, Volume 183, Issue 1, pp 41–53 | Cite as

Effects of intranucleus accumbens shell administration of dopamine agonists and antagonists on cocaine-taking and cocaine-seeking behaviors in the rat

  • Ryan K. Bachtell
  • Kimberly Whisler
  • David Karanian
  • David W. Self
Original Investigation



Dopamine signaling in the nucleus accumbens (NAc) plays an important role in regulating drug-taking and drug-seeking behaviors, but the role of D1- and D2-like receptors in this regulation remains unclear.


Our objective was to study the role of NAc D1- and D2-like receptors in the reinstatement of cocaine-seeking behavior and the regulation of stabilized cocaine intake in rats.


Using a within-session reinstatement procedure, whereby animals self-administer cocaine (90 min) and extinguish responding (150 min) in a single session, we assessed the ability of NAc microinfusions of the D1 agonist SKF 81297 and the D2 agonist 7-OH-DPAT to reinstate extinguished cocaine seeking. The effects of the D1 antagonist SCH 23390 and the D2 antagonist eticlopride pretreatment on agonist- and cocaine-primed reinstatement were also measured. Similar agonist and antagonist treatments were tested for their ability to modulate stabilized cocaine and sucrose self-administration.


Intra-NAc infusions of either SKF 81297 (0.3–3.0 μg) or 7-OH-DPAT (1.0–10.0 μg) dose-dependently reinstated cocaine seeking with greater efficacy in the medial core than in the shell subregion and at doses that also stimulated locomotor behavior. Intra-NAc shell infusions of SCH 23390 (1.0 μg) and eticlopride (3.0–10.0 μg) blocked cocaine-primed reinstatement (2.0 mg/kg, i.v.) and indiscriminately blocked reinstatement induced by either intra-NAc D1 or D2 agonists. Doses of agonists that triggered reinstatement failed to alter stabilized cocaine intake, whereas doses of antagonists that blocked reinstatement increased cocaine intake in the shell.


Both D1 and D2 receptors in the NAc play a prominent, and perhaps cooperative, role in regulating cocaine-taking and cocaine-seeking behaviors.


D1 receptor D2 receptor Self-administration Craving Relapse Reinstatement Reward Incentive motivation 



This work was supported by United States Public Health Services grants DA 10460, DA 08227, and DA 18481 (R.K.B.), and the Wesley Gilliland Professorship in Biomedical Research.


