, Volume 179, Issue 1, pp 189–197

NMDA or AMPA/kainate receptor blockade prevents acquisition of conditioned place preference induced by D2/3 dopamine receptor stimulation in rats

  • Anna-Maria Biondo
  • Robert L. H. Clements
  • David J. Hayes
  • Brendan Eshpeter
  • Andrew J. Greenshaw
Original Investigation



Recent experiments from this laboratory demonstrated synergistic effects of AMPA/kainate receptor blockade and D2/3 dopamine (DA) receptor stimulation on brain stimulation reward and locomotor activity.


Using place conditioning, this study explored further the interaction between DA and glutamate (Glu) using the N-methyl-d-aspartate (NMDA) receptor antagonist MK-801, the AMPA/kainate receptor antagonist NBQX, and the D2/3 DA receptor agonist 7-OH-DPAT.


Effects of these compounds, alone and combined, were measured in male Sprague–Dawley rats using an unbiased two-compartment place conditioning procedure.


7-OH-DPAT (0.03–5.0 mg kg−1, s.c.) administered immediately prior to conditioning was ineffective; when administered 15 min prior to conditioning, only the highest dose (5.0 mg kg−1, s.c.) induced conditioned place preference (CPP). Acquisition of 7-OH-DPAT-induced CPP was blocked by MK-801 (0.06 or 0.13 mg kg−1, i.p.) or NBQX (0.5 μg) microinjected into the nucleus accumbens (NAS) shell subregion. Intra-NAS shell administration of 7-OH-DPAT (5.0 μg) or NBQX (0.5 μg), alone or combined, failed to induce place conditioning, and this lack of effect was not due to state dependency. Administration of MK-801 or 7-OH-DPAT (5.0 mg kg−1) during the conditioning phase acutely increased horizontal activity, but neither compound, alone or combined, induced conditioned locomotor effects.


Acquisition of place conditioning induced by systemic administration of 7-OH-DPAT is blocked by systemic NMDA receptor antagonism by MK-801 or by the AMPA/kainate receptor antagonist NBQX microinjected into the NAS shell subregion.


7-OH-DPAT AMPA/kainate Dopamine Glutamate Locomotor activity MK-801 NMDA Place conditioning Place preference Reward 


