, Volume 191, Issue 3, pp 719–730 | Cite as

Differential ability of D1 and D2 dopamine receptor agonists to induce and modulate expression and reinstatement of cocaine place preference in rats

  • Danielle L. Graham
  • Regis Hoppenot
  • April Hendryx
  • David W. Self
Original Investigation



D1-Like agonists are self-administered by drug-naive animals, whereas D2-like agonists reinstate cocaine-seeking behavior, but the rewarding and reinstating effects of D1- and D2-like agonists in pavlovian-based conditioned place preference are equivocal.


To compare the ability of D1 and D2 agonists to produce conditioned place preference with their modulation of expression and reinstatement of an established cocaine place preference.


Using an unbiased procedure, we measured the place preference induced by the D1 receptor agonist SKF 81297 and the D2/D3 receptor agonist quinpirole in drug-naive or cocaine-exposed rats. The rewarding effects of the D1 agonists SKF 82958, ABT-431, A-77636, and the D2/D3 receptor agonist 7-OH-DPAT were also tested. Additionally, we tested the ability of SKF 81297 and quinpirole to modulate expression and reinstatement of an established cocaine place preference.


The D1 receptor agonists SKF 81297, SKF 82958, and ABT-431 produced dose-dependent conditioned place preferences, whereas A-77636 produced only place aversion, and the D2/D3 agonists quinpirole and 7-OH-DPAT were without effect in drug naive rats. In cocaine-treated rats, SKF-81297-induced place preference was reduced, whereas quinpirole-induced place preference was revealed. Pretreatment using either D1 or D2/D3 agonists blocked expression of an established cocaine place preference, but only the D1 agonist SKF 81297 and cocaine dose-dependently reinstated an extinguished cocaine place preference, whereas the D2/D3 agonist quinpirole induced place aversion but failed to alter cocaine-induced reinstatement.


D1, but not D2/D3, agonists mediate rewarding effects and reinstatement of cocaine place preference, but the reinstating effects differ markedly from self-administration paradigms.