  1. Adell A, Artigas F (2004) The somatodendritic release of dopamine in the ventral tegmental area and its regulation by afferent transmitter systems. Neurosci Biobehav Rev 28:415–431CrossRefPubMedGoogle Scholar
  2. Aizman O, Brismar H, Uhlen P, Zettergren E, Levey AI, Forssberg H, Greengard P, Aperia A (2000) Anatomical and physiological evidence for D1 and D2 dopamine receptor colocalization in neostriatal neurons. Nat Neurosci 3:226–230CrossRefPubMedGoogle Scholar
  3. Alleweireldt AT, Weber SM, Kirschner KF, Bullock BL, Neisewander JL (2002) Blockade or stimulation of D1 dopamine receptors attenuates cue reinstatement of extinguished cocaine-seeking behavior in rats. Psychopharmacology 159:284–293CrossRefPubMedGoogle Scholar
  4. Andersen PH (1988) Comparison of the pharmacological characteristics of [3H]raclopride and [3H]SCH 23390 binding to dopamine receptors in vivo in mouse brain. Eur J Pharmacol 146:113–120CrossRefPubMedGoogle Scholar
  5. Andersen PH, Jansen JA (1990) Dopamine receptor agonists: selectivity and dopamine D1 receptor efficacy. Eur J Pharmacol 188:335–347CrossRefPubMedGoogle Scholar
  6. Anderson SM, Bari AA, Pierce RC (2003) Administration of the D1-like dopamine receptor antagonist SCH-23390 into the medial nucleus accumbens shell attenuates cocaine priming-induced reinstatement of drug-seeking behavior in rats. Psychopharmacology 168:132–138CrossRefPubMedGoogle Scholar
  7. Aubert I, Ghorayeb I, Normand E, Bloch B (2000) Phenotypical characterization of the neurons expressing the D1 and D2 dopamine receptors in the monkey striatum. J Comp Neurol 418:22–32CrossRefPubMedGoogle Scholar
  8. Bouthenet ML, Souil E, Martres MP, Sokoloff P, Giros B, Schwartz JC (1991) Localization of dopamine D3 receptor mRNA in the rat brain using in situ hybridization histochemistry: comparison with dopamine D2 receptor mRNA. Brain Res 564:203–219CrossRefPubMedGoogle Scholar
  9. Britton DR, Curzon P, Mackenzie RG, Kebabian JW, Williams JE, Kerkman D (1991) Evidence for involvement of both D1 and D2 receptors in maintaining cocaine self-administration. Pharmacol Biochem Behav 39:911–915CrossRefPubMedGoogle Scholar
  10. Caine SB, Heinrichs SC, Coffin VL, Koob GF (1995) Effects of the dopamine D-1 antagonist SCH 23390 microinjected into the accumbens, amygdala or striatum on cocaine self-administration in the rat. Brain Res 692:47–56CrossRefPubMedGoogle Scholar
  11. Caine SB, Negus SS, Mello NK, Bergman J (1999) Effects of dopamine D(1-like) and D(2-like) agonists in rats that self-administer cocaine. J Pharmacol Exp Ther 291:353–360PubMedGoogle Scholar
  12. Capriles N, Rodaros D, Sorge RE, Stewart J (2003) A role for the prefrontal cortex in stress- and cocaine-induced reinstatement of cocaine seeking in rats. Psychopharmacology 168:66–74CrossRefPubMedGoogle Scholar
  13. Cornish JL, Kalivas PW (2000) Glutamate transmission in the nucleus accumbens mediates relapse in cocaine addiction. J Neurosci 20:RC89PubMedGoogle Scholar
  14. Corrigall WA, Coen KM (1991) Cocaine self-administration is increased by both D1 and D2 dopamine antagonists. Pharmacol Biochem Behav 39:799–802CrossRefPubMedGoogle Scholar
  15. De Vries TJ, Schoffelmeer ANM, Binnekade R, Vanderschuren LJMJ (1999) Dopaminergic mechanisms mediating the incentive to seek cocaine and heroin following long-term withdrawal in IV drug self-administration. Psychopharmacology 143:254–260CrossRefPubMedGoogle Scholar
  16. Dias C, Lachize S, Boilet V, Huitelec E, Cador M (2004) Differential effects of dopaminergic agents on locomotor sensitisation and on the reinstatement of cocaine-seeking and food-seeking behaviour. Psychopharmacology 175:105–115Google Scholar
  17. Diaz J, Levesque D, Lammers CH, Griffon N, Martres MP, Schwartz JC, Sokoloff P (1995) Phenotypical characterization of neurons expressing the dopamine D3 receptor in the rat brain. Neuroscience 65:731–745CrossRefPubMedGoogle Scholar
