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Nucleus accumbens shell and core involvement in drug context-induced reinstatement of cocaine seeking in rats

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Abstract

Rationale

The nucleus accumbens (NAC) is a functionally heterogeneous brain region with respect to its involvement in cocaine-seeking behavior triggered by drug-associated explicit conditioned stimuli, foot shock stress, or cocaine itself in the reinstatement animal model of drug relapse. However, it is not known whether the NAC or its subregions are critical for reinstatement of cocaine-seeking behavior produced by re-exposure to a previously cocaine-paired environmental context.

Objectives

The present study was designed to evaluate potentially unique contributions of the NAC core and shell to this behavior.

Materials and methods

Rats were trained to lever press for unsignaled cocaine infusions (0.15 mg/infusion, intravenous) in a distinct environmental context. Lever responding was then extinguished in a distinctly different environmental context (extinction context) during a minimum of seven daily training sessions. Subsequently, using a counterbalanced testing design, rats were re-exposed to the cocaine-paired context or the extinction context while cocaine seeking (i.e., responding on the previously cocaine-reinforced lever) was assessed. Before each test session, neural activity was inhibited selectively in the NAC core or shell using bilateral microinfusions of the γ-aminobutyric acid agonists, baclofen and muscimol (0/0 or 1.0/0.1 mM; 0.3 μl per hemisphere).

Results

Neural inactivation of the NAC shell or core attenuated responding in the cocaine context and, interestingly, increased responding in the extinction context. Control experiments indicated no effects on general activity or food-reinforced instrumental behavior.

Conclusions

These findings suggest that both subregions of the NAC may promote context-induced reinstatement by facilitating drug context-induced motivation for cocaine and context discrimination.

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References

  • Amaral DG, Witter MP (1995) Hippocampal formation. In: Paxinos, G (eds) The rat nervous system. Academic, Los Angeles, CA, pp 443–493

    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 (Berl) 168:132–138

    Article  CAS  Google Scholar 

  • Anderson SM, Famous KR, Sadri-Vakili G, Kumaresan V, Schmidt HD, Bass CE, Terwilliger EF, Cha J-HJ, Pierce RC (2008) CaMKII: a biochemical bridge linking accumbens dopamine and glutamate systems in cocaine seeking. Nat Neurosci 11:344–353

    Article  PubMed  CAS  Google Scholar 

  • Arikan R, Blake NM, Erinjeri JP, Woolsey TA, Giraud L, Highstein SM (2002) A method to measure the effective spread of focally injected muscimol into the central nervous system with electrophysiology and light microscopy. J Neurosci Methods 118:51–57

    Article  PubMed  CAS  Google Scholar 

  • Bäckström P, Hyytiä P (2007) Involvement of AMPA/kainate, NMDA, and mGlu5 receptors in the nucleus accumbens core in cue-induced reinstatement of cocaine seeking in rats. Psychopharmacology 192(4):571–580

    Article  PubMed  CAS  Google Scholar 

  • Belin D, Everitt BJ (2008) Cocaine seeking habits depend upon dopamine-dependent serial connectivity linking the ventral with the dorsal striatum. Neuron 57:432–441

    Article  PubMed  CAS  Google Scholar 

  • Bossert JM, Ghitza UE, Lu L, Epstein DH, Shaham Y (2005) Neurobiology of relapse to heroin and cocaine seeking: an update and clinical implications. Eur J Pharmacol 526:36–50

    Article  PubMed  CAS  Google Scholar 

  • Bossert JM, Gray SM, Lu L, Shaham Y (2006) Activation of group II metabotropic glutamate receptors in the nucleus accumbens shell attenuates context-induced relapse to heroin seeking. Neuropsychopharmacology 31:2197–2209

    PubMed  CAS  Google Scholar 

  • Bossert JM, Poles GC, Wihbey KA, Koya E, Shaham Y (2007) Differential effects of blockade of dopamine D1-family receptors in nucleus accumbens core or shell on reinstatement of heroin seeking induced by contextual and discrete cues. J Neurosci 27:12655–12663

    Article  PubMed  CAS  Google Scholar 

  • Carroll ME, Comer SD (1996) Animal models of relapse. Exp Clin Psychopharmacol 4:11–18

    Article  CAS  Google Scholar 

  • Childress AR, Hole AV, Ehrman RN, Robbins SJ, McLellan AT, O’Brien CP (1993) Cue reactivity and cue reactivity interventions in drug dependence. NIDA Res Monogr 137:73–95

