Skip to main content
SpringerLink
Log in

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

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

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.

Objectives

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.

Methods

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.

Results

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.

Conclusions

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

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • 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 28:415–431

    Article  PubMed  CAS  Google Scholar 

  • 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 3:226–230

    Article  PubMed  CAS  Google Scholar 

  • 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 159:284–293

    Article  PubMed  CAS  Google Scholar 

  • 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 146:113–120

    Article  PubMed  CAS  Google Scholar 

  • Andersen PH, Jansen JA (1990) Dopamine receptor agonists: selectivity and dopamine D1 receptor efficacy. Eur J Pharmacol 188:335–347

    Article  PubMed  CAS  Google Scholar 

  • 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 168:132–138

    Article  PubMed  CAS  Google Scholar 

  • 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 418:22–32

    Article  PubMed  CAS  Google Scholar 

  • 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 564:203–219

    Article  PubMed  CAS  Google Scholar 

  • 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 39:911–915

    Article  PubMed  CAS  Google Scholar 

  • 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 692:47–56

    Article  PubMed  CAS  Google Scholar 

  • 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 291:353–360

    PubMed  CAS  Google Scholar 

  • 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 168:66–74

    Article  PubMed  CAS  Google Scholar 

  • Cornish JL, Kalivas PW (2000) Glutamate transmission in the nucleus accumbens mediates relapse in cocaine addiction. J Neurosci 20:RC89

    PubMed  CAS  Google Scholar 

  • Corrigall WA, Coen KM (1991) Cocaine self-administration is increased by both D1 and D2 dopamine antagonists. Pharmacol Biochem Behav 39:799–802

    Article  PubMed  CAS  Google Scholar 

  • 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 143:254–260

    Article  PubMed  Google Scholar 

  • 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 175:105–115

    Google Scholar 

  • 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 65:731–745

    Article  PubMed  CAS  Google Scholar 

  • 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 487:267–277

    Article  PubMed  CAS  Google Scholar 

  • 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 784:105–115

    Article  PubMed  CAS  Google Scholar 

  • 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 112:233–241

    Article  PubMed  CAS  Google Scholar 

  • Franklin SR, Tang AH (1995) Dopamine agonists facilitate footshock-elicited locomotion in rats, and suppress level-press responding for food. Psychopharmacology 121:480–484

    Article  PubMed  CAS  Google Scholar 

  • 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–R3

    Article  PubMed  CAS  Google Scholar 

  • Hall H, Sallemark M, Jerning E (1986) Effects of remoxipride and some related new substituted salicylamides on rat brain receptors. Acta Pharmacol Toxicol 58:61–70

    CAS  Google Scholar 

  • Haney M, Foltin RW, Fischman MW (1998) Effects of pergolide on intravenous cocaine self-administration in men and women. Psychopharmacology 137:15–24

    Article  PubMed  CAS  Google Scholar 

  • 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 143:102–110

    Article  PubMed  CAS  Google Scholar 

  • 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 372:143–155

    Article  PubMed  CAS  Google Scholar 

  • 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 41:89–125

    Article  PubMed  CAS  Google Scholar 

  • 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 22:269–274

    Article  PubMed  CAS  Google Scholar 

  • 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 23:5079–5087

    PubMed  CAS  Google Scholar 

  • Hubner CB, Koob GF (1990) Bromocriptine produces decreases in cocaine self-administration in the rat. Neuropsychopharmacology 3:101–108

    PubMed  CAS  Google Scholar 

  • 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 116:177–186

    Article  PubMed  CAS  Google Scholar 

  • 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 9:2541–2548

    Article  PubMed  CAS  Google Scholar 

  • 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 17:8580–8587

    PubMed  CAS  Google Scholar 

  • 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 20:7489–7495

    PubMed  CAS  Google Scholar 

  • 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 294:680–687

    PubMed  CAS  Google Scholar 

  • 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 126:185–190

    Article  PubMed  CAS  Google Scholar 

  • Lachowicz JE, Sibley DR (1997) Molecular characteristics of mammalian dopamine receptors. Pharmacol Toxicol 81:105–113

    Article  PubMed  CAS  Google Scholar 

  • Levant B, Bancroft GN, Selkirk CM (1996) In vivo occupancy of D2 dopamine receptors by 7-OH-DPAT. Synapse 24:60–64