Dopamine Reward Conditioned reward Craving Relapse Addiction 


  1. Abrahams BS, Rutherford JD, Mallet PE, Beninger RJ (1998) Place conditioning with the dopamine D1-like receptor agonist SKF 82958 but not SKF 81297 or SKF 77434. Eur J Pharmacol 343:111–118PubMedCrossRefGoogle Scholar
  2. Acquas E, Di Chiara (1994) D1 receptor blockade stereospecifically impairs the acquisition of drug-conditioned place preference and place aversion. Behav Pharmacol 5:555–569PubMedCrossRefGoogle Scholar
  3. Adams JU, Careri JM, Efferen TR, Rotrosen J (2001) Differential effects of dopamine antagonists on locomotor activity, conditioned activity and conditioned place preference induced by cocaine in rats. Behav Pharmacol 12:603–611PubMedGoogle Scholar
  4. Alleweireldt AT, Weber SM, Kirschener KF, Bullock BL, Neisewander JL (2002) Blockade or stimulation of D1 dopamine receptors attenuates cue reinstatement of extinguished cocaine-seeking behavior in rats. Psychopharmacology (Berl) 159:284–293CrossRefGoogle Scholar
  5. Alleweireldt AT, Kirschner KF, Blake CB, Neisewander JL (2003) D1-Receptor drugs and cocaine-seeking behavior: investigation of receptor mediation and behavioral disruption in rats. Psychopharmacology (Berl) 168:109–117CrossRefGoogle Scholar
  6. Baker DA, Khroyan TV, O’Dell LE, Fuchs RA, Neisewander JL (1996) Differential effects of intra-accumbens sulpiride on cocaine-induced locomotion and conditioned place preference. J Pharmacol Exp Ther 279:392–401PubMedGoogle Scholar
  7. Baker DA, Fuchs RA, Specio SE, Khroyan TV, Neisewander JL (1998) Effects of intra-accumbens administration of SCH-23390 on cocaine-induced locomotion and conditioned place preference. Synapse 30:181–193PubMedCrossRefGoogle Scholar
  8. Beninger RJ, Ranaldi R (1992) The effect of amphetamine, apomorphine, SKF 38393, quinpirole and bromocriptine on responding for conditioned reward in rats. Behav Pharmacol 3:155–163PubMedCrossRefGoogle Scholar
  9. Beninger RJ, Rolfe NG (1995) Dopamine D1-like receptor agonists impair responding for conditioned reward in rats. Behav Pharmacol 6:785–793PubMedCrossRefGoogle Scholar
  10. Biondo AM, Clements RL, Hayes DJ, Eshpeter B, Greenshaw AJ (2005) NMDA or AMPA/kainate receptor blockade prevents acquisition of conditioned place preference induced by D(2/3) dopamine receptor stimulation in rats. Psychopharmacology (Berl) 179:189–197CrossRefGoogle Scholar
  11. Blanchet PJ, Grondin, R, Bedard PJ, Shiosaki, K, Britton DR (1996) Dopamine D1 receptor desensitization profile in MPTP-lesioned primates. Eur J Pharmacol 309:13–20PubMedCrossRefGoogle Scholar
  12. Brown EE, Fibiger HC (1993) Differential effects of excitotoxic lesions of the amygdala on cocaine-induced conditioned locomotion and conditioned place preference. Psychopharmacology (Berl) 113:123–130CrossRefGoogle Scholar
  13. Caine SB, Koob GF (1993) Modulation of cocaine self-administration in the rat through D-3 dopamine receptors. Science 260:1814–1816PubMedCrossRefGoogle Scholar
  14. Callahan PM, Appel JB, Cunningham KA (1991) Dopamine D1 and D2 mediation of the discriminative stimulus properties of d-amphetamine and cocaine. Psychopharmacology (Berl) 103:50–55CrossRefGoogle Scholar
  15. Cervo L, Samanin R (1995) Effects of dopaminergic and glutaminergic receptor antagonists on the acquisition and expression of cocaine conditioning place preference. Brain Res 673:242–250PubMedCrossRefGoogle Scholar
  16. De Vries TJ, Schoffelmeer ANM, Binnekade R, Vanderschuren LJMJ (1999) Dopaminergic mechanisms mediating the incentive to seek cocaine and heroin following long-term withdrawal if IV drug self-administration. Psychopharmacology (Berl) 143:254–260CrossRefGoogle Scholar
  17. Dias C, Lachize S, Boilet V, Huitelec E, Cador M (2004) Differential effects of dopaminergic agents on locomotor sensitization and on the reinstatement of cocaine-seeking and food-seeking behavior. Psychopharmacology (Berl) 175:105–115Google Scholar
  18. Duarte C, Lefebvre C, Chaperon F, Hamon M, Thiebot M (2003) Effects of a dopamine D3 receptor ligand, BP 897, on acquisition and expression of food-morphine- and cocaine-induced conditioned place preference, and food-seeking behavior in rats. Neuropsychopharmacology 28:1903–1915PubMedGoogle Scholar
  19. Edwards S, Whisler KN, Fuller DC, Orsulak PJ, Self DW (2006) Addiction-related alterations in D1 and D2 dopamine receptor behavioral responses following chronic cocaine self-administration. Neuropsychopharmacology doi:10.1038/sj.npp.1301062
  20. Goeders NE, Kuhar MJ (1987) Chronic cocaine administration induces opposite changes in dopamine receptors in the striatum and nucleus accumbens. Alcohol Drug Res 7:207–216PubMedGoogle Scholar
  21. Goto Y, Grace AA (2005) Dopaminergic modulation of limbic and cortical drive of nucleus accumbens in goal-directed behavior. Nat Neurosci 8:805–812PubMedCrossRefGoogle Scholar
