Abstract
Adenosine is an endogenous purine nucleoside that regulates several physiological functions, at the central and peripheral levels. Besides, adenosine has emerged as a major player in the regulation of motor behavior. In fact, adenosine receptors of the A2A subtype are highly enriched in the caudate–putamen, which is richly innervated by dopamine. Moreover, several studies in experimental animals have consistently demonstrated that the pharmacological antagonism of A2A receptors has a facilitatory influence on motor behavior. Taken together, these findings have envisaged A2A receptors as a promising target for symptomatic therapies aimed at ameliorating motor deficits. Accordingly, A2A receptor antagonists have been extensively studied as new agents for the treatment of Parkinson’s disease (PD), the epitome of motor disorders. In this review, we provide an overview of the effects that adenosine A2A receptor antagonists elicit in rodent and primate experimental models of PD, with regard to the counteraction of motor deficits as well as to manifestation of dyskinesia and motor fluctuations. Moreover, we briefly present the results of clinical trials of A2A receptor antagonists in PD patients experiencing motor fluctuations, with particular regard to dyskinesia. Finally, we discuss the interaction between A2A receptor antagonists and serotonin receptor agonists, since combined administration of these drugs has recently emerged as a new potential therapeutic strategy in the treatment of dyskinesia.
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References
Antonelli T, Fuxe K, Tomasini MC et al (2005) Effects of sarizotan on the corticostriatal glutamate pathways. Synapse 58:193–199. https://doi.org/10.1002/syn.20195
Aoyama S, Kase H, Borrelli E (2000) Rescue of locomotor impairment in dopamine D2 receptor-deficient mice by an adenosine A2A receptor antagonist. J Neurosci 20:5848–5852
Armentero MT, Pinna A, Ferré S et al (2011) Past, present and future of A(2A) adenosine receptor antagonists in the therapy of Parkinson’s disease. Pharmacol Ther 132:280–299. https://doi.org/10.1016/j.pharmthera.2011.07.004
Augood SJ, Emson PC (1994) Adenosine A2a receptor mRNA is expressed by enkephalin cells but not somatostatin cells in rat striatum: a co-expression study. Mol Brain Res 22:204–210. https://doi.org/10.1016/0169-328X(94)90048-5
Bara-Jimenez W, Sherzai A, Dimitrova T et al (2003) Adenosine A2A receptor antagonist treatment of Parkinson’s disease. Neurology 61:293–296. https://doi.org/10.1212/01.WNL.0000073136.00548.D4
Bastide MF, Meissner WG, Picconi B et al (2015) Pathophysiology of l-dopa-induced motor and non-motor complications in Parkinson’s disease. Prog Neurobiol 132:96–168. https://doi.org/10.1016/j.pneurobio.2015.07.002
Baumgarten HG, Grozdanovic Z (1995) Psychopharmacology of central serotonergic systems. Pharmacopsychiatry 2:73–79. https://doi.org/10.1055/s-2007-979623
Bezard E, Carta M (2015) Could the serotonin theory give rise to a treatment for levodopa-induced dyskinesia in Parkinson’s disease? Brain 138:829–830. https://doi.org/10.1093/brain/awu407
Bezard E, Muñoz A, Tronci E et al (2013a) Anti-dyskinetic effect of anpirtoline in animal models of l-DOPA-induced dyskinesia. Neurosci Res 77:242–246. https://doi.org/10.1016/j.neures.2013.10.002
Bezard E, Tronci E, Pioli EY et al (2013b) Study of the antidyskinetic effect of eltoprazine in animal models of levodopa-induced dyskinesia. Mov Disord 28:1088–1096. https://doi.org/10.1002/mds.25366
Bibbiani F, Oh JD, Petzer JP et al (2003) A2A antagonist prevents dopamine agonist-induced motor complications in animal models of Parkinson’s disease. Exp Neurol 184:285–294. https://doi.org/10.1016/S0014-4886(03)00250-4
Bibbiani F, Costantini LC, Patel R, Chase TN (2005) Continuous dopaminergic stimulation reduces risk of motor complications in parkinsonian primates. Exp Neurol 192:73–78. https://doi.org/10.1016/j.expneurol.2004.11.013