  1. Bardo MT, Valone JM, Bevins RA (1999) Locomotion and conditioned place preference produced by acute intravenous amphetamine: role of dopamine receptors and individual differences in amphetamine self-administration. Psychopharmacology (Berl) 143:39–46CrossRefGoogle Scholar
  2. Beninger RJ, Hahn BL (1983) Pimozide blocks establishment but not expression of amphetamine-produced environment-specific conditioning. Science 220:1304–1306Google Scholar
  3. Biala G, Kotlinska J (1999) Blockade of the acquisition of ethanol-induced conditioned place preference by N-methyl-d-aspartate receptor antagonists. Alcohol Alcohol 34:175–182Google Scholar
  4. Biala G, Langwinski R (1996) Rewarding properties of some drugs studied by place preference conditioning. Pol J Pharmacol 48:425–430Google Scholar
  5. Bozarth MA, Wise RA (1981) Heroin reward is dependent on a dopaminergic substrate. Life Sci 29:1881–1886CrossRefGoogle Scholar
  6. Bubser M, Tzschentke T, Hauber W (1995) Behavioural and neurochemical interactions of the AMPA antagonist GYKI 52466 and the non-competitive NMDA antagonist dizocilpine in rats. J Neural Transm 101:115–126Google Scholar
  7. Cabeza de Vaca S, Carr KD (1998) Food restriction enhances the central rewarding effect of abused drugs. J Neurosci 18:7502–7510Google Scholar
  8. Carlezon WA Jr, Wise RA (1993) Morphine-induced potentiation of brain stimulation reward is enhanced by MK-801. Brain Res 620:339–342CrossRefGoogle Scholar
  9. Carlezon WA Jr, Wise RA (1996) Microinjections of phencyclidine (PCP) and related drugs into nucleus accumbens shell potentiate medial forebrain bundle brain stimulation reward. Psychopharmacology (Berl) 128:413–420CrossRefGoogle Scholar
  10. Cervo L, Samanin R (1995) Effects of dopaminergic and glutamatergic receptor antagonists on acquisition and expression of cocaine conditioning place preference. Brain Res 673:242–250PubMedGoogle Scholar
  11. Chaperon F, Thiebot MH (1996) Effects of dopaminergic D3-receptor-preferring ligands on the acquisition of place conditioning in rats. Behav Pharmacol 7:105–109Google Scholar
  12. Choi KH, Zarandi B, Todd KG, Biondo AM, Greenshaw AJ (2000) Effects of AMPA/kainate receptor blockade on responses to dopamine receptor agonists in the core and shell of the rat nucleus accumbens. Psychopharmacology (Berl) 150:102–111CrossRefGoogle Scholar
  13. Choi KH, Clements RLH, Greenshaw AJ (2005) Simultaneous AMPA/kainate receptor blockade and dopamine D2/3 receptor stimulation in the nucleus accumbens decreases brain stimulation reward in rats. Behav Brain Res 158:79–88CrossRefGoogle Scholar
  14. Corbett D (1989) Possible abuse potential of the NMDA antagonist MK-801. Behav Brain Res 34:239–246Google Scholar
  15. Dall’Olio R, Gandolfi O, Montanaro N (1992) Effect of chronic treatment with dizocilpine (MK-801) on the behavioral response to dopamine receptor agonists in the rat. Psychopharmacology (Berl) 107:591–594Google Scholar
  16. Daly SA, Waddington JL (1993) Behavioural effects of the putative d-3 dopamine receptor agonist 7-OH-DPAT in relation to other “D-2-like” agonists. Neuropharmacology 32:509–510CrossRefGoogle Scholar
  17. Damsma G, Bottema T, Westerink BH, Tepper PG, Dijkstra D, Pugsley TA, MacKenzie RG, Heffner TG, Wikstrom H (1993) Pharmacological aspects of R-(+)-7-OH-DPAT, a putative dopamine D3 receptor ligand. Eur J Pharmacol 249:R9–R10CrossRefGoogle Scholar
  18. Danysz W, Essmann U, Bresink I, Wilke R (1994) Glutamate antagonists have different effects on spontaneous locomotor activity in rats. Pharmacol Biochem Behav 48:111–118CrossRefPubMedGoogle Scholar
  19. De Vry J, Horvath E, Schreiber R (2001) Neuroprotective and behavioral effects of the selective metabotropic glutamate mGlu(1) receptor antagonist BAY 36-7620. Eur J Pharmacol 428:203–214CrossRefGoogle Scholar
  20. Deutch AY, Bourdelais AJ, Zahm DS (1993) The nucleus accumbens core and shell: accumbal compartments and their functional attributes. In: Kalivas PW, Barner CD (eds) Limbic motor circuits and neuropsychiatry. CRC Press, Boca Raton, FL, pp 45–88Google Scholar
  21. Ford LM, Norman AB, Sanberg PR (1989) The topography of MK-801-induced locomotor patterns in rats. Physiol Behav 46:755–758CrossRefGoogle Scholar
  22. Goldman-Rakic PS (1992) Dopamine-mediated mechanisms of the prefrontal cortex. Semin Neurosci 4:149–159CrossRefGoogle Scholar