  18. Dreher JK, Jackson DM (1989) Role of D1 and D2 dopamine receptors in mediating locomotor activity elicited from the nucleus accumbens of rats. Brain Res 487:267–277CrossRefPubMedGoogle Scholar
  19. Epping-Jordan MP, Markou A, Koob GF (1998) The dopamine D-1 receptor antagonist SCH 23390 injected into the dorsolateral bed nucleus of the stria terminalis decreased cocaine reinforcement in the rat. Brain Res 784:105–115CrossRefPubMedGoogle Scholar
  20. Essman WD, McGonigle P, Lucki I (1993) Anatomical differentiation within the nucleus accumbens of the locomotor stimulatory actions of selective dopamine agonists and d-amphetamine. Psychopharmacology 112:233–241PubMedCrossRefGoogle Scholar
  21. Franklin SR, Tang AH (1995) Dopamine agonists facilitate footshock-elicited locomotion in rats, and suppress level-press responding for food. Psychopharmacology 121:480–484PubMedCrossRefGoogle Scholar
  22. Gonzalez AM, Sibley DR (1995) [3H]7-OH-DPAT is capable of labeling dopamine D2 as well as D3 receptors. Eur J Pharmacol 272:R1–R3CrossRefPubMedGoogle Scholar
  23. Hall H, Sallemark M, Jerning E (1986) Effects of remoxipride and some related new substituted salicylamides on rat brain receptors. Acta Pharmacol Toxicol 58:61–70Google Scholar
  24. Haney M, Foltin RW, Fischman MW (1998) Effects of pergolide on intravenous cocaine self-administration in men and women. Psychopharmacology 137:15–24CrossRefPubMedGoogle Scholar
  25. Haney M, Collins ED, Ward AS, Foltin RW, Fischman MW (1999) Effect of a selective dopamine D1 agonist (ABT-431) on smoked cocaine self-administration in humans. Psychopharmacology 143:102–110CrossRefPubMedGoogle Scholar
  26. Hedou G, Feldon J, Heidbreder CA (1999) Effects of cocaine on dopamine in subregions of the rat prefrontal cortex and their efferents to subterritories of the nucleus accumbens. Eur J Pharmacol 372:143–155CrossRefPubMedGoogle Scholar
  27. Heimer L, Zahm DS, Churchill L, Kalivas PW, Wohltmann C (1991) Specificity in the projection patterns of accumbal core and shell in the rat. Neuroscience 41:89–125CrossRefPubMedGoogle Scholar
  28. Hoffman PL, Ishizawa H, Giri PR, Dave JR, Grant KA, Liu L-I, Gulya K, Tabakoff B (1990) The role of arginine vasopressin in alcohol tolerance. Ann Med 22:269–274PubMedCrossRefGoogle Scholar
  29. Hopf FW, Cascini MG, Gordon AS, Diamond I, Bonci A (2003) Cooperative activation of dopamine D1 and D2 receptors increases spike firing of nucleus accumbens neurons via G-protein betagamma subunits. J Neurosci 23:5079–5087PubMedGoogle Scholar
  30. Hubner CB, Koob GF (1990) Bromocriptine produces decreases in cocaine self-administration in the rat. Neuropsychopharmacology 3:101–108PubMedGoogle Scholar
  31. Hurd YL, Ponten M (2000) Cocaine self-administration behavior can be reduced or potentiated by the addition of specific dopamine concentrations in the nucleus accumbens and amygdala using in vivo microdialysis. Behav Brain Res 116:177–186CrossRefPubMedGoogle Scholar
  32. Hurd YL, McGregor A, Ponten M (1997) In vivo amygdala dopamine levels modulate cocaine self-administration behaviour in the rat: D1 dopamine receptor involvement. Eur J Neurosci 9:2541–2548PubMedCrossRefGoogle Scholar
  33. Ikemoto S, Glazier BS, Murphy JM, McBride WJ (1997) Role of dopamine D1 and D2 receptors in the nucleus accumbens in mediating reward. J Neurosci 17:8580–8587PubMedGoogle Scholar
  34. Ito R, Dalley JW, Howes SR, Robbins TW, Everitt BJ (2000) Dissociation in conditioned dopamine release in the nucleus accumbens core and shell in response to cocaine cues and during cocaine-seeking behavior in rats. J Neurosci 20:7489–7495PubMedGoogle Scholar
  35. Khroyan TV, Barrett-Larimore RL, Rowlett JK, Spealman RD (2000) Dopamine D1- and D2-like receptor mechanisms in relapse to cocaine-seeking behavior: effects of selective antagonists and agonists. J Pharmacol Exp Ther 294:680–687PubMedGoogle Scholar
