, Volume 236, Issue 2, pp 699–708 | Cite as

Effects of adenosine A2A receptor antagonists on cocaine-induced locomotion and cocaine seeking

  • Nicholas S. Haynes
  • Casey E. O’Neill
  • Benjamin D. Hobson
  • Ryan K. BachtellEmail author
Original Investigation


Rationale and objectives

Adenosine signaling through adenosine A2A receptors (A2ARs) is known to influence cocaine-induced behaviors. These studies sought to elucidate how two A2AR antagonists distinguished by their antagonist effects at presynaptic and postsynaptic A2AR influence cocaine-induced locomotion and cocaine seeking.


Sprague-Dawley rats were used to assess the differential effects of SCH 442416 and istradefylline that antagonize presynaptic and postsynaptic A2AR, respectively. We evaluated the effects of these antagonists on both basal and cocaine-induced locomotion in cocaine-naïve rats and rats that received seven daily cocaine treatments. The effects of SCH 442416 or istradefylline on cocaine seeking were measured in animals extinguished from cocaine self-administration. We assessed the effects of the A2AR antagonists to induce cocaine seeking when administered alone and their effects on cocaine seeking induced by a cocaine-priming injection. Lastly, we evaluated the effects of the antagonists on sucrose seeking in animals extinguished from sucrose self-administration.


Neither istradefylline nor SCH 442416 significantly altered basal locomotion. Istradefylline enhanced acute cocaine-induced locomotion but had no effect on the expression of locomotor sensitization. SCH 44216 had no effect on acute cocaine-induced locomotion but inhibited the expression of locomotor sensitization. Istradefylline was sufficient to induce cocaine seeking and augmented both cocaine-induced seeking and sucrose seeking. SCH 442416 inhibited cocaine-induced seeking, but had no effect on sucrose seeking and did not induce cocaine seeking when administered alone.


These findings demonstrate differential effects of two A2AR antagonists distinguished by their effects at pre- and postsynaptic A2AR on cocaine-induced behaviors.


Purinergic receptors Psychostimulant Relapse Behavioral sensitization KW 6002 



This work was funded by the National Institutes of Health (Grant DA033358).

Compliance with ethical standards

All procedures complied with the Guide for Care and Use of Animals as adopted and promulgated by the U.S. National Institutes of Health and were approved by the Institutional Animal Care and Use Committee at the University of Colorado Boulder.

Conflict of interest

The authors declare that there are no conflicts of interest.