  22. Graziella De Montis M, Co C, Dworkin SI, Smith JE (1998) Modifications of dopamine D1 receptor complex in rats self-administering cocaine. Eur J Pharmacol 362:9–15PubMedCrossRefGoogle Scholar
  23. Grech DM, Spealman RD, Bergman J (1996) Self-administration of D1 receptor agonists by squirrel monkeys. Psychopharmacology (Berl) 125:97–104CrossRefGoogle Scholar
  24. Gyertyan I, Gal K (2003) Dopamine D3 receptor ligands show place conditioning effect but do not influence cocaine-induced place preference. NeuroReport 14:93–98PubMedCrossRefGoogle Scholar
  25. Henry DJ, White FJ (1991) Repeated cocaine administration causes persistent enhancement of D1 dopamine receptor sensitivity within the rat nucleus accumbens. J Pharmacol Exp Ther 258:882–890PubMedGoogle Scholar
  26. Hoffman DC, Beninger RJ (1988) Selective D1 and D2 dopamine agonists produce opposing effects in place conditioning but not in conditioned taste aversion learning. Pharmacol Biochem Behav 31:1–8PubMedCrossRefGoogle Scholar
  27. Itzhak Y, Martin JL (2002) Cocaine-induced conditioned place preference in mice: induction, extinction, and reinstatement by related psychostimulants. Neuropsychopharmacology 26:130–134PubMedCrossRefGoogle Scholar
  28. Kebabian JW, Britton DR, Deninno MP, Perner R, Smith L, Jenner P, Schoenleber R, Williams M (1992) A-77636: a potent and selective D1 receptor agonist with antiparkinsonian activity in marmosets. Eur J Pharmacol 229:203–209PubMedCrossRefGoogle Scholar
  29. 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) 122:351–357CrossRefGoogle Scholar
  30. King GR, Ellinwood EH Jr, Silvia C, Joyner CM, Xue Z, Caron MG, Lee TH (1994) Withdrawal from continuous or intermittent cocaine administration: changes in D2 receptor function. J Pharmacol Exp Ther 269:743–749PubMedGoogle Scholar
  31. Kivastik T, Vuorikallas K, Piepponen TP, Zharkovsky A, Ahtee L (1996) Morphine- and cocaine-induced conditioned place preference: effects of quinpirole and preclamol. Pharmacol Biochem Behav 54:371–375PubMedCrossRefGoogle Scholar
  32. Kleven MS, Pery BD, Woolverton WL, Seiden LS (1990) Effects of repeated injections of cocaine on D1 and D2 dopamine receptors in rat brain. Brain Res 532:265–270PubMedCrossRefGoogle Scholar
  33. Kling-Petersen T, Ljung E, Wollter L, Svensson K (1995) Effects of dopamine D3 preferring compounds on conditional place preference and intracranial self-stimulation in the rat. J Neural Trans 101:27–39CrossRefGoogle Scholar
  34. Kreibich AS, Blendy JA (2004) cAMP response element-binding protein is required for stress but not cocaine-induced reinstatement. J Neurosci 24:6686–6692PubMedCrossRefGoogle Scholar
  35. Lawley SI, Kantak KM (1990) Postconditioning effects of magnesium on cocaine conditioned place preference in mice. Pharmacol Biochem Behav 36:531–538PubMedCrossRefGoogle Scholar
  36. Liao RM, Chang YH, Wang SH (1998) Influence of SCH23390 and spiperone on the expression of conditioned place preference induced by d-amphetamine or cocaine in the rat. Chin J Physiol 41:85–92PubMedGoogle Scholar
  37. Lin CW, Bianchi BR, Miller TR, Stashko MA, Wang SS, Curzon P, Bednarz L, Asin KE, Britton DR (1996) Persistent activation of the dopamine D1 receptor contributes to prolonged receptor desensitization: studies with A-77636. J Pharmacol Exp Ther 276:1022–1029PubMedGoogle Scholar
  38. Mallet PE, Beninger RJ (1994) 7-OH-DPAT produces place conditioning in rats. Eur J Pharmacol 261:R5–R6PubMedCrossRefGoogle Scholar
  39. Mayfield RD, Larson G, Zahniser NR (1992) Cocaine-induced behavioral sensitization in D1 dopamine receptor function in rat nucleus accumbens and striatum. Brain Res 573:331–335PubMedCrossRefGoogle Scholar
  40. Mueller D, Stewart J (2000) Cocaine-induced conditioned place preference: reinstatement by priming injections of cocaine after extinction. Behav Brain Res 115:39–47PubMedCrossRefGoogle Scholar
  41. Nader MA, Mach RH (1996) Self-administration of the dopamine D3 agonist 7-OH-DPAT in rhesus monkeys is modified by prior cocaine exposure. Psychopharmacology (Berl) 125:13–22CrossRefGoogle Scholar
  42. Nazarian A, Russo SJ, Festa ED, Kraish M, Quinones-Jenab V (2004) The role of D1 and D2 receptors in the cocaine conditioned place preference of male and female rats. Brain Res Bull 63:295–299PubMedCrossRefGoogle Scholar
  43. Nomikos GG, Spyraki C (1988) Cocaine-induced place conditioning: importance of route of administration and other procedural variables. Psychopharmacology (Berl) 94:119–125CrossRefGoogle Scholar
  44. Papp M, Willner P, Muscat R (1993) Behavioural sensitization to a dopamine agonist is associated with reversal of stress-induced anhedonia. Psychopharmacology (Berl) 110:159–164CrossRefGoogle Scholar