  36. Koshikawa N, Kitamura M, Kobayashi M, Cools AR (1996) Contralateral turning elicited by unilateral stimulation of dopamine D2 and D1 receptors in the nucleus accumbens of rats is due to stimulation of these receptors in the shell, but not the core, of this nucleus. Psychopharmacology 126:185–190PubMedCrossRefGoogle Scholar
  37. Lachowicz JE, Sibley DR (1997) Molecular characteristics of mammalian dopamine receptors. Pharmacol Toxicol 81:105–113PubMedCrossRefGoogle Scholar
  38. Levant B, Bancroft GN, Selkirk CM (1996) In vivo occupancy of D2 dopamine receptors by 7-OH-DPAT. Synapse 24:60–64CrossRefPubMedGoogle Scholar
  39. 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 89:8155–8159PubMedCrossRefGoogle Scholar
  40. Lu XY, Ghasemzadeh MB, Kalivas PW (1998) Expression of D1 receptor, D2 receptor, substance P and enkephalin messenger RNAs in the neurons projecting from the nucleus accumbens. Neuroscience 82:767–780CrossRefPubMedGoogle Scholar
  41. Maldonado R, Robledo P, Chover AJ, Caine SB, Koob GF (1993) D1 dopamine receptors in the nucleus accumbens modulate cocaine self-administration in the rat. Pharmacol Biochem Behav 45:239–242CrossRefPubMedGoogle Scholar
  42. McFarland K, Kalivas PW (2001) The circuitry mediating cocaine-induced reinstatement of drug-seeking behavior. J Neurosci 21:8655–8663PubMedGoogle Scholar
  43. McGregor A, Roberts DC (1993) Dopaminergic antagonism within the nucleus accumbens or the amygdala produces differential effects on intravenous cocaine self-administration under fixed and progressive ratio schedules of reinforcement. Brain Res 624:245–252CrossRefPubMedGoogle Scholar
  44. McGregor A, Roberts DC (1995) Effect of medial prefrontal cortex injections of SCH 23390 on intravenous cocaine self-administration under both a fixed and progressive ratio schedule of reinforcement. Behav Brain Res 67:75–80CrossRefPubMedGoogle Scholar
  45. McQuade JA, Benoit SC, Woods SC, Seeley RJ (2003) 7-OH-DPAT selectively reduces intake of both chow and high fat diets in different food intake regimens. Pharmacol Biochem Behav 76:517–523CrossRefPubMedGoogle Scholar
  46. O'Donnell P (2003) Dopamine gating of forebrain neural ensembles. Eur J Neurosci 17:429–435CrossRefPubMedGoogle Scholar
  47. Park WK, Bari AA, Jey AR, Anderson SM, Spealman RD, Rowlett JK, Pierce RC (2002) Cocaine administered into the medial prefrontal cortex reinstates cocaine-seeking behavior by increasing AMPA receptor-mediated glutamate transmission in the nucleus accumbens. J Neurosci 22:2916–2925PubMedGoogle Scholar
  48. Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates, 4th edn. Academic, New YorkGoogle Scholar
  49. Phillips AG, Broekkamp CL, Fibiger HC (1983) Strategies for studying the neurochemical substrates of drug reinforcement in rodents. Prog Neuropsychopharmacol Biol Psychiatry 7:585–590CrossRefPubMedGoogle Scholar
  50. Pontieri FE, Tanda G, Di Chiara G (1995) Intravenous cocaine, morphine, and amphetamine preferentially increase extracellular dopamine in the “shell” as compared with the “core” of the rat nucleus accumbens. Proc Natl Acad Sci U S A 92:12304–12308PubMedCrossRefGoogle Scholar
  51. Pulvirenti L, Koob GF (1994) Dopamine receptor agonists, partial agonists and psychostimulant addiction. Trends Pharmacol Sci 15:374–379CrossRefPubMedGoogle Scholar
  52. Ranaldi R, Wise RA (2001) Blockade of D1 dopamine receptors in the ventral tegmental area decreases cocaine reward: possible role for dendritically released dopamine. J Neurosci 21:5841–5846PubMedGoogle Scholar
  53. Schwartz JC, Diaz J, Bordet R, Griffon N, Perachon S, Pilon C, Ridray S, Sokoloff P (1998) Functional implications of multiple dopamine receptor subtypes: the D1/D3 receptor coexistence. Brain Res Rev 26:236–242CrossRefPubMedGoogle Scholar