    Article  PubMed  CAS  Google Scholar 

  • 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 89:8155–8159

    Article  PubMed  CAS  Google Scholar 

  • 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 82:767–780

    Article  PubMed  CAS  Google Scholar 

  • 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 45:239–242

    Article  PubMed  CAS  Google Scholar 

  • McFarland K, Kalivas PW (2001) The circuitry mediating cocaine-induced reinstatement of drug-seeking behavior. J Neurosci 21:8655–8663

    PubMed  CAS  Google Scholar 

  • 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 624:245–252

    Article  PubMed  CAS  Google Scholar 

  • 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 67:75–80

    Article  PubMed  CAS  Google Scholar 

  • 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 76:517–523

    Article  PubMed  CAS  Google Scholar 

  • O'Donnell P (2003) Dopamine gating of forebrain neural ensembles. Eur J Neurosci 17:429–435

    Article  PubMed  Google Scholar 

  • 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 22:2916–2925

    PubMed  CAS  Google Scholar 

  • Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates, 4th edn. Academic, New York

    Google Scholar 

  • Phillips AG, Broekkamp CL, Fibiger HC (1983) Strategies for studying the neurochemical substrates of drug reinforcement in rodents. Prog Neuropsychopharmacol Biol Psychiatry 7:585–590

    Article  PubMed  CAS  Google Scholar 

  • 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 92:12304–12308

    Article  PubMed  CAS  Google Scholar 

  • Pulvirenti L, Koob GF (1994) Dopamine receptor agonists, partial agonists and psychostimulant addiction. Trends Pharmacol Sci 15:374–379

    Article  PubMed  CAS  Google Scholar 

  • 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 21:5841–5846

    PubMed  CAS  Google Scholar 

  • 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 26:236–242

    Article  PubMed  CAS  Google Scholar 

  • 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 154:301–310

    Article  PubMed  CAS  Google Scholar 

  • Seeman P, Van Tol HH (1994) Dopamine receptor pharmacology. Trends Pharmacol Sci 15:264–270

    Article  PubMed  CAS  Google Scholar 

  • Self DW, Barnhart WJ, Lehman DA, Nestler EJ (1996) Opposite modulation of cocaine-seeking behavior by D1- and D2-like dopamine receptor agonists. Science 271:1586–1589

    Article  PubMed  CAS  Google Scholar 

  • 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 18:1848–1859

    PubMed  CAS  Google Scholar 

  • 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 909:133–144

    PubMed  CAS  Google Scholar 

  • 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 64:327–336

    Article  PubMed  CAS  Google Scholar 

  • Steiner H, Gerfen CR (1998) Role of dynorphin and enkephalin in the regulation of striatal output pathways and behavior. Exp Brain Res 123:60–76

    Article  PubMed  CAS  Google Scholar 

  • Sun W, Rebec GV (2005) The role of prefrontal cortex D1-like and D2-like receptors in cocaine-seeking behavior in rats. Psychopharmacology 177:315–323

    Article  PubMed  CAS  Google Scholar 

  • 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 88:7491–7495

    Article  PubMed  CAS  Google Scholar 

  • 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 65:2790–2795

    Article  PubMed  CAS  Google Scholar 

  • 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 350:610–614

    Article  PubMed  Google Scholar 

  • 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 203–233

    Google Scholar 

  • 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 97:4321–4326

    Article  PubMed  CAS  Google Scholar 

  • 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 126:311–322

    Article  PubMed  CAS  Google Scholar 

  • White FJ (1987) D-1 dopamine receptor stimulation enables the inhibition of nucleus accumbens neurons by a D-2 receptor agonist. Eur J Pharmacol 135:101–105

    Article  PubMed  CAS  Google Scholar 

  • Wise RA, Murray A, Bozarth MA (1990) Bromocriptine self-administration and bromocriptine-reinstatement of cocaine-trained and heroin-trained lever pressing in rats. Psychopharmacology 100:355–360

    Article  PubMed  CAS  Google Scholar 

  • 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 334:117–124

    Article  CAS  Google Scholar 

Download references

Acknowledgements

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.

Author information

Authors and Affiliations

  1. Department of Psychiatry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390-9070, USA

    Ryan K. Bachtell, Kimberly Whisler, David Karanian & David W. Self

Authors
  1. Ryan K. Bachtell
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kimberly Whisler
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David Karanian
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. David W. Self
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David W. Self.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bachtell, R.K., Whisler, K., Karanian, D. et al. Effects of intranucleus accumbens shell administration of dopamine agonists and antagonists on cocaine-taking and cocaine-seeking behaviors in the rat. Psychopharmacology 183, 41–53 (2005). https://doi.org/10.1007/s00213-005-0133-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-005-0133-1

Keywords

Search

Navigation