, Esposito E, Mazzon E, Di Paola R, Bramanti P, Pedata F, Cuzzocrea S (2009) The selective adenosine A2A receptor agonist CGS 21680 reduces JNK MAPK activation in oligodendrocytes in injured spinal cord. Shock 32:578–585

    Article  CAS  PubMed  Google Scholar 

  46. Kochanek PM, Hendrich KS, Jackson EK, Wisniewski SR, Melick JA, Shore PM, Janesko KL, Zacharia L, Ho C (2005) Characterization of the effects of adenosine receptor agonists on cerebral blood flow in uninjured and traumatically injured rat brain using continuous arterial spin-labeled magnetic resonance imaging. J Cereb Blood Flow Metab 25:1596–1612

    Article  CAS  PubMed  Google Scholar 

  47. Cassada DC, Tribble CG, Young JS, Gangemi JJ, Gohari AR, Butler PD, Rieger JM, Kron IL, Linden J, Kern JA (2002) Adenosine A2A analogue improves neurologic outcome after spinal cord trauma in the rabbit. J Trauma 53:225–229

    Article  CAS  PubMed  Google Scholar 

  48. Reece TB, Davis JD, Okonkwo DO, Maxey TS, Ellman PI, Li X, Linden J, Tribble CG, Kron IL, Kern JA (2004) Adenosine A2A analogue reduces long-term neurologic injury after blunt spinal trauma. J Surg Res 121:130–134

    Article  CAS  PubMed  Google Scholar 

  49. Reece TB, Okonkwo DO, Ellman PI, Maxey TS, Tache-Leon C, Warren PS, Laurent JJ, Linden J, Kron IL, Tribble CG, Kern JA (2006) Comparison of systemic and retrograde delivery of adenosine A2A agonist for attenuation of spinal cord injury after thoracic aortic crossclamping. Ann Thorac Surg 81:902–909

    Article  PubMed  Google Scholar 

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Acknowledgements

This work was supported by a grant funded by Monte dei Paschi di Siena Foundation.

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Authors and Affiliations

  1. Department of Psychiatry, Neurobiology, Pharmacology and Biotechnology, University of Pisa, Via Bonanno, 6, 56127, Pisa, Italy

    Maria Letizia Trincavelli, Serena Cuboni, Mario Catena Dell’Osso, Anna Panighini, Simona Daniele & Claudia Martini

  2. Department of Experimental Medicine, University of L’Aquila, L’Aquila, Italy

    Roberto Maggio

  3. Institut für Pharmakologie und Toxikologie, Universität Würzburg, Würzburg, Germany

    Karl-Norbert Klotz

  4. Department of Neuroscience, University of Pisa, Pisa, Italy

    Francesca Novi

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  1. Maria Letizia Trincavelli
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  2. Serena Cuboni
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  3. Mario Catena Dell’Osso
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  4. Roberto Maggio
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  9. Claudia Martini
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Correspondence to Claudia Martini.

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M. Letizia Trincavelli and S. Cuboni equally contributed to the study.

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Fig. 1

Scatchard plot of [3H]YM09151-2 (D2DRs) (a) and [3H]NECA (A2AARs) (b) binding data performed in CHO cells co-expressing both D2DRs and A2AARs. Graphs show a representative Scatchard plot from saturation (a) and competition (b) binding studies performed three times with similar results (PPT 144 kb)

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Trincavelli, M.L., Cuboni, S., Catena Dell’Osso, M. et al. Receptor crosstalk: haloperidol treatment enhances A2A adenosine receptor functioning in a transfected cell model. Purinergic Signalling 6, 373–381 (2010). https://doi.org/10.1007/s11302-010-9201-z

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