  1. 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. CrossRefGoogle Scholar
  2. Bachtell RK, Self DW (2009) Effects of adenosine A(2A) receptor stimulation on cocaine-seeking behavior in rats. Psychopharmacol Berl 206:469–478. CrossRefGoogle Scholar
  3. Barrie AP, Nicholls DG (1993) Adenosine A1 receptor inhibition of glutamate exocytosis and protein kinase C-mediated decoupling. J Neurochem 60:1081–1086CrossRefGoogle Scholar
  4. Bobadilla A-C, Garcia-Keller C, Heinsbroek JA, Scofield MD, Chareunsouk V, Monforton C, Kalivas PW (2017) Accumbens mechanisms for cued sucrose seeking. Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol 42:2377–2386. CrossRefGoogle Scholar
  5. Chen JF, Moratalla R, Impagnatiello F, Grandy DK, Cuellar B, Rubinstein M, Beilstein MA, Hackett E, Fink JS, Low MJ, Ongini E, Schwarzschild MA (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 U A 98:1970–1975. CrossRefGoogle Scholar
  6. Ciruela F, Casado V, Rodrigues RJ et al (2006) Presynaptic control of striatal glutamatergic neurotransmission by adenosine A1-A2A receptor heteromers. J Neurosci 26:2080–2087. CrossRefGoogle Scholar
  7. Doyle SE, Breslin FJ, Rieger JM, Beauglehole A, Lynch WJ (2012) Time and sex-dependent effects of an adenosine A2A/A1 receptor antagonist on motivation to self-administer cocaine in rats. Pharmacol Biochem Behav 102:257–263. CrossRefGoogle Scholar
  8. Dungo R, Deeks ED (2013) Istradefylline: first global approval. Drugs 73:875–882. CrossRefGoogle Scholar
  9. Dunwiddie TV, Masino SA (2001) The role and regulation of adenosine in the central nervous system. Annu Rev Neurosci 24:31–55. CrossRefGoogle Scholar
  10. Farrar AM, Segovia KN, Randall PA, Nunes EJ, Collins LE, Stopper CM, Port RG, Hockemeyer J, Müller CE, Correa M, Salamone JD (2010) Nucleus accumbens and effort-related functions: behavioral and neural markers of the interactions between adenosine A2A and dopamine D2 receptors. Neuroscience 166:1056–1067. CrossRefGoogle Scholar
  11. Ferré S (2016) Mechanisms of the psychostimulant effects of caffeine: implications for substance use disorders. Psychopharmacology 233:1963–1979. CrossRefGoogle Scholar
  12. Ferré S, Agnati LF, Ciruela F, Lluis C, Woods AS, Fuxe K, Franco R (2007) Neurotransmitter receptor heteromers and their integrative role in “local modules”: the striatal spine module. Brain Res Rev 55:55–67. CrossRefGoogle Scholar
  13. Ferre S, Quiroz C, Woods AS, Cunha R, Popoli P, Ciruela F, Lluis C, Franco R, Azdad K, Schiffmann S (2008) An update on adenosine A2A-dopamine D2 receptor interactions: implications for the function of G protein-coupled receptors. Curr Pharm Des 14:1468–1474CrossRefGoogle Scholar
  14. Ferré S, Bonaventura J, Zhu W, Hatcher-Solis C, Taura J, Quiroz C, Cai NS, Moreno E, Casadó-Anguera V, Kravitz AV, Thompson KR, Tomasi DG, Navarro G, Cordomí A, Pardo L, Lluís C, Dessauer CW, Volkow ND, Casadó V, Ciruela F, Logothetis DE, Zwilling D (2018) Essential control of the function of the striatopallidal neuron by pre-coupled complexes of adenosine A2A-dopamine D2 receptor heterotetramers and adenylyl cyclase. Front Pharmacol 9:243. CrossRefGoogle Scholar
  15. Filip M, Frankowska M, Zaniewska M, Przegaliński E, Műller CE, Agnati L, Franco R, Roberts DCS, Fuxe K (2006) Involvement of adenosine A2A and dopamine receptors in the locomotor and sensitizing effects of cocaine. Brain Res 1077:67–80CrossRefGoogle Scholar
  16. Gerfen CR, Surmeier DJ (2011) Modulation of striatal projection systems by dopamine. Annu Rev Neurosci 34:441–466. CrossRefGoogle Scholar
  17. Hakansson K, Galdi S, Hendrick J et al (2006) Regulation of phosphorylation of the GluR1 AMPA receptor by dopamine D2 receptors. J Neurochem 96:482–488. CrossRefGoogle Scholar
  18. Harper LK, Beckett SR, Marsden CA, McCreary AC, Alexander SPH (2006) Effects of the A 2A adenosine receptor antagonist KW6002 in the nucleus accumbens in vitro and in vivo. Pharmacol Biochem Behav 83:114–121. CrossRefGoogle Scholar
  19. 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 431:331–346CrossRefGoogle Scholar
  20. Higley MJ, Sabatini BL (2010) Competitive regulation of synaptic Ca2+ influx by D2 dopamine and A2A adenosine receptors. Nat Neurosci 13:958–966. CrossRefGoogle Scholar
  21. Ho T, Jobling AI, Greferath U, Chuang T, Ramesh A, Fletcher EL, Vessey KA (2015) Vesicular expression and release of ATP from dopaminergic neurons of the mouse retina and midbrain. Front Cell Neurosci 9:389. CrossRefGoogle Scholar
  22. Hobson BD, Merritt KE, Bachtell RK (2012) Stimulation of adenosine receptors in the nucleus accumbens reverses the expression of cocaine sensitization and cross-sensitization to dopamine D2 receptors in rats. Neuropharmacology 63:1172–1181. CrossRefGoogle Scholar
  23. Justinova Z, Ferre S, Segal PN, Antoniou K, Solinas M, Pappas LA, Highkin JL, Hockemeyer J, Munzar P, Goldberg SR (2003) Involvement of adenosine A1 and A2A receptors in the adenosinergic modulation of the discriminative-stimulus effects of cocaine and methamphetamine in rats. J Pharmacol Exp Ther 307:977–986. CrossRefGoogle Scholar
  24. Justinová Z, Redhi GH, Goldberg SR, Ferré S (2014) Differential effects of presynaptic versus postsynaptic adenosine A2A receptor blockade on Δ9-tetrahydrocannabinol (THC) self-administration in squirrel monkeys. J Neurosci 34:6480–6484. CrossRefGoogle Scholar
  25. Kalivas PW (2009) The glutamate homeostasis hypothesis of addiction. Nat Rev Neurosci 10:561–572. CrossRefGoogle Scholar
  26. Kalivas PW, Volkow ND (2011) New medications for drug addiction hiding in glutamatergic neuroplasticity. Mol Psychiatry 16:974–986. CrossRefGoogle Scholar
  27. Karcz-Kubicha M, Antoniou K, Terasmaa A, Quarta D, Solinas M, Justinova Z, Pezzola A, Reggio R, Müller CE, Fuxe K, Goldberg SR, Popoli P, Ferré S (2003) Involvement of adenosine A1 and A2A receptors in the motor effects of caffeine after its acute and chronic administration. Neuropsychopharmacology 28:1281–1291. CrossRefGoogle Scholar
  28. Knapp CM, Foye MM, Cottam N, Ciraulo DA, Kornetsky C (2001) Adenosine agonists CGS 21680 and NECA inhibit the initiation of cocaine self-administration. Pharmacol Biochem Behav 68:797–803CrossRefGoogle Scholar
  29. Marchi M, Raiteri L, Risso F, Vallarino A, Bonfanti A, Monopoli A, Ongini E, Raiteri M (2002) Effects of adenosine A1 and A2A receptor activation on the evoked release of glutamate from rat cerebrocortical synaptosomes. Br J Pharmacol 136:434–440. CrossRefGoogle Scholar
  30. Matsumoto JPP, Almeida MG, Castilho-Martins EA, Costa MA, Fior-Chadi DR (2014) Protein kinase A mediates adenosine A2a receptor modulation of neurotransmitter release via synapsin I phosphorylation in cultured cells from medulla oblongata. Neurosci Res 85:1–11. CrossRefGoogle Scholar
  31. McFarland K, Lapish CC, Kalivas PW (2003) Prefrontal glutamate release into the core of the nucleus accumbens mediates cocaine-induced reinstatement of drug-seeking behavior. J Neurosci 23:3531–3537CrossRefGoogle Scholar
  32. Navarro G, Borroto-Escuela DO, Fuxe K, Franco R (2016) Purinergic signaling in Parkinson’s disease. Relevance for treatment. Neuropharmacology 104:161–168. CrossRefGoogle Scholar
  33. Nunes EJ, Randall PA, Santerre JL, Given AB, Sager TN, Correa M, Salamone JD (2010) Differential effects of selective adenosine antagonists on the effort-related impairments induced by dopamine D1 and D2 antagonism. Neuroscience 170:268–280. CrossRefGoogle Scholar
  34. O’Neill CE, LeTendre ML, Bachtell RK (2012) Adenosine A2A receptors in the nucleus accumbens bi-directionally alter cocaine seeking in rats. Neuropsychopharmacology 37:1245–1256. CrossRefGoogle Scholar
  35. O’Neill CE, Hobson BD, Levis SC, Bachtell RK (2014) Persistent reduction of cocaine seeking by pharmacological manipulation of adenosine A1 and A2A receptors during extinction training in rats. Psychopharmacology 231:3179–3188. CrossRefGoogle Scholar
  36. Orru M, Bakesova J, Brugarolas M et al (2011a) Striatal pre- and postsynaptic profile of adenosine A(2A) receptor antagonists. PLoS One 6:e16088. CrossRefGoogle Scholar
  37. Orru M, Quiroz C, Guitart X, Ferre S (2011b) Pharmacological evidence for different populations of postsynaptic adenosine A2A receptors in the rat striatum. Neuropharmacology 61:967–974. CrossRefGoogle Scholar
  38. Pierce RC, Bell K, Duffy P, Kalivas PW (1996) Repeated cocaine augments excitatory amino acid transmission in the nucleus accumbens only in rats having developed behavioral sensitization. J Neurosci 16:1550–1560CrossRefGoogle Scholar
  39. Poelchen W, Sieler D, Wirkner K, Illes P (2001) Co-transmitter function of ATP in central catecholaminergic neurons of the rat. Neuroscience 102:593–602CrossRefGoogle Scholar
  40. Poleszak E, Malec D (2002a) Adenosine receptor ligands and cocaine in conditioned place preference (CPP) test in rats. Pol J Pharmacol 54:119–126CrossRefGoogle Scholar
  41. Poleszak E, Malec D (2002b) Cocaine-induced hyperactivity is more influenced by adenosine receptor agonists than amphetamine-induced hyperactivity. Pol J Pharmacol 54:359–366Google Scholar
  42. Popoli P, Betto P, Reggio R, Ricciarello G (1995) Adenosine A2A receptor stimulation enhances striatal extracellular glutamate levels in rats. Eur J Pharmacol 287:215–217CrossRefGoogle Scholar
  43. Quiroz C, Lujan R, Uchigashima M et al (2009) Key modulatory role of presynaptic adenosine A2A receptors in cortical neurotransmission to the striatal direct pathway. ScientificWorldJournal 9:1321–1344. CrossRefGoogle Scholar
  44. Rodrigues RJ, Alfaro TM, Rebola N, Oliveira CR, Cunha RA (2005) Co-localization 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. CrossRefGoogle Scholar
  45. Rosin DL, Hettinger BD, Lee A, Linden J (2003) Anatomy of adenosine A2A receptors in brain: morphological substrates for integration of striatal function. Neurology 61:S12–S18CrossRefGoogle Scholar
  46. Schiffmann SN, Fisone G, Moresco R, Cunha RA, Ferré S (2007) Adenosine A2A receptors and basal ganglia physiology. Prog Neurobiol 83:277–292. CrossRefGoogle Scholar
  47. Schmidt HD, Pierce RC (2010) Cocaine-induced neuroadaptations in glutamate transmission: potential therapeutic targets for craving and addiction. Ann N Acad Sci 1187:35–75. CrossRefGoogle Scholar
  48. Self DW, Choi KH, Simmons D, Walker JR, Smagula CS (2004) Extinction training regulates neuroadaptive responses to withdrawal from chronic cocaine self-administration. Learn Mem 11:648–657. CrossRefGoogle Scholar
  49. Shen HY, Canas PM, Garcia-Sanz P, Lan JQ, Boison D, Moratalla R, Cunha RA, Chen JF (2013) Adenosine A(2)A receptors in striatal glutamatergic terminals and GABAergic neurons oppositely modulate psychostimulant action and DARPP-32 phosphorylation. PLoS One 8:e80902. CrossRefGoogle Scholar
  50. Steketee JD, Kalivas PW (2011) Drug wanting: behavioral sensitization and relapse to drug-seeking behavior. Pharmacol Rev 63:348–365. CrossRefGoogle Scholar
  51. Svenningsson P, Le Moine C, Kull B et al (1997) Cellular expression of adenosine A2A receptor messenger RNA in the rat central nervous system with special reference to dopamine innervated areas. Neuroscience 80:1171–1185CrossRefGoogle Scholar
  52. Svenningsson P, Le Moine C, Fisone G, Fredholm BB (1999) Distribution, biochemistry and function of striatal adenosine A2A receptors. Prog Neurobiol 59:355–396CrossRefGoogle Scholar
  53. Wydra K, Golembiowska K, Suder A et al (2015a) On the role of adenosine (A)(2)A receptors in cocaine-induced reward: a pharmacological and neurochemical analysis in rats. Psychopharmacol Berl 232:421–435. CrossRefGoogle Scholar
  54. Wydra K, Suder A, Borroto-Escuela DO, Filip M, Fuxe K (2015b) On the role of A(2)A and D(2) receptors in control of cocaine and food-seeking behaviors in rats. Psychopharmacol Berl 232:1767–1778. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Psychology and Neuroscience; Center for NeuroscienceUniversity of Colorado BoulderBoulderUSA

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