  23. Gong W, Justice JB Jr, Neill D (1997) Dissociation of locomotor and conditioned place preference responses following manipulation of GABA-A and AMPA receptors in ventral pallidum. Prog Neuropsychopharmacol Biol Psychiatry 21:839–852CrossRefGoogle Scholar
  24. Greenshaw AJ (1997) A simple technique for determining stereotaxic coordinates for brain implantation of probes at rotated angles in one or two planes. J Neurosci Methods 78:169–172CrossRefGoogle Scholar
  25. Gyertyán I, Gál K (2003) Dopamine D3 receptor ligands show place conditioning effect but do not influence cocaine-induced place preference. Neuroreport 14:93–98CrossRefGoogle Scholar
  26. Herberg LJ, Rose IC (1989) The effect of MK-801 and other antagonists of NMDA-type glutamate receptors on brain-stimulation reward. Psychopharmacology (Berl) 99:87–90CrossRefGoogle Scholar
  27. Hoffman DC (1994) The noncompetitive NMDA antagonist MK-801 fails to block amphetamine-induced place conditioning in rats. Pharmacol Biochem Behav 47:907–912CrossRefGoogle Scholar
  28. Hoffman DC, Dickson PR, Beninger RJ (1988) The dopamine D2 receptor agonists, quinpirole and bromocriptine produce conditioned place preferences. Prog Neuropsychopharmacol Biol Psychiatry 12:315–322CrossRefGoogle Scholar
  29. Jackson A, Koek W, Colpaert FC (1992) NMDA antagonists make learning and recall state-dependent. Behav Pharmacol 3:415–421Google Scholar
  30. Jackson A, Mead AN, Rocha BA, Stephens DN (1998) AMPA receptors and motivation for drug: effect of the selective antagonist NBQX on behavioural sensitization and on self-administration in mice. Behav Pharmacol 9:457–467Google Scholar
  31. Kaddis FG, Uretsky NJ, Wallace LJ (1995) DNQX in the nucleus accumbens inhibits cocaine-induced conditioned place preference. Brain Res 697:76–82CrossRefGoogle Scholar
  32. Kamei J, Ohsawa M (1996) Effects of diabetes on methamphetamine-induced place preference in mice. Eur J Pharmacol 318:251–256CrossRefGoogle Scholar
  33. Kenny PJ, Gasparini F, Markou A (2003) Group II metabotropic and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)/kainate glutamate receptors regulate the deficit in brain reward function associated with nicotine withdrawal in rats. J Pharmacol Exp Ther 306:1068–1076CrossRefPubMedGoogle Scholar
  34. Khroyan TV, Baker DA, Neisewander JL (1995) Dose-dependent effects of the D3-preferring agonist 7-OH-DPAT on motor behaviors and place conditioning. Psychopharmacology (Berl) 122:351–357Google Scholar
  35. Kim HS, Jang CG (1997) MK-801 inhibits methamphetamine-induced conditioned place preference and behavioral sensitization to apomorphine in mice. Brain Res Bull 44:221–227CrossRefGoogle Scholar
  36. Kim HS, Park WK, Jang CG, Oh S (1996) Inhibition by MK-801 of cocaine-induced sensitization, conditioned place preference, and dopamine-receptor supersensitivity in mice. Brain Res Bull 40:201–207CrossRefGoogle Scholar
  37. Kling-Petersen T, Ljung E, Wollter L, Svensson K (1995) Effects of dopamine D3 preferring compounds on conditioned place preference and intracranial self-stimulation in the rat. J Neural Transm 101:27–39Google Scholar
  38. Kotlinska J, Biala G (2000) Memantine and ACPC affect conditioned place preference induced by cocaine in rats. Pol J Pharmacol 52:179–185Google Scholar
  39. Layer RT, Kaddis FG, Wallace LJ (1993a) The NMDA receptor antagonist MK-801 elicits conditioned place preference in rats. Pharmacol Biochem Behav 44:245–247CrossRefGoogle Scholar
  40. Layer RT, Uretsky NJ, Wallace LJ (1993b) Effects of the AMPA/kainate receptor antagonist DNQX in the nucleus accumbens on drug-induced conditioned place preference. Brain Res 617:267–273CrossRefGoogle Scholar
  41. Levesque D, Diaz J, Pilon C, Martres MP, Giros B, Souil E, Schott D, Morgat JL, Schwartz JC, Sokoloff P (1992) Identification, characterization, and localization of the dopamine D3 receptor in rat brain using 7-[3H]hydroxy-N,N-di-n-propyl-2-aminotetralin. Proc Natl Acad Sci U S A 89:8155–8159Google Scholar
  42. Lewis RC, Elliot KAC (1950) Clinical uses of an artificial cerebrospinal fluid. J Neurosurg 7:256–260Google Scholar
  43. Li Y, Vartanian AJ, White FJ, Xue CJ, Wolf ME (1997) Effects of the AMPA receptor antagonist NBQX on the development and expression of behavioral sensitization to cocaine and amphetamine. Psychopharmacology (Berl) 134:266–276CrossRefGoogle Scholar