Bogenpohl JW, Ritter SL, Hall RA, Smith Y (2012) Adenosine A2A receptor in the monkey basal ganglia: ultrastructural localization and colocalization with the metabotropic glutamate receptor 5 in the striatum. J Comp Neurol 520:570–589. https://doi.org/10.1002/cne.22751
Boison D, Chen JF, Fredholm BB (2010) Adenosine signalling and function in glial cells. Cell Death Differ 17:1071–1082. https://doi.org/10.1038/cdd.2009.131
Bové J, Marin C, Bonastre M, Tolosa E (2002) Adenosine A2A antagonism reverses levodopa-induced motor alterations in hemiparkinsonian rats. Synapse 46:251–257. https://doi.org/10.1002/syn.10112
Bové J, Serrats J, Mengod G et al (2006) Reversion of levodopa-induced motor fluctuations by the A2A antagonist CSC is associated with an increase in striatal preprodynorphin mRNA expression in 6-OHDA-lesioned rats. Synapse 59:435–444. https://doi.org/10.1002/syn.20259
Braak H, Del Tredici K, Rüb U et al (2013) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24:197–211. https://doi.org/10.1016/S0197-4580(02)00065-9
Burnstock G (2013) Introduction to purinergic signalling in the brain. Adv Exp Med Biol 986:1–12. https://doi.org/10.1007/978-94-007-4719-7_1
Burnstock G (2017) Purinergic signalling: therapeutic developments. Front Pharmacol 2017(8):661. https://doi.org/10.3389/fphar.2017.00661
Carriba P, Ortiz O, Patkar K et al (2007) Striatal adenosine A2A and cannabinoid CB1 receptors form functional heteromeric complexes that mediate the motor effects of cannabinoids. Neuropsychopharmacology 32:2249–2259. https://doi.org/10.1038/sj.npp.1301375
Carriba P, Navarro G, Ciruela F et al (2008) Detection of heteromerization of more than two proteins by sequential BRET–FRET. Nat Methods 5:727–733. https://doi.org/10.1038/nmeth.1229
Carta M, Bezard E (2011) Contribution of pre-synaptic mechanisms to l-DOPA-induced dyskinesia. Neuroscience 198:245–251. https://doi.org/10.1016/j.neuroscience.2011.07.070
Carta M, Tronci E (2014) Serotonin system implication in l-DOPA-induced dyskinesia: from animal models to clinical investigations. Front Neurol 5:78. https://doi.org/10.3389/fneur.2014.00078
Carta M, Carlsson T, Kirik D, Björklund A (2007) Dopamine released from 5-HT terminals is the cause of l-DOPA-induced dyskinesia in parkinsonian rats. Brain 130:1819–1833. https://doi.org/10.1093/brain/awm082
Cenci MA, Lundblad M (2006) Post-versus pre-synaptic plasticity in l-DOPA-induced dyskinesia. J Neurochem 99:381–392. https://doi.org/10.1111/j.1471-4159.2006.04124.x
Cerri S, Siani F, Blandini F (2017) Investigational drugs in phase I and phase II for levodopa-induced dyskinesias. Expert Opin Investig Drugs 26:777–791. https://doi.org/10.1080/13543784.2017.1333598
Chen JF, Pedata F (2008) Modulation of ischemic brain injury and neuroinflammation by adenosine A2A receptors. Curr Pharm Des 14:1490–1499. https://doi.org/10.2174/138161208784480126
Chen JF, Moratalla R, Impagnatiello F et al (2001) The role of the D(2) dopamine receptor (D(2)R) in A(2A) adenosine receptor (A(2A)R)-mediated behavioral and cellular responses as revealed by A(2A) and D(2) receptor knockout mice. Proc Natl Acad Sci USA 98:1970–1975
Ciruela F, Casadó V, Rodrigues RJ et al (2006) Presynaptic control of striatal glutamatergic neurotransmission by adenosine A1–A2A receptor heteromers. J Neurosci 26:2080–2087. https://doi.org/10.1523/JNEUROSCI.3574-05.2006
Collins-Praino LE, Paul NE, Rychalsky KL et al (2011) Pharmacological and physiological characterization of the tremulous jaw movement model of parkinsonian tremor: potential insights into the pathophysiology of tremor. Front Syst Neurosci 5:49. https://doi.org/10.3389/fnsys.2011.00049
Cunha RA (2001) Adenosine as a neuromodulator and as a homeostatic regulator in the nervous system: different roles, different sources and different receptors. Neurochem Int 38:107–125. https://doi.org/10.1016/S0197-0186(00)00034-6