  54. See RE, Kruzich PJ, Grimm JW (2001) Dopamine, but not glutamate, receptor blockade in the basolateral amygdala attenuates conditioned reward in a rat model of relapse to cocaine-seeking behavior. Psychopharmacology 154:301–310CrossRefPubMedGoogle Scholar
  55. Seeman P, Van Tol HH (1994) Dopamine receptor pharmacology. Trends Pharmacol Sci 15:264–270CrossRefPubMedGoogle Scholar
  56. Self DW, Barnhart WJ, Lehman DA, Nestler EJ (1996) Opposite modulation of cocaine-seeking behavior by D1- and D2-like dopamine receptor agonists. Science 271:1586–1589PubMedCrossRefGoogle Scholar
  57. Self DW, Genova LM, Hope BT, Barnhart WJ, Spencer JJ, Nestler EJ (1998) Involvement of cAMP-dependent protein kinase in the nucleus accumbens in cocaine self-administration and relapse of cocaine-seeking behavior. J Neurosci 18:1848–1859PubMedGoogle Scholar
  58. 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 909:133–144PubMedGoogle Scholar
  59. Spealman RD, Barrett-Larimore RL, Rowlett JK, Platt DM, Khroyan TV (1999) Pharmacological and environmental determinants of relapse to cocaine-seeking behavior. Pharmacol Biochem Behav 64:327–336CrossRefPubMedGoogle Scholar
  60. Steiner H, Gerfen CR (1998) Role of dynorphin and enkephalin in the regulation of striatal output pathways and behavior. Exp Brain Res 123:60–76CrossRefPubMedGoogle Scholar
  61. Sun W, Rebec GV (2005) The role of prefrontal cortex D1-like and D2-like receptors in cocaine-seeking behavior in rats. Psychopharmacology 177:315–323CrossRefPubMedGoogle Scholar
  62. Tiberi M, Jarvie KR, Silvia C, Falardeau P, Gingrich JA, Godinot N, Bertrand L, Yang-Feng TL, Fremeau RT Jr, Caron MG (1991) Cloning, molecular characterization, and chromosomal assignment of a gene encoding a second D1 dopamine receptor subtype: differential expression pattern in rat brain compared with the D1A receptor. Proc Natl Acad Sci U S A 88:7491–7495PubMedCrossRefGoogle Scholar
  63. Tomiyama K, Koshikawa N, Funada K, Oka K, Kobayashi M (1995) In vivo microdialysis evidence for transient dopamine release by benzazepines in rat striatum. J Neurochem 65:2790–2795PubMedCrossRefGoogle Scholar
  64. Van Tol HH, Bunzow JR, Guan HC, Sunahara RK, Seeman P, Niznik HB, Civelli O (1991) Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Nature 350:610–614CrossRefPubMedGoogle Scholar
  65. Waddington JL, Daly SA (1993) Regulation of unconditioned motor behaviour by D1:D2 interaction. In: Waddington JL (ed) D-1:D-2 dopamine receptor interactions. Academic, London, pp 203–233Google Scholar
  66. Weiss F, Maldonado-Vlaar CS, Parsons LH, Kerr TM, Smith DL, Ben-Shahar O (2000) Control of cocaine-seeking behavior by drug-associated stimuli in rats: effects on recovery of extinguished operant-responding and extracellular dopamine levels in amygdala and nucleus accumbens. Proc Natl Acad Sci U S A 97:4321–4326CrossRefPubMedGoogle Scholar
  67. Weissenborn R, Deroche V, Koob GF, Weiss F (1996) Effects of dopamine agonists and antagonists on cocaine-induced operant responding for a cocaine-associated stimulus. Psychopharmacology 126:311–322PubMedCrossRefGoogle Scholar
  68. White FJ (1987) D-1 dopamine receptor stimulation enables the inhibition of nucleus accumbens neurons by a D-2 receptor agonist. Eur J Pharmacol 135:101–105CrossRefPubMedGoogle Scholar
  69. Wise RA, Murray A, Bozarth MA (1990) Bromocriptine self-administration and bromocriptine-reinstatement of cocaine-trained and heroin-trained lever pressing in rats. Psychopharmacology 100:355–360PubMedCrossRefGoogle Scholar
  70. Zetterstrom T, Sharp T, Ungerstedt U (1986) Effect of dopamine D-1 and D-2 receptor selective drugs on dopamine release and metabolism in rat striatum in vivo. Naunyn-Schmiedeberg's Arch Pharmacol 334:117–124CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Ryan K. Bachtell
    • 1
  • Kimberly Whisler
    • 1
  • David Karanian
    • 1
  • David W. Self
    • 1
  1. 1.Department of PsychiatryUniversity of Texas Southwestern Medical CenterDallasUSA

Personalised recommendations