  45. Phillips PE, Stuber GD, Heien ML, Wightman RM, Carelli RM (2003) Subsecond dopamine release promotes cocaine seeking. Nature 422:614–618PubMedCrossRefGoogle 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 274:47–55PubMedCrossRefGoogle Scholar
  47. Schultz W (1998) Predictive reward signal of dopamine neurons. J Neurophysiol 80:1–27PubMedGoogle Scholar
  48. Self DW, Barnhart WJ, Lehman DA, Nestler EJ (1996a) Opposite modulation of cocaine-seeking behavior by D1 and D2-like dopamine receptor agonists. Science 271:1586–1589PubMedCrossRefGoogle Scholar
  49. Self DW, Belluzzi JD, Kossuth S, Stein L (1996b) Self-administration of the D1 agonist SKF 82958 is mediated by D1, and not D2, receptors. Psychopharmacology (Berl) 123:303–306CrossRefGoogle Scholar
  50. Self DW, Karanian DA, Spencer JJ (2000) Effects of the novel D1 agonist ABT-431 on cocaine self-administration and reinstatement. Ann N Y Acad Sci 909:133–144PubMedCrossRefGoogle Scholar
  51. Self DW, Stein L (1992) The D1 agonists SKF 82958 and SKF 77434 are self-administered by rats. Brain Res 582:349–352PubMedCrossRefGoogle Scholar
  52. Shiosaki, K, Jenner P, Asin KE, Britton DR, Lin CW, Michaelides M, Smith L, Bianchi B, Didomenico S, Hodges L, Hong Y, Mahan L, Mikusa J, Miller T, Nikkel A, Stashko M, Witte D, Williams M (1996) ABT-431: the diacetyl prodrug of A-86929, a potent and selective dopamine D1 receptor agonist: in vitro characterization and effects in animal models of Parkinson’s disease. J Pharmacol Exp Ther 276:150–160PubMedGoogle Scholar
  53. Shippenberg TS, Bals-Kubik R, Herz A (1991) Neuroanatomical substrates mediating the aversive effects of D-1 dopamine receptor antagonists. Psychopharmacology (Berl) 103:209–214CrossRefGoogle Scholar
  54. Stuber GD, Roitman MF, Phillips PE, Carelli RM, Wightman RM (2005) Rapid dopamine signaling in the nucleus accumbens during contingent and noncontingent cocaine administration. Neuropsychopharmacology 30:853–863PubMedCrossRefGoogle Scholar
  55. Szumlinski KK, Price KL, Frys KA, Middaugh LD (2002) Unconditioned and conditioned factors contribute to the “reinstatement” of cocaine place conditioning following extinction in C57BL/6 mice. Behav Brain Res 136:151–160PubMedCrossRefGoogle Scholar
  56. Tsukada H, Kreuter J, Maggos CE, Unterwald EM, Kakiuchi T, Nishiyama S, Futatsubashi M, Kreek MJ (1996) Effects of binge pattern cocaine administration on dopamine D1 and D2 receptors in the rat brain: an in vivo study using positron emission tomography. J Neurosci 16:7670–7677PubMedGoogle Scholar
  57. Tzschentke TM (1998) Measuring reward with the conditioned place preference paradigm: a comprehensive review of drug effects, recent progress and new issues. Prog Neurobiol 56:613–672PubMedCrossRefGoogle Scholar
  58. Unterwald EM, Fillmore J, Kreek MJ (1996) Chronic repeated cocaine administration increases dopamine D1 receptor-mediated signal transduction. Eur J Pharmacol 318:31–35PubMedCrossRefGoogle Scholar
  59. Vanderschuren LJ, Schoffelmeer AN, Mulder AH, De Vries TJ (1999) Dopaminergic mechanisms mediating the long-term expression of locomotor sensitization following pre-exposure to morphine or amphetamine. Psychopharmacology (Berl) 143:244–253CrossRefGoogle Scholar
  60. Weed MR, Vanover KE, Woolverton WL (1993) Reinforcing effect of the D1 dopamine agonist SKF 81297 in rhesus monkeys. Psychopharmacology (Berl) 113:51–52CrossRefGoogle Scholar
  61. Weed MR, Woolverton WL (1995) The reinforcing effects of dopamine D1 receptor agonists in rhesus monkeys. J Pharmacol Exp Ther 275:1367–1374PubMedGoogle Scholar
  62. White NM, Packard MG, Hiroi N (1991) Place conditioning with dopamine D1 and D2 agonists induced peripherally or into nucleus accumbens. Psychopharmacology (Berl) 103:271–276CrossRefGoogle Scholar
  63. Witkin JM, Nichols DE, Terry P, Katz J (1991) Behavioral effects of selective dopaminergic compounds in rats discriminating cocaine injections. J Pharmacol Exp Ther 257:706–713PubMedGoogle Scholar
  64. Wise RA (2004) Dopamine, learning, and motivation. Nat Rev Neurosci 5:483–494PubMedCrossRefGoogle Scholar
  65. Woolverton WL, Goldberg LI, Jinos JZ (1984) Intravenous self-administration of dopamine receptor agonists by rhesus monkeys. J Pharmacol Exp Ther 230:678–683PubMedGoogle Scholar
  66. Woolverton WL, Ranaldi R (2002) Comparison of the reinforcing efficacy of two dopamine D2-like receptor agonists in rhesus monkeys using a progressive-ratio schedule of reinforcement. Pharmacol Biochem Behav 72:803–809PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Danielle L. Graham
    • 1
  • Regis Hoppenot
    • 1
  • April Hendryx
    • 1
  • David W. Self
    • 1
  1. 1.Department of Psychiatry, The Seay Center for Basic and Applied Research in Psychiatric IllnessThe University of Texas Southwestern Medical CenterDallasUSA

Personalised recommendations