Delwaide PJ (2001) Parkinsonian rigidity. Funct Neurol 16:147–156
Dixon AK, Gubitz AK, Sirinathsinghji DJ et al (1996) Tissue distribution of adenosine receptor mRNAs in the rat. Br J Pharmacol 118:1461–1468. https://doi.org/10.1111/j.1476-5381.1996.tb15561.x
Dungo R, Deeks ED (2013) Istradefylline: first global approval. Drugs 73:875–882. https://doi.org/10.1007/s40265-013-0066-7
Duty S, Jenner P (2011) Animal models of Parkinson’s disease: a source of novel treatments and clues to the cause of the disease. Br J Pharmacol 164:1357–1391. https://doi.org/10.1111/j.1476-5381.2011.01426.x
Factor SA, Wolski K, Togasaki DM et al (2013) Long-term safety and efficacy of preladenant in subjects with fluctuating Parkinson’s disease. Mov Disord 28:817–820. https://doi.org/10.1002/mds.25395
Feoktistov I, Biaggioni I (1997) Adenosine A2B receptors. Pharmacol Rev 49:381–402
Ferré S, Fredholm BB, Morelli M et al (1997) Adenosine–dopamine receptor–receptor interactions as an integrative mechanism in the basal ganglia. Trends Neurosci 20:482–487. https://doi.org/10.1016/S0166-2236(97)01096-5
Ferré S, Karcz-Kubicha M, Hope BT et al (2002) Synergistic interaction between adenosine A2A and glutamate mGlu5 receptors: implications for striatal neuronal function. Proc Natl Acad Sci USA 99:11940–11945. https://doi.org/10.1073/pnas.172393799
Ferré S, Lluís C, Justinova Z et al (2010) Adenosine–cannabinoid receptor interactions. Implications for striatal function. Br J Pharmacol 160:443–453. https://doi.org/10.1111/j.1476-5381.2010.00723.x
Fredduzzi S, Moratalla R, Monopoli A et al (2002) Persistent behavioral sensitization to chronic l-DOPA requires A2A adenosine receptors. J Neurosci 22:1054–1062
Fredholm BB, Chen JF, Cunha RA et al (2005) Adenosine and brain function. Int Rev Neurobiol 63:191–270. https://doi.org/10.1016/S0074-7742(05)63007-3
Fredholm BB, IJzerman AP, Jacobson KA et al (2011) International union of basic and clinical pharmacology. LXXXI. Nomenclature and classification of adenosine receptors—an update. Pharmacol Rev 63:1–34. https://doi.org/10.1124/pr.110.003285
Freitas ME, Fox SH (2016) Non dopaminergic treatments for Parkinson’s disease: current and future prospects. Neurodegener Dis Manag 6:249–268. https://doi.org/10.2217/nmt-2016-0005
Fuxe K, Borroto-Escuela DO, Marcellino D et al (2012) GPCR heteromers and their allosteric receptor-receptorinteractions. Curr Med Chem 19:356–363. https://doi.org/10.2174/092986712803414259
Fuzzati-Armentero MT, Cerri S, Levandis G et al (2015) Dual target strategy: combining distinct non-dopaminergic treatments reduces neuronal cell loss and synergistically modulates l-DOPA-induced rotational behavior in a rodent model of Parkinson’s disease. J Neurochem 134:740–747. https://doi.org/10.1111/jnc.13162
Gebicke-Haerter PJ, Christoffel F, Timmer J et al (1996) Both adenosine A1 and A2-receptors are required to stimulate microglial proliferation. Neurochem Int 29:37–42. https://doi.org/10.1016/0197-0186(95)00137-9
Gerevich Z, Wirkner K, Illes P (2002) Adenosine A2A receptors inhibit the N-methyl-d-aspartate component of excitatory synaptic currents in rat striatal neurons. Eur J Pharmacol 451:161–164. https://doi.org/10.1016/S0014-2999(02)02301-4
Gessi S, Merighi S, Varani K et al (2008) The A3 adenosine receptor: an enigmatic player in cell biology. Pharmacol Ther 117:123–140. https://doi.org/10.1016/j.pharmthera.2007.09.002
Ghiglieri V, Mineo D, Vannelli A et al (2016) Modulation of serotonergic transmission by eltoprazine in l-DOPA-induced dyskinesia: behavioral, molecular and synapticmechanisms. Neurobiol Dis 86:140–153. https://doi.org/10.1016/j.nbd.2015.11.022
Goetz CG, Damier P, Hicking C et al (2007) Sarizotan as a treatment for dyskinesias in Parkinson’s disease: a double-blind placebo-controlled trial. Mov Disord 22:179–186. https://doi.org/10.1002/mds.21226