    PubMed  CAS  Google Scholar 

  • Ciccocioppo R, Sanna PP, Weiss F (2001) Cocaine-predictive stimulus induces drug-seeking behavior and neural activation in limbic brain regions after multiple months of abstinence: reversal by D(1) antagonists. Proc Natl Acad Sci USA 98:1976–1981

    Article  PubMed  CAS  Google Scholar 

  • Crombag HS, Shaham Y (2002) Renewal of drug seeking by contextual cues after prolonged extinction in rats. Behav Neurosci 116:169–173

    Article  PubMed  CAS  Google Scholar 

  • Crombag HS, Grimm JW, Shaham Y (2002) Effect of dopamine receptor antagonists on renewal of cocaine seeking by reexposure to drug-associated contextual cues. Neuropsychopharmacology 27:1006–1015

    Article  PubMed  CAS  Google Scholar 

  • Dayas CV, McGranahan TM, Martin-Fardon R, Weiss F (2008) Stimuli linked to ethanol availability activate hypothalamic CART and orexin neurons in a reinstatement model of relapse. Biol Psychiatry 63:152–157

    Article  PubMed  CAS  Google Scholar 

  • de Wit H, Stewart J (1981) Reinstatement of cocaine-reinforced responding in the rat. Psychopharmacology 75:134–143

    Article  PubMed  Google Scholar 

  • Di Ciano P, Everitt BJ (2004) Direct interactions between the basolateral amygdala and nucleus accumbens core underlie cocaine-seeking behavior by rats. J Neurosci 24:7167–7173

    Article  PubMed  CAS  Google Scholar 

  • Di Ciano P, Cardinal RN, Cowell RA, Little SJ, Everitt BJ (2001) Differential involvement of NMDA, AMPA/kainate, and dopamine receptors in the nucleus accumbens core in the acquisition and performance of Pavlovian approach behavior. J Neurosci 21:9471–9477

    PubMed  Google Scholar 

  • Di Ciano P, Robbins TW, Everitt BJ (2008) Differential effects of nucleus accumbens core, shell, or dorsal striatal inactivations on the persistence, reacquisition, or reinstatement of responding for a drug-paired conditioned reinforcer. Neuropsychopharmacology 33:1413–25

    Article  PubMed  CAS  Google Scholar 

  • Epstein DH, Preston KL, Stewart J, Shaham Y (2006) Toward a model of drug relapse: an assessment of the validity of the reinstatement procedure. Psychopharmacology (Berl) 189:1–16

    Article  CAS  Google Scholar 

  • Everitt BJ, Robbins TW (2005) Neural systems of reinforcement for drug addiction: from actions to habits to compulsion. Nat Neurosci 8:1481–1489

    Article  PubMed  CAS  Google Scholar 

  • Everitt BJ, Morris KA, O’Brien A, Robbins TW (1991) The basolateral amygdale–ventral striatal system and conditioned place preference: further evidence of limbic–striatal interactions underlying reward-related processes. Neuroscience 42:1–18

    Article  PubMed  CAS  Google Scholar 

  • Fadel J, Deutch AY (2002) Anatomical substrates of orexin–dopamine interactions: lateral hypothalamic projections to the ventral tegmental area. Neuroscience 111:379–387

    Article  PubMed  CAS  Google Scholar 

  • Ferbinteanu J, McDonald RJ (2001) Dorsal/ventral hippocampus, fornix, and conditioned place preference. Hippocampus 11:187–200

    Article  PubMed  CAS  Google Scholar 

  • Fibiger HC, LePaine FG, Jakubovic A, Phillips AG (1987) The role of dopamine in intracranial self-stimulation of the ventral tegmental area. J Neurosci 7:3888–3896

    PubMed  CAS  Google Scholar 

  • Fuchs RA, See RE (2002) Basolateral amygdala inactivation abolishes conditioned stimulus- and heroin-induced reinstatement of extinguished heroin-seeking behavior in rats. Psychopharmacology (Berl) 160:425–433

    Article  CAS  Google Scholar 

  • Fuchs RA, Tran-Nguyen LT, Specio SE, Groff RS, Neisewander JL (1998) Predictive validity of the extinction/reinstatement model of drug craving. Psychopharmacology (Berl) 135:151–160

    Article  CAS  Google Scholar 

  • Fuchs RA, Evans KA, Parker MC, See RE (2004) Differential involvement of the core and shell subregions of the nucleus accumbens in conditioned cue-induced reinstatement of cocaine seeking in rats. Psychopharmacology (Berl) 176:459–65