  44. Mallet PE, Beninger RJ (1994) 7-OH-DPAT produces place conditioning in rats. Eur J Pharmacol 261:R5–R6CrossRefGoogle Scholar
  45. Martin-Iverson MT, Reimer AR (1996) Classically conditioned motor effects do not occur with cocaine in an unbiased conditioned place preference procedure. Behav Pharmacol 7:303–314Google Scholar
  46. Mead AN, Stephens DN (1999) CNQX but not NBQX prevents expression of amphetamine-induced place preference conditioning: a role for the glycine site of the NMDA receptor, but not AMPA receptors. J Pharmacol Exp Ther 290:9–15PubMedGoogle Scholar
  47. Mead AN, Vasilaki A, Spyraki C, Duka T, Stephens DN (1999) AMPA-receptor involvement in c-fos expression in the medial prefrontal cortex and amygdala dissociates neural substrates of conditioned activity and conditioned reward. Eur J Neurosci 11:4089–4098Google Scholar
  48. Meririnne E, Kankaanpaa A, Lillsunde P, Seppala T (1999) The effects of diazepam and zolpidem on cocaine- and amphetamine-induced place preference. Pharmacol Biochem Behav 62:159–164CrossRefGoogle Scholar
  49. Meyer ME (1996) Mesolimbic 7-OH-DPAT affects locomotor activities in rats. Pharmacol Biochem Behav 55:209–214CrossRefGoogle Scholar
  50. Olds ME (1996) Dopaminergic basis for the facilitation of brain stimulation reward by the NMDA receptor antagonist, MK-801. Eur J Pharmacol 306:23–32CrossRefGoogle Scholar
  51. Oles RJ, Singh L, Tricklebank MD (1990) Differential effects on the behavioral and anticonvulsant properties of MK-801 following repeated administration in mice. Br J Pharmacol 99:286PGoogle Scholar
  52. Ouagazzal AM, Creese I (2000) Intra-accumbens infusion of D(3) receptor agonists reduces spontaneous and dopamine-induced locomotion. Pharmacol Biochem Behav 67:637–645CrossRefGoogle Scholar
  53. Panos JJ, Rademacher DJ, Renner SL, Steinpreis RE (1999) The rewarding properties of NMDA and MK-801 (dizocilpine) as indexed by the conditioned place preference paradigm. Pharmacol Biochem Behav 64:591–595CrossRefGoogle Scholar
  54. Papp M, Moryl E (1994) Rewarding properties of non-competitive and competitive NMDA antagonists as measured by place preference conditioning in rats. Pol J Pharmacol 46:79–81Google Scholar
  55. Papp M, Moryl E, Maccecchini ML (1996) Differential effects of agents acting at various sites of the NMDA receptor complex in a place preference conditioning model. Eur J Pharmacol 317:191–196CrossRefGoogle Scholar
  56. Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates, 2nd edn. Academic, New YorkGoogle Scholar
  57. Pugsley TA, Davis MD, Akunne HC, MacKenzie RG, Shih YH, Damsma G, Wikstrom H, Whetzel SZ, Georgic LM, Cooke LW et al (1995) Neurochemical and functional characterization of the preferentially selective dopamine D3 agonist PD 128907. J Pharmacol Exp Ther 275:1355–1366Google Scholar
  58. Riters LV, Bingham VP (1994) The NMDA-receptor antagonist MK-801 impairs navigational learning in homing pigeons. Behav Neural Biol 62:50–59Google Scholar
  59. Rodriguez De Fonseca F, Rubio P, Martin-Calderon JL, Caine SB, Koob GF, Navarro M (1995) The dopamine receptor agonist 7-OH-DPAT modulates the acquisition and expression of morphine-induced place preference. Eur J Pharmacol 274:47–55CrossRefGoogle Scholar
  60. Rothman RB, Reid AA, Silverthorn M, DeCosta BR, Monn JA, Thurkauf A, Jacobson AE, Rice KC, Rogawski MA (1992) Structure activity studies on the interaction of biogenic amine reuptake inhibitors and potassium channel blockers with MK-801 sensitive (PCP site 1) and insensitive (PCP site 2) [3H]TCP binding sites in guinea pig brain. In: Kamenka JM, Domino EF (eds) Multiple sigma and PCP receptor ligands. NPP Books, Ann Arbor, MI, pp 137–146Google Scholar
  61. Sesack SR, Pickel VM (1992) Prefrontal cortical efferents in the rat synapse on unlabeled neuronal targets of catecholamine terminals in the nucleus accumbens septi and on dopamine neurons in the ventral tegmental area. J Comp Neurol 320:145–160CrossRefGoogle Scholar
  62. Sokoloff P, Giros B, Martres MP, Bouthenet ML, Schwartz JC (1990) Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. Nature 347:146–151CrossRefPubMedGoogle Scholar
  63. Spyraki C, Fibiger HC, Phillips AG (1982) Dopaminergic substrates of amphetamine-induced place preference conditioning. Brain Res 253:185–193CrossRefGoogle Scholar
  64. Spyraki C, Kazandjian A, Varonos D (1985) Diazepam-induced place preference conditioning: appetitive and antiaversive properties. Psychopharmacology (Berl) 87:225–232CrossRefGoogle Scholar
  65. Steinpreis RE, Kramer MA, Mix KS, Piwowarczyk MC (1995) The effects of MK801 on place conditioning. Neurosci Res 22:427–430CrossRefGoogle Scholar
  66. Sufka KJ (1994) Conditioned place preference paradigm: a novel approach for analgesic drug assessment against chronic pain. Pain 58:355–366CrossRefGoogle Scholar
  67. Sukhotina I, Dravolina O, Bespalov A (1998) Place conditioning of mice with the NMDA receptor antagonists, eliprodil and dizocilpine. Eur J Pharmacol 362:103–110CrossRefGoogle Scholar
  68. Sukhotina IA, Dravolina OA, Medvedev IO, Bespalov AY (1999) Effects of calcium channel blockers on behaviors induced by the N-methyl-d-aspartate receptor antagonist, dizocilpine, in rats. Pharmacol Biochem Behav 63:569–580CrossRefPubMedGoogle Scholar
  69. Sundstrom JM, Hall FS, Stellar JR, Waugh EJ (2002) Effects of isolation-rearing on intracranial self-stimulation reward of the lateral hypothalamus: baseline assessment and drug challenges. Life Sci 70:2799–2810CrossRefGoogle Scholar
  70. Suzuki T, Aoki T, Kato H, Yamazaki M, Misawa M (1999) Effects of the 5-HT(3) receptor antagonist ondansetron on the ketamine- and dizocilpine-induced place preferences in mice. Eur J Pharmacol 385:99–102CrossRefGoogle Scholar
  71. Svensson K, Carlsson A, Waters N (1994) Locomotor inhibition by the D3 ligand R-(+)-7-OH-DPAT is independent of changes in dopamine release. J Neural Transm 95:71–74Google Scholar
  72. Swerdlow NR, Gilbert D, Koob GF (1989) Conditioned drug effects on spatial preference. In: Boulton AA, Baker GB, Greenshaw AJ (eds) Psychopharmacology (Neuromethods 13). Humana Press Inc, New Jersey, pp 399–446Google Scholar
  73. Thompson LT, Disterhoft JF (1997) N-methyl-d-aspartate receptors in associative eyeblink conditioning: both MK-801 and phencyclidine produce task- and dose-dependent impairments. J Pharmacol Exp Ther 281:928–940Google Scholar
  74. Turski L, Jacobsen P, Honore T, Stephens DN (1992) Relief of experimental spasticity and anxiolytic/anticonvulsant actions of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline. J Pharmacol Exp Ther 260:742–747Google Scholar
  75. Tzschentke TM, Schmidt WJ (1995) N-methyl-d-aspartic acid-receptor antagonists block morphine-induced conditioned place preference in rats. Neurosci Lett 193:37–40CrossRefGoogle Scholar
  76. Tzschentke TM, Schmidt WJ (1997) Interactions of MK-801 and GYKI 52466 with morphine and amphetamine in place preference conditioning and behavioural sensitization. Behav Brain Res 84:99–107CrossRefGoogle Scholar
  77. Tzschentke TM, Schmidt WJ (1998) Blockade of morphine- and amphetamine-induced conditioned place preference in the rat by riluzole. Neurosci Lett 242:114–116CrossRefGoogle Scholar
  78. Wolf ME, Khansa MR (1991) Repeated administration of MK-801 produces sensitization to its own locomotor stimulant effects but blocks sensitization to amphetamine. Brain Res 562:164–168CrossRefGoogle Scholar
  79. Wolf ME, White FJ, Hu XT (1993) Behavioral sensitization to MK-801 (dizocilpine): neurochemical and electrophysiological correlates in the mesoaccumbens dopamine system. Behav Pharmacol 4:429–442Google Scholar
  80. Wong EH, Kemp JA, Priestley T, Knight AR, Woodruff GN, Iversen LL (1986) The anticonvulsant MK-801 is a potent N-methyl-d-aspartate antagonist. Proc Natl Acad Sci U S A 83:7104–7108Google Scholar
  81. Zajaczkowski W, Frankiewicz T, Parsons CG, Danysz W (1997) Uncompetitive NMDA receptor antagonists attenuate NMDA-induced impairment of passive avoidance learning and LTP. Neuropharmacology 36:961–971CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Anna-Maria Biondo
    • 1
  • Robert L. H. Clements
    • 2
    • 3
  • David J. Hayes
    • 2
    • 3
  • Brendan Eshpeter
    • 4
  • Andrew J. Greenshaw
    • 2
    • 3
  1. 1.Department of SociologyUniversity of AlbertaEdmontonCanada
  2. 2.W.G. Dewhurst Laboratory, Department of Psychiatry, 1E7.44 Mackenzie Health Sciences CentreUniversity of AlbertaEdmontonCanada
  3. 3.Centre for NeuroscienceUniversity of AlbertaEdmontonCanada
  4. 4.Department of PsychologyUniversity of AlbertaEdmontonCanada

Personalised recommendations