Grondin R, Bédard PJ, Tahar AH et al (1999) Antiparkinsonian effect of a new selective adenosine A2A receptor antagonist in MPTP-treated monkeys. Neurology 52:1673–1677
Hammarberg C, Schulte G, Fredholm BB (2003) Evidence for functional adenosine A3 receptors in microglia cells. J Neurochem 86:1051–1054. https://doi.org/10.1046/j.1471-4159.2003.01919.x
Hauser RA, Hubble JP, Truong DD, Istradefylline US-001 Study Group (2003) Randomized trial of the adenosine A(2A) receptor antagonist istradefylline in advanced PD. Neurology 61:297–303
Hauser RA, Cantillon M, Pourcher E et al (2011) Preladenant in patients with Parkinson’s disease and motor fluctuations: a phase 2, double-blind, randomised trial. Lancet Neurol 10:221–229. https://doi.org/10.1016/S1474-4422(11)70012-6
Hauser RA, Olanow CW, Kieburtz KD et al (2014) Tozadenant (SYN115) in patients with Parkinson’s disease who have motor fluctuations on levodopa: a phase 2b, double-blind, randomised trial. Lancet Neurol 13:767–776. https://doi.org/10.1016/S1474-4422(14)70148-6
Hauser RA, Stocchi F, Rascol O et al (2015) Preladenant as an adjunctive therapy with levodopa in Parkinson disease: two randomized clinical trials and lessons learned. JAMA Neurol 72:1491–1500. https://doi.org/10.1001/jamaneurol.2015.2268
Henry B, Crossman AR, Brotchie JM (1998) Characterization of enhanced behavioral responses to l-DOPA following repeated administration in the 6-hydroxydopamine-lesioned rat model of Parkinson’s disease. Exp Neurol 151:334–342. https://doi.org/10.1006/exnr.1998.6819
Heumann R, Moratalla R, Herrero MT et al (2014) Dyskinesia in Parkinson’s disease: mechanisms and current non-pharmacological interventions. J Neurochem 130:472–489. https://doi.org/10.1111/jnc.12751
Hodgson RA, Bertorelli R, Varty GB et al (2009) Characterization of the potent and highly selective A2A receptor antagonists preladenant and SCH 412348 [7-[2-[4-2,4-difluorophenyl]-1-piperazinyl]ethyl]-2-(2-furanyl)-7H-pyrazolo[4,3-][1,2,4]triazolo[1,5-c]pyrimidin-5-amine] in rodent models of movement disorders and depression. J Pharmacol Exp Ther 330:294–303. https://doi.org/10.1124/jpet.108.149617
Hodgson RA, Bedard PJ, Varty GB et al (2010) Preladenant, a selective A(2A) receptor antagonist, is active in primate models of movement disorders. Exp Neurol 225:384–390. https://doi.org/10.1016/j.expneurol.2010.07.011
Hout P, Fox SH, Brotchie JM (2011) The serotonergic system in Parkinson’s disease. Prog Neurobiol 95:163–212. https://doi.org/10.1016/j.pneurobio.2011.08.004
Jacobs BL, Azmitia EC (1992) Structure and function of the brain serotonin system. Physiol Rev 72:165–229
Jankovic J (2005) Motor fluctuations and dyskinesias in Parkinson’s disease: clinical manifestations. Mov Disord 11:S11–S16. https://doi.org/10.1002/mds.20458
Jenner P (2008) Molecular mechanisms of l-DOPA-induced dyskinesia. Nat Rev Neurosci 9:665–677. https://doi.org/10.1038/nrn2471
Jenner P (2014) An overview of adenosine A2A receptor antagonists in Parkinson’s disease. Int Rev Neurobiol 119:71–86. https://doi.org/10.1016/B978-0-12-801022-8.00003-9
Jones CK, Bubser M, Thompson AD et al (2012) The metabotropic glutamate receptor 4-positive allosteric modulator VU0364770 produces efficacy alone and in combination with l-DOPA or an adenosine 2A antagonist in preclinical rodent models of Parkinson’s disease. J Pharmacol Exp Ther 340:404–421. https://doi.org/10.1124/jpet.111.187443
Jones N, Bleickardt C, Mullins D, Parker E, Hodgson R (2013) A2A receptor antagonists do not induce dyskinesias in drug-naive or l-dopa sensitized rats. Brain Res Bull 98:163–169. https://doi.org/10.1016/j.brainresbull.2013.07.001
Kachroo A, Orlando LR, Grandy DK et al (2005) Interactions between metabotropic glutamate 5 and adenosine A2A receptors in normal and parkinsonian mice. J Neurosci 25:10414–10419. https://doi.org/10.1523/JNEUROSCI.3660-05.2005
Kanda T, Uchida S (2014) Clinical/pharmacological aspect of adenosine A2A receptor antagonist for dyskinesia. Int Rev Neurobiol 119:127–150. https://doi.org/10.1016/B978-0-12-801022-8.00006-4
Kanda T, Shiozaki S, Shimada J et al (1994) KF17837: a novel selective adenosine A2A receptor antagonist with anticataleptic activity. Eur J Pharmacol 256:263–268. https://doi.org/10.1016/0014-2999(94)90551-7
Kanda T, Jackson MJ, Smith LA et al (1998) Adenosine A2A antagonist: a novel antiparkinsonian agent that does not provoke dyskinesia in parkinsonian monkeys. Ann Neurol 43:507–513. https://doi.org/10.1002/ana.410430415
Kanda T, Jackson MJ, Smith LA et al (2000) Combined use of the adenosine A(2A) antagonist KW-6002 with l-DOPA or with selective D1 or D2 dopamine agonists increases antiparkinsonian activity but not dyskinesia in MPTP-treated monkeys. Exp Neurol 162:321–327. https://doi.org/10.1006/exnr.2000.7350
Ko WKD, Li Q, Cheng LY et al (2017) A preclinical study on the combined effects of repeated eltoprazine and preladenant treatment for alleviating l-DOPA-induced dyskinesia in Parkinson’s disease. Eur J Pharmacol 813:10–16. https://doi.org/10.1016/j.ejphar.2017.07.030
Koga K, Kurokawa M, Ochi M et al (2000) Adenosine A(2A) receptor antagonists KF17837 and KW-6002 potentiate rotation induced by dopaminergic drugs in hemi-Parkinsonian rats. Eur J Pharmacol 408:249–255. https://doi.org/10.1016/S0014-2999(00)00745-7
Lazarus M, Shen HY, Cherasse Y, Qu WM, Huang ZL, Bass CE, Winsky-Sommerer R, Semba K, Fredholm BB, Boison D, Hayaishi O, Urade Y, Chen JF (2011) Arousal effect of caffeine depends on adenosine A2A receptors in the shell of the nucleus accumbens. J Neurosci 31:10067–10075. https://doi.org/10.1523/JNEUROSCI.6730-10.2011
Lewitt PA, Guttman M, Tetrud JW et al (2008) Adenosine A2A receptor antagonist istradefylline (KW-6002) reduces “off” time in Parkinson’s disease: a double-blind, randomized, multicenter clinical trial (6002-US-005). Ann Neurol 63:295–302. https://doi.org/10.1002/ana.21315
Łukasiewicz S, Blasiak E, Faron-Gorecka A et al (2007) Fluorescence studies of homooligomerization of adenosine A2A and serotonin 5-HT1A receptors reveal the specificity of receptor interactions in the plasma membrane. Pharmacol Rep 59:379–392
Lundblad M, Andersson M, Winkler C et al (2002) Pharmacological validation of behavioural measures of akinesia and dyskinesia in a rat model of Parkinson’s disease. Eur J Neurosci 15:120–132. https://doi.org/10.1046/j.0953-816x.2001.01843.x
Lundblad M, Vaudano E, Cenci MA (2003) Cellular and behavioural effects of the adenosine A2a receptor antagonist KW-6002 in a rat model of l-DOPA-induced dyskinesia. J Neurochem 84:1398–1410. https://doi.org/10.1046/j.1471-4159.2003.01632.x
Marin C, Aguilar E, Bonastre M et al (2005) Early administration of entacapone prevents levodopa-induced motor fluctuations in hemiparkinsonian rats. Exp Neurol 192:184–193. https://doi.org/10.1016/j.expneurol.2004.10.008
Meredith GE, Kang UJ (2006) Behavioral models of Parkinson’s disease in rodents: a new look at an old problem. Mov Disord 21:1595–1606. https://doi.org/10.1002/mds.21010
Morelli M, Di Paolo T, Wardas J et al (2007) Role of adenosine A2A receptors in parkinsonian motor impairment and l-DOPA-induced motor complications. Prog Neurobiol 83:293–309. https://doi.org/10.1016/j.pneurobio.2007.07.001
Morelli M, Blandini F, Simola N, Hauser RA (2012) A(2A) receptor antagonism and dyskinesia in Parkinson’s disease. Parkinsons Dis 2012:489853. https://doi.org/10.1155/2012/489853
Muñoz A, Li Q, Gardoni F et al (2008) Combined 5-HT1A and 5-HT1B receptor agonists for the treatment of l-DOPA-induced dyskinesia. Brain 131:3380–3394. https://doi.org/10.1093/brain/awn235
Navailles S, De Deurwaerdère P (2011) Presynaptic control of serotonin on striatal dopamine function. Psychopharmacology 213:213–242. https://doi.org/10.1007/s00213-010-2029-y