    Article  CAS  Google Scholar 

  • Fuchs RA, Evans KA, Ledford CC, Parker MP, Case JM, Mehta RH, See RE (2005) The role of the dorsomedial prefrontal cortex, basolateral amygdala, and dorsal hippocampus in contextual reinstatement of cocaine seeking in rats. Neuropsychopharmacology 30:296–309

    Article  PubMed  CAS  Google Scholar 

  • Fuchs RA, Branham RK, See RE (2006) Different neural substrates mediate cocaine seeking after abstinence versus extinction training: a critical role for the dorsolateral caudate-putamen. J Neurosci 26:3584–3588

    Article  PubMed  CAS  Google Scholar 

  • Fuchs RA, Eaddy JL, Su ZI, Bell GH (2007) Interactions of the basolateral amygdala with the dorsal hippocampus and dorsomedial prefrontal cortex regulate drug context-induced reinstatement of cocaine-seeking in rats. Eur J Neurosci 26:487–498

    Article  PubMed  Google Scholar 

  • Gordon WC, Klein RL (1994) In: Animal memory. The effects of context change on retention performance. 2nd edn. Academic, San Diego, CA

    Google Scholar 

  • Goto Y, O’Donnell P (2002) Timing-dependent limbic-motor synaptic integration in the nucleus accumbens. Proc Natl Acad Sci USA 99:13189–13193

    Article  PubMed  CAS  Google Scholar 

  • Grimm JW, See RE (2000) Dissociation of primary and secondary reward-relevant limbic nuclei in an animal model of relapse. Neuropsychopharmacology 22:473–479

    Article  PubMed  CAS  Google Scholar 

  • Hamlin AS, Clemens KJ, McNally GP (2008) Renewal of extinguished cocaine-seeking. Neuroscience 151:659–670

    Article  PubMed  CAS  Google Scholar 

  • Heidbreder CA, Groenewegen HJ (2003) The medial prefrontal cortex in the rat: evidence for a dorso-ventral distinction based upon functional and anatomical characteristics. Neurosci Biobehav Rev 27:555–579

    Article  PubMed  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 

  • Ikemoto S (2003) Involvement of the olfactory tubercle in cocaine reward: intracranial self-administration studies. J Neurosci 23:9305–11

    PubMed  CAS  Google Scholar 

  • Ikemoto S (2007) Dopamine reward circuitry: two projection systems from the ventral midbrain to the nucleus accumbens–olfactory tubercle complex. Brain Res Rev 56:27–78

    Article  PubMed  CAS  Google Scholar 

  • Institute of Laboratory Animal Resources, Commission on Life Sciences (1996) Guide for the Care and Use of Laboratory Animals. National Academy Press, Washington D.C.

  • Jaffe JH, Cascella NG, Kumor KM, Sherer MA (1989) Cocaine-induced cocaine craving. Psychopharmacology 97:59–64

    Article  PubMed  CAS  Google Scholar 

  • Kalivas PW, McFarland K (2003) Brain circuitry and the reinstatement of cocaine-seeking behavior. Psychopharmacology (Berl) 168:44–56

    Article  CAS  Google Scholar 

  • Kornetsky C, Huston-Lyons D, Porrino LJ (1991) The role of the olfactory tubercle in the effects of cocaine, morphine and brain-stimulation reward. Brain Res 541:75–81

    Article  PubMed  CAS  Google Scholar 

  • Kruzich PJ, Grimm JW, Rustay NR, Parks CD, See RE (1999) Predicting relapse to cocaine-seeking behavior: a multiple regression approach. Behav Pharmacol 10:513–521

    Article  PubMed  CAS  Google Scholar 

  • Leisen C, Langguth P, Herbert B, Dressler C, Koggel A, Spahn-Langguth H (2003) Lipophilicities of baclofen ester prodrugs correlate with affinities to the ATP-dependent efflux pump P-glycoprotein: relevance for their permeation across the blood–brain barrier? Pharm Res 20:772–778

    Article  PubMed  CAS  Google Scholar 

  • Léna I, Dh tel H, Garbay C, Dauqé V (2001) Involvement of D2 dopamine receptors in the opposing effects of two CCK-B agonists in a spatial recognition memory task: role of the anterior nucleus accumbens. Psychopharmacology (Berl) 153:170–179

    Article  Google Scholar 

  • Levita L, Dalley JW, Robbins TW (2002) Disruption of Pavlovian contextual conditioning by excitotoxic lesions of the nucleus accumbens core. Behav Neurosci 116:539–552

    Article  PubMed  Google Scholar 

  • Martin JH (1991) Autoradiographic estimation of the extent of reversible inactivation produced by microinjection of lidocaine and muscimol in the rat. Neurosci Lett 127:160–164

    Article  PubMed  CAS  Google Scholar 

  • Martin JH, Ghez C (1999) Pharmacological inactivation in the analysis of the central control of movement. J Neurosci Methods 86:145–159

    Article  PubMed  CAS  Google Scholar 

  • McDonald AJ (1991) Topographical organization of amygdaloid projections to the caudatoputamen, nucleus accumbens, and related striatal-like areas of the rat brain. Neuroscience 44:15–33

    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 

  • McFarland K, Davidge SB, Lapish CC, Kalivas PW (2004) Limbic and motor circuitry underlying footshock-induced reinstatement of cocaine-seeking behavior. J Neurosci 24:1551–1560

    Article  PubMed  CAS  Google Scholar 

  • McLaughlin J, See RE (2003) Selective inactivation of the dorsomedial prefrontal cortex and the basolateral amygdala attenuates conditioned-cued reinstatement of extinguished cocaine-seeking behavior in rats. Psychopharmacology (Berl) 168:57–65

    Article  CAS  Google Scholar 

  • Miller CA, Marshall JF (2005) Molecular substrates for retrieval and reconsolidation of cocaine-associated contextual memory. Neuron 47:873–884

    Article  PubMed  CAS  Google Scholar 

  • Narita M, Nagumo Y, Hashimoto S, Narita M, Khotib J, Miyatake M, Sakurai T, Yanagisawa M, Nakamachi T, Shioda S, Suzuki T (2006) Direct involvement of orexinergic systems in the activation of the mesolimbic dopamine pathway and related behaviors induced by morphine. J Neurosci 26:398–405

    Article  PubMed  CAS  Google Scholar 

  • Neisewander JL, Baker DA, Fuchs RA, Tran-Nguyen LT, Palmer A, Marshall JF (2000) Fos protein expression and cocaine-seeking behavior in rats after exposure to a cocaine self-administration environment. J Neurosci 20:798–805

    PubMed  CAS  Google Scholar 

  • Neisewander JL, Fuchs RA, Tran-Nguyen LT, Webber SM, Coffee GP, Joyce JN (2004) Increases in dopamine D3 receptor binding in rats receiving a cocaine challenge at various time points after cocaine self-administration: implications for cocaine-seeking behavior. Neuropsychopharmacology 29:1479–1487

    Article  PubMed  CAS  Google Scholar 

  • O’Brien CP, Childress AR, Ehrman R, Robbins SJ (1998) Conditioning factors in drug abuse: can they explain compulsion? J Psychopharmacol 12:15–22

    Article  PubMed  CAS  Google Scholar 

  • O’Donnell P, Grace AA (1995) Synaptic interactions among excitatory afferents to nucleus accumbens neurons: hippocampal gating of prefrontal cortical input. J Neurosci 15:3622–3639

    PubMed  CAS  Google Scholar 

  • Parkinson JA, Dalley JW, Cardinal RN, Bamford A, Fehnert B, Lachenal G, Rudarakanchana N, Halkerston KM, Robbins TW, Everitt BJ (2002) Nucleus accumbens dopamine depletion impairs both acquisition and performance of appetitive Pavlovian approach behaviour: implications for mesoaccumbens dopamine function. Behav Brain Res 137:149–163

    Article  PubMed  CAS  Google Scholar 

  • Paxinos G, Watson C (1997) The rat brain in stereotaxic coordinates, 3rd edn. Academic, Los Angeles, CA

    Google Scholar 

  • Peters J, Kalivas PW (2006) The group II metabotropic glutamate receptor agonist, LY379268, inhibits both cocaine- and food-seeking behavior in rats. Psychopharmacology 186:143–149

    Article  PubMed  CAS  Google Scholar 

  • Peters J, Vallone J, Laurendi K, Kalivas PW (2007) Opposing roles for the ventral prefrontal cortex and the basolateral amygdala on the spontaneous recovery of cocaine-seeking in rats. Psychopharmacology (Berl) 197:319–326

    Article  CAS  Google Scholar 

  • Peters J, LaLumiere RT, Kalivas PW (2008) Infralimbic prefrontal cortex is responsible for inhibiting cocaine seeking in extinguished rats. J Neurosci 28:6046–6053

    Article  PubMed  CAS  Google Scholar 

  • Rogers JL, See RE (2007) Selective inactivation of the ventral hippocampus attenuates cue-induced and cocaine-primed reinstatement of drug-seeking in rats. Neurobiol Learