, Volume 175, Issue 2, pp 127–133

Dopamine D3 receptor ligands modulate the acquisition of morphine-conditioned place preference

  • Henriette Francès
  • Maria Smirnova
  • Ludovic Leriche
  • Pierre Sokoloff
Original Investigation



The dopamine D3 receptor has been shown to mediate conditioned effects of psychostimulants such as cocaine. The present work was aimed at determining whether drugs acting at D3 receptors alter acquisition of conditioned effects of opiates.


We have used the conditioned place preference (CPP) in mice, which permits the measurement of approach behaviour to environmental stimuli previously paired with drug effects. To assess the interaction of morphine and D3 receptor ligands during acquisition of CPP, we have used a particular procedure, in which the animals were given the choice between compartments associated with either morphine alone or the combination of morphine with the tested agent.


D3 receptor agonists (7-OH-DPAT, quinelorane, BP 897) did not induce, alone, a significant CPP but, all of them, at the doses tested, and notably BP 897, a highly selective partial agonist, significantly enhanced acquisition of morphine-induced CPP when administered together with morphine at each conditioning session. PNU-99194A, a D3 receptor-preferring antagonist, induced a CPP itself at the dose of 10 mg/kg but not at 5 or 15 mg/kg and impaired significantly at 10 and 15 mg/kg the morphine-induced CPP. In contrast, BP 897 did not alter morphine-induced analgesia, an unconditioned effect of this drug.


These results suggest the stimulation of D3 receptors has no rewarding effect per se, but may synergize upon opiate-induced dopamine release with stimulation of other dopamine receptor subtypes to enhance approach behaviour to morphine-associated environment.


Dopamine D3  receptor Conditioned place preference BP 897 PNU-99194A 7-OH-DPAT Quinelorane Analgesia Mouse 


  1. Acquas E, Carboni E, Leone P, Di Chiara G (1989) SCH 23390 blocks drug-conditioned place preference and place aversion: anhedonia (lack of reward) or apathy (lack of motivation) after dopamine-receptor blockade? Psychopharmacology 99:151–155PubMedGoogle Scholar
  2. Arroyo M, Markou A, Robbins TW, Everitt BJ (1999) Acquisition, maintenance and reinstatement of intravenous cocaine self-administration under a second-order schedule of reinforcement in rats: effects of conditioned cues and continuous access to cocaine. Neuropsychopharmacology 140:331–344Google Scholar
  3. Ashby CRJ, Mousumi P, Gardner EL, Heibreder CA, Hagan JJ (2003) Acute administration of the selective D3 receptor antagonist SB-277701A blocks the acquisition and expression of the conditioned place preference response to heroin in male rats. Synapse 48:154–156CrossRefPubMedGoogle Scholar
  4. Aujla H, Sokoloff P, Beninger BJ (2002) A dopamine D3 receptor partial agonist blocks the expression of conditioned activity. Neuroreport 13:173–176CrossRefPubMedGoogle Scholar
  5. Bardo MT, Rowlett JK, Harris MJ (1995) Conditioned place preference using opiate and stimulant drugs: a meta-analysis. Neurosci Biobehav Rev 19:39–51PubMedGoogle Scholar
  6. Beardsley PM, Sokoloff P, Balster RL, Schwartz J-C (2001) The D3R partial agonist, BP 897, attenuates the discriminative stimulus effects of cocaine and d-amphetamine and is not self-administered. Behav Pharmacol 12:1–11PubMedGoogle Scholar
  7. Berridge KC, Robinson TE (1998) What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience? Brain Res Rev 28:309–369PubMedGoogle Scholar
  8. Bezard E, Ferry S, Mach U, Leriche L, Boraud T, Stark H, Gross C, Sokoloff P (2003) Attenuation of levodopa-induced dyskinesia by normalizing dopamine D3 receptor function. Nat Med 6:762–767CrossRefGoogle Scholar
  9. Caine SB, Koob GF (1993) Modulation of cocaine self-administration in the rat through D3 dopamine receptors. Science 260:1814–1816PubMedGoogle Scholar
  10. Caine SB, Koob GF (1995) Pretreatment with the dopamine agonist 7-OH-DPAT shifts the cocaine self-administration dose-effect function to the left under different schedules in the rat. Behav Pharmacol 6:333–347Google Scholar
  11. Caine SB, Koob GF, Parsons LH, Everitt BJ, Schwartz J-C, Sokoloff P (1997) D3 receptor test in vitro predicts decreased cocaine self-administration in rats. Neuroreport 8:2373–2377PubMedGoogle Scholar
  12. Chaperon F, Thiébot MH (1996) Effects of dopaminergic D3 receptor-preferring ligands on the acquisition of place preference in rats. Behav Pharmacol 7:105–109Google Scholar
  13. Coudereau J-P, Debray M, Monier C, Bourre J-M, Francès H (1997) Isolation impairs place preference conditioning to morphine but not aversive learning in mice. Psychopharmacology 130:117–123CrossRefPubMedGoogle Scholar
  14. Di Chiara G, Imperato A (1988) Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci USA 85:5274–5278PubMedGoogle Scholar
  15. Di Ciano P, Understood RJ, Hagan JJ, Everitt BJ (2003) Attenuation of cue-controlled cocaine-seeking by a selective D3 receptor antagonist SB-277011-A. Neuropsychopharmacology 28:329–338CrossRefPubMedGoogle Scholar
  16. Diaz J, Pilon C, Le Foll B, Gros C, Triller A, Schwartz J-C, Sokoloff P (2000) Dopamine D3 receptors expressed by all mesencephalic dopamine neurons. J Neurosci 20:8677–8684PubMedGoogle Scholar
  17. Dworkin SI, Guerin GF, Co C, Goeders NE, Smith JE (1988) Lack of an effect of 6-hydroxydopamine lesions of the nucleus accumbens on intravenous morphine self-administration. Pharmacol Biochem Behav 30:1051–1057PubMedGoogle Scholar
  18. Elmer GI, Pieper JO, Rubinstein M, Low MJ, Grandy DK, Wise RA (2002) Failure of intravenous morphine to serve as an effective instrumental reinforcer in dopamine D2 receptor knock-out mice. J Neurosci 15:RC224Google Scholar
  19. Gerrits MA, Van Ree JM (1996) Effect of nucleus accumbens dopamine depletion on motivational aspects involved in initiation of cocaine and heroin self-administration in rats. Brain Res 713:114–124PubMedGoogle Scholar
  20. Goldberg SR, Gardner ML (1981) Second-order schedules: extended sequences of behavior controlled by brief environmental stimuli associated with drug self-administration. NIDA Res Monogr 37:241–270PubMedGoogle Scholar
  21. Griffon N, Pilon C, Sautel F, Schwartz JC, Sokoloff P (1997) Two intracellular signaling pathways for the dopamine D3 receptor: opposite and synergistic interactions with cyclic AMP. J Neurochem 68:1–9PubMedGoogle Scholar
  22. Gyertyan I, Gal K (2003) Dopamine D3 receptor ligands show place conditioning effect but do not influence cocaine-induced place preference. Neuroreport 14:93–98CrossRefPubMedGoogle Scholar
  23. Joseph JD, Wang Y-M, Miles PR, Budygin EA, Picetti R, Gainetdinov RR, Caron MG, Wightman RM (2002) Dopamine autoreceptor regulation of release and uptake in mouse slices in the absence of D3 receptors. Neuroscience 112:39–49CrossRefPubMedGoogle Scholar
  24. Khroyan TV, Baker DA, Niesewander JL (1995) Dose-dependent effects of the D3-preferring agonist 7-OH-DPAT on motor behaviors and place conditioning. Psychopharmacology 122:351–357PubMedGoogle Scholar
  25. Khroyan TV, Fuchs RA, Baker DA, Neisewander JL (1997) Effects of D3-preferring agonists 7-OH-PIPAT and PD-128,907 on motor behaviors and place conditioning. Behav Pharmacol 8:65–74Google Scholar
  26. Khroyan TV, Fuchs RA, Beck AM, Groff RS, Neisewander JL (1999) Behavioral interactions produced by co-administration of 7-OH-DPAT with cocaine or apomorphine in the rat. Psychopharmacology 142:383–392CrossRefPubMedGoogle Scholar
  27. Kling-Petersen T, Ljung E, Svensson K (1995) Effects on locomotor activity after local application of D3 preferring compounds in discrete areas of the rat brain. J Neural Transm [Gen Sect] 102:209–220Google Scholar
  28. Koob GF (1992) Drugs of abuse: anatomy, pharmacology and function of reward pathways. Trends Pharmacol Sci 13:177–184PubMedGoogle Scholar
  29. Le Foll B, Francès H, Diaz J, Schwartz J-C, Sokoloff P (2002) Role of the dopamine D3 receptor in reactivity to cocaine-associated cues in mice. Eur J Neurosci 15:2016–2026PubMedGoogle Scholar
  30. Le Foll B, Schwartz J-C, Sokoloff P (2003) Disruption of nicotine conditioning by dopamine D3 receptor ligands. Mol Psychiatr 8:225–230CrossRefGoogle Scholar
  31. Leone P, Pocock D, Wise RA (1991) Morphine-dopamine interaction: ventral tegmental morphine increases nucleus accumbens dopamine release. Pharmacol Biochem Behav 39:469–472PubMedGoogle Scholar
  32. Leriche L, Schwartz JC, Sokoloff P (2003) The dopamine D3 receptor mediates locomotor hyperactivity induced by NMDA receptor blockade. Neuropharmacology 45:174–181CrossRefPubMedGoogle Scholar
  33. Lubow RE (1973) Latent inhibition. Psychol Bull 79:398–407PubMedGoogle Scholar
  34. Mackey WB, van der Kooy D (1985) Neuroleptics block the positive reinforcing effects of amphetamine but not morphine as measured by place preference. Pharmacol Biochem Behav 22:101–105PubMedGoogle Scholar
  35. Maldonado R, Saiardi A, Valverde O, Samad TA, Roques BP, Borrelli E (1997) Absence of opiate rewarding effects in mice lacking dopamine D2 receptors. Nature 388:586–589PubMedGoogle Scholar
  36. Mallet PE, Beninger RJ (1994) 7-OH-DPAT produces place conditioning in rats. Eur J Pharmacol 261:R4–R5CrossRefGoogle Scholar
  37. Manzanedo C, Aguilar MA, Rodriguez-Arias M, Minarro J (2001) Effects of dopamine antagonists with different receptor blockade profiles on morphine-induced place preference in male mice. Behav Brain Res 121:189–197CrossRefPubMedGoogle Scholar
  38. O’Brien CP, Childress AR, McMellan AT, Ehrman RA (1992) A learning model of addiction. Res Publ Assoc Res Nerv Ment Dis 70:157–177PubMedGoogle Scholar
  39. Pettit HO, Justice JBJ (1989) Dopamine in the nucleus accumbens during cocaine self-administration as studied by in vivo microdialysis. Pharmacol Biochem Behav 34:899–904PubMedGoogle Scholar
  40. Pettit HO, Ettenberg A, Bloom FE, Koob GF (1984) Destruction of dopamine in the nucleus accumbens selectively attenuates cocaine but not heroin self-administration in rats. Psychopharmacology 84:167–173PubMedGoogle Scholar
  41. Perachon S, Betancur C, Pilon C, Rostene W, Schwartz JC, Sokoloff P (2000) Role of dopamine D3 receptors in thermoregulation: a reappraisal. Neuroreport 11:221–225PubMedGoogle Scholar
  42. Pilla M, Hutcheson DM, Adib-Samil P, Everitt BJ (2001) Seeking responses for cocaine, heroin and natural reinforcers are differentially modulated by dopamine D3 receptors. Soc Neurosci Abstr 27:647.16Google Scholar
  43. Pilla M, Perachon S, Sautel F, Garrido F, Mann A, Wermuth CG, Schwartz J-C, Everitt BJ, Sokoloff P (1999) Selective inhibition of cocaine-seeking behaviour by a partial dopamine D3 receptor agonist. Nature 400:371–375PubMedGoogle Scholar
  44. Reavill C, Taylor SG, Wood MD, Ashmeade T, Austin NE, Avenell KY, Boyfield I, Branch CL, Cilia J, Coldwell MC, Hadley MS, Hunter AJ, Jeffrey P, Jewitt F, Johnson CN, Jones DNC, Medhurst AD, Middlemiss DN, Nash DJ, Riley GJ, Routledge C, Stemp G, Thewlis KM, Trail B, Vong AKK, Hagan JJ (2000) Pharmacological actions of a novel high-affinity, and selective human dopamine D3 receptor antagonist, SB-277011-A. J Pharmacol Exp Ther 294:1154–1165PubMedGoogle Scholar
  45. Ridray S, Griffon N, Souil E, Mignon V, Carboni S, Diaz J, Schwartz J-C, Sokoloff P (1998) Coexpression of dopamine D1 and D3 receptors in rat ventral striatum: opposite and synergistic functional interactions. Eur J Neurosci 10:1676–1686CrossRefPubMedGoogle Scholar
  46. 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 274:47–55PubMedGoogle Scholar
  47. Sautel F, Griffon N, Lévesque D, Pilon C, Schwartz JC, Sokoloff P (1995a) A functional test identifies dopamine agonists selective for D3 versus D2 receptors. NeuroReport 6:329–332PubMedGoogle Scholar
  48. Sautel F, Griffon N, Sokoloff P, Schwartz J-C, Launay C, Simon P, Costentin J, Schoenfelder A, Garrido F, Mann A, Wermuth CG (1995b) Nafadotride, a potent preferential dopamine D3 receptor antagonist, activates locomotion in rodents. J Pharmacol Exp Ther 275:1239–1246PubMedGoogle Scholar
  49. Schotte A, Janssen PF, Gommeren W, Luyten WH, Leysen JE (1992) Autoradiographic evidence for the occlusion of rat brain dopamine D3 receptors in vivo. Eur J Pharmacol 218:373–375CrossRefPubMedGoogle Scholar
  50. Schultz W (2002) Getting formal with dopamine and reward. Neuron 36:241–263PubMedGoogle Scholar
  51. Shippenberg TS, Bals-Kubib R, Herz A (1993) Examination of the neurochemical substrates mediating the motivational effects of opioids: role of the mesolimbic dopamine system and D-1 vs. D-2 receptors. J Pharmacol Exp Ther 265:53–59PubMedGoogle Scholar
  52. Spyraki C, Fibiger HC, Phillips AG (1983) Attenuation of heroin reward in rats by disruption of the mesolimbic dopamine system. Psychopharmacology 79:278–283PubMedGoogle Scholar
  53. van Ree JM, Gerrits MA, Vanderschuren LJ (1999) Opioids, reward and addiction: an encounter of biology, psychology, and medicine. Pharmacol Rev 51:341–396PubMedGoogle Scholar
  54. Vorel SR, Ashby CRJ, Paul M, Liu X, Hayes R, Hagan JJ, Middlemiss DN, Stemp G, Gardner EL (2002) Dopamine D3 receptor antagonism inhibits cocaine-seeking and cocaine-enhanced brain reward in rats. J Neurosci 22:9595–9603PubMedGoogle Scholar
  55. Waters N, Svensson K, Haadsma-Svensson SR, Smith MW, Carlsson A (1993) The dopamine D3 receptor: a postsynaptic receptor inhibitory on rat locomotor activity. J Neural Transm [Gen Sect] 94:11–19Google Scholar
  56. Wicke K, Garcia-Ladona J (2001) The dopamine D3 receptor partial agonist, BP 897, is an antagonist at human dopamine D3 receptors and at rat somatodendritic dopamine D3 receptors. Eur J Pharmacol 424:85–90CrossRefPubMedGoogle Scholar
  57. Wise RA (1989) Opiate reward: sites and substrates. Neurosci Biobehav Rev 13:129–133PubMedGoogle Scholar
  58. Wood MD, Boyfield I, Nash DJ, Jewitt FR, Avenell KY, Riley GJ (2000) Evidence for antagonist activity of the dopamine D3 receptor partial agonist, BP 897, at human dopamine D3 receptor. Eur J Pharmacol 407:47–51CrossRefPubMedGoogle Scholar
  59. Xu M, Koeltzow TE, Cooper DC, Tonegawa S, White FJ (1999) Dopamine D3 receptor mutant and wild-type mice exhibit identical responses to putative D3 receptor-selective agonists and antagonists. Synapse 31:210–215PubMedGoogle Scholar
  60. Zapata A, Witkins JM, Shippenberg TS (2001) Selective D3 receptor agonist effects of (+)-PD 128907 on dialysate dopamine at low doses. Neuropharmacology 41:351–359PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Henriette Francès
    • 1
    • 2
  • Maria Smirnova
    • 2
  • Ludovic Leriche
    • 1
  • Pierre Sokoloff
    • 1
  1. 1.Unité de Neurobiologie et Pharmacologie Moléculaire (INSERM U 573)Centre Paul BrocaParisFrance
  2. 2.Modulation des Echanges Moléculaires entre le Cerveau et le Sang (INSERM U 26)Hôpital Fernand WidalParisFrance

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