Navarro G, Carriba P, Gandía J et al (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. Sci World J 8:1088–1097. https://doi.org/10.1100/tsw.2008.136
Nevalainen N, Bjerkén S, Gerhardt GA, Strömberg I (2014) Serotonergic nerve fibers in l-DOPA-derived dopamine release and dyskinesia. Neuroscience 260:73–86. https://doi.org/10.1016/j.neuroscience.2013.12.029
Obeso JA, Rodríguez-Oroz MC, Rodríguez M et al (2000) Pathophysiology of the basal ganglia in Parkinson’s disease. Trends Neurosci 23:S8–S19. https://doi.org/10.1016/S1471-1931(00)00028-8
Obeso JA, Rodriguez-Oroz M, Marin C et al (2004) The origin of motor fluctuations in Parkinson’s disease: importance of dopaminergic innervation and basal ganglia circuits. Neurology 62:S17–S30
Ochi M, Shiozaki S, Kase H (2004) Adenosine A(2A) receptor-mediated modulation of GABA and glutamate release in the output regions of the basal ganglia in a rodent model of Parkinson’s disease. Neuroscience 127:223–231. https://doi.org/10.1016/j.neuroscience.2004.04.050
Oh JD, Chase TN (2002) Glutamate-mediated striatal dysregulation and the pathogenesis of motor response complications in Parkinson’s disease. Amino Acids 23:133–139. https://doi.org/10.1007/s00726-001-0118-2
Ohno Y, Shimizu S, Tokudome K et al (2015) New insight into the therapeutic role of the serotonergic system in Parkinson’s disease. Prog Neurobiol 134:104–121. https://doi.org/10.1016/j.pneurobio.2015.09.005
Olanow CW, Tatton WG (1999) Etiology and pathogenesis of Parkinson’s disease. Annu Rev Neurosci 22:123–144. https://doi.org/10.1146/annurev.neuro.22.1.123
Olanow CW, Damier P, Goetz CG et al (2004) Multicenter, open-label, trial of sarizotan in Parkinson disease patients with levodopa-induced dyskinesias (the SPLENDID Study). Clin Neuropharmacol 27:58–62. https://doi.org/10.1097/00002826-200403000-00003
Olanow CW, Stern MB, Sethi K (2009) The scientific and clinical basis for the treatment of Parkinson disease. Neurology 72:S1–S136. https://doi.org/10.1212/WNL.0b013e3181a1d44c
Papa SM, Engber TM, Kask AM, Chase TN (1994) Motor fluctuations in levodopa treated parkinsonian rats: relation to lesion extent and treatment duration. Brain Res 662:69–74. https://doi.org/10.1016/0006-8993(94)90796-X
Pascual O, Casper KB, Kubera C et al (2005) Astrocytic purinergic signalling coordinates synaptic networks. Science 310:113–116. https://doi.org/10.1126/science.1116916
Pedata F, Dettori I, Coppi E et al (2016) Purinergic signalling in brain ischemia. Neuropharmacology 104:105–130. https://doi.org/10.1016/j.neuropharm.2015.11.007
Pinna A (2014) Adenosine A2A receptor antagonists in Parkinson’s disease: progress in clinical trials from the newly approved istradefylline to drugs in early development and those already discontinued. CNS Drugs 28:455–474. https://doi.org/10.1007/s40263-014-0161-7
Pinna A, Morelli M (2014) A critical evaluation of behavioral rodent models of motor impairment used for screening of antiparkinsonian activity: the case of adenosine; A(2A) receptor antagonists. Neurotox Res 25:392–401. https://doi.org/10.1007/s12640-013-9446-8
Pinna A, Fenu S, Morelli M (2001) Motor stimulant effects of the adenosine A2A receptor antagonist SCH 58261 do not develop tolerance after repeated treatments in 6-hydroxydopamine-lesioned rats. Synapse 39:233–238. https://doi.org/10.1002/1098-2396(20010301)39:3<233::aid-syn1004>3.0.co;2-k
Pinna A, Wardas J, Simola N, Morelli M (2005) New therapies for the treatment of Parkinson’s disease: adenosine A2A receptor antagonists. Life Sci 77:3259–3267. https://doi.org/10.1016/j.lfs.2005.04.029
Pinna A, Pontis S, Borsini F, Morelli M (2007) Adenosine A2A receptor antagonists improve deficits in initiation of movement and sensory motor integration in the unilateral 6-hydroxydopamine rat model of Parkinson’s disease. Synapse 61:606–614. https://doi.org/10.1002/syn.20410
Pinna A, Tronci E, Schintu N et al (2010) A new ethyladenine antagonist of adenosine A(2A) receptors: behavioral and biochemical characterization as an antiparkinsonian drug. Neuropharmacology 58:613–623. https://doi.org/10.1016/j.neuropharm.2009.11.012
Pinna A, Bonaventura J, Farré D et al (2014) l-DOPA disrupts adenosine A(2A)-cannabinoid CB(1)-dopamine D(2) receptor heteromer cross-talk in the striatum of hemiparkinsonian rats: biochemical and behavioral studies. Exp Neurol 253:180–191. https://doi.org/10.1016/j.expneurol.2013.12.021
Pinna A, Ko WK, Costa G et al (2016) Antidyskinetic effect of A2A and 5HT1A/1B receptor ligands in two animal models of Parkinson’s disease. Mov Disord 31:501–511. https://doi.org/10.1002/mds.26475
Politis M, Wu K, Loane C et al (2010) Serotonergic neurons mediate dyskinesia side effects in Parkinson’s patients with neural transplants. Sci Transl Med 2:38–46. https://doi.org/10.1126/scitranslmed.3000976
Politis M, Wu K, Loane C et al (2014) Serotonergic mechanisms responsible for levodopa-induced dyskinesias in Parkinson’s disease patients. J Clin Investig 124:1340–1349. https://doi.org/10.1172/JCI71640
Popoli P, Pepponi R (2012) Potential therapeutic relevance of adenosine A2B and A2A receptors in the central nervous system. CNS Neurol Disord Drug Targets 11:664–674. https://doi.org/10.2174/187152712803581100
Rascol O, Perez-Lloret S, Ferreira JJ (2015) New treatments for levodopa-induced motor complications. Mov Disord 30:1451–1460. https://doi.org/10.1002/mds.26362
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. https://doi.org/10.1016/j.neuroscience.2005.01.014
Rivkees SA, Thevananther S, Hao H (2000) Are A3 adenosine receptors expressed in the brain? NeuroReport 11:1025–1030
Rodrigues RJ, Alfaro TM, Rebola N et al (2005) Colocalization and functional interaction between adenosine A(2A) and metabotropic group 5 receptors in glutamatergic nerve terminals of the rat striatum. J Neurochem 92:433–441. https://doi.org/10.1111/j.1471-4159.2004.02887.x
Rose S, Jackson MJ, Smith LA et al (2006) The novel adenosine A2a receptor antagonist ST1535 potentiates the effects of a threshold dose of l-DOPA in MPTP treated common marmosets. Eur J Pharmacol 546:82–87. https://doi.org/10.1016/j.ejphar.2006.07.017
Rosin DL, Robeva A, Woodard RL et al (1998) Immunohistochemical localization of adenosine A2A receptors in the rat central nervous system. J Comp Neurol 401:163–186. https://doi.org/10.1002/(sici)1096-9861(19981116)401:2<163::aid-cne2>3.0.co;2-d
Salamone JD, Betz AJ, Ishiwari K et al (2008) Tremorolytic effects of adenosine A2A antagonists: implications for parkinsonism. Front Biosci 13:3594–3605. https://doi.org/10.2741/2952
Schapira AHV, Chaudhuri KR, Jenner P (2017) Non-motor features of Parkinson disease. Nat Rev Neurosci 18:435–450. https://doi.org/10.1038/nrn.2017.62
Schiffmann SN, Jacobs O, Vanderhaeghen JJ (1991) Striatal restricted adenosine A2 receptor (RDC8) is expressed by enkephalin but not by substance P neurons: an in situ hybridization histochemistry study. J Neurochem 57:1062–1067. https://doi.org/10.1111/j.1471-4159.1991.tb08257.x
Schwarzschild MA, Agnati L, Fuxe K et al (2006) Targeting adenosine A2A receptors in Parkinson’s disease. Trends Neurosci 29:647–654. https://doi.org/10.1016/j.tins.2006.09.004
Sebastião AM, Ribeiro JA (2009) Adenosine receptors and the central nervous system. Handb Exp Pharmacol 193:471–534. https://doi.org/10.1007/978-3-540-89615-9_16
Shindou T, Mori A, Kase H, Ichimura M (2001) Adenosine A(2A) receptor enhances GABA(A)-mediated IPSCs in the rat globus pallidus. J Physiol 532:423–434. https://doi.org/10.1111/j.1469-7793.2001.0423f.x
Simola N, Fenu S, Baraldi PG et al (2004) Blockade of adenosine A2A receptors antagonizes parkinsonian tremor in the rat tacrine model by an action on specific striatal regions. Exp Neurol 189:182–188. https://doi.org/10.1016/j.expneurol.2004.05.027
Simola N, Fenu S, Baraldi PG et al (2006a) Involvement of globus pallidus in the antiparkinsonian effects of adenosine A(2A) receptor antagonists. Exp Neurol 202:255–257. https://doi.org/10.1016/j.expneurol.2006.05.015
Simola N, Fenu S, Baraldi PG et al (2006b) Dopamine and adenosine receptor interaction as basis for the treatment of Parkinson’s disease. J Neurol Sci 248:48–52. https://doi.org/10.1016/j.jns.2006.05.038
Simola N, Morelli M, Pinna A (2008a) Adenosine A2A receptor antagonists and Parkinson’s disease: state of the art and future directions. Curr Pharm Des 14:1475–1489. https://doi.org/10.2174/138161208784480072
Simola N, Fenu S, Baraldi PG et al (2008b) Blockade of globus pallidus adenosine A(2A) receptors displays antiparkinsonian activity in 6-hydroxydopamine-lesioned rats treated with D(1) or D(2) dopamine receptor agonists. Synapse 62:345–351. https://doi.org/10.1002/syn.20504
Simola N, Costa G, Morelli M (2016) Activation of adenosine A2A receptors suppresses the emission of pro-social and drug-stimulated 50-kHz ultrasonic vocalizations in rats: possible relevance to reward and motivation. Psychopharmacology 233:507–519. https://doi.org/10.1007/s00213-015-4130-8
Stacy M, Silver D, Mendis T et al (2008) A 12-week, placebo-controlled study (6002-US-006) of istradefylline in Parkinson disease. Neurology 70:2233–2240. https://doi.org/10.1212/01.wnl.0000313834.22171.17
Stayte S, Vissel B (2014) Advances in non-dopaminergic treatments for Parkinson’s disease. Front Neurosci 8:113. https://doi.org/10.3389/fnins.2014.00113
Svenningsson P, Le Moine C, Aubert I, Burbaud P, Fredholm BB, Bloch B (1998) Cellular distribution of adenosine A2A receptor mRNA in the primate striatum. J Comp Neurol 399:229–240. https://doi.org/10.1002/(sici)1096-9861(19980921)399:2<229::aid-cne6>3.0.co;2-2
Svenningsson P, Rosenblad C, Af Edholm Arvidsson K et al (2015) Eltoprazine counteracts l-DOPA-induced dyskinesias in Parkinson’s disease: a dose-finding study. Brain 138:963–973. https://doi.org/10.1093/brain/awu409
Tronci E, Simola N, Borsini F et al (2007) Characterization of the antiparkinsonian effects of the new adenosine A2A receptor antagonist ST1535: acute and subchronic studies in rats. Eur J Pharmacol 566:94–102. https://doi.org/10.1016/j.ejphar.2007.03.021
Varty GB, Hodgson RA, Pond AJ et al (2008) The effects of adenosine A2A receptor antagonists on haloperidol-induced movement disorders in primates. Psychopharmacology 200:393–401. https://doi.org/10.1007/s00213-008-1214-8
Wardas J (2003) Synergistic effect of SCH 58261, an adenosine A2A receptor antagonist, and l-DOPA on the reserpine-induced muscle rigidity in rats. Pol J Pharmacol 55:155–164
Wardas J, Konieczny J, Lorenc-Koci E (2001) SCH 58261, an A(2A) adenosine receptor antagonist, counteracts parkinsonian-like muscle rigidity in rats. Synapse 41:160–171. https://doi.org/10.1002/syn.1070
Xiao D, Bastia E, Xu YH et al (2006) Forebrain adenosine A2A receptors contribute to l-3,4-dihydroxyphenylalanine-induced dyskinesia in hemiparkinsonian mice. J Neurosci 26:13548–13555. https://doi.org/10.1523/JNEUROSCI.3554-06.2006
Yamada H, Aimi Y, Nagatsu I et al (2007) Immunohistochemical detection of l-DOPA-derived dopamine within serotonergic fibers in the striatum and the substantia nigra pars reticulata in Parkinsonian model rats. Neurosci Res 59:1–7. https://doi.org/10.1016/j.neures.2007.05.002
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Dr. Nicola Simola gratefully acknowledges the financial support of the Autonomous Region of Sardinia (L.R. n 7/2007-2015).
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Pinna, A., Serra, M., Morelli, M. et al. Role of adenosine A2A receptors in motor control: relevance to Parkinson’s disease and dyskinesia. J Neural Transm 125, 1273–1286 (2018). https://doi.org/10.1007/s00702-018-1848-6
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DOI: https://doi.org/10.1007/s00702-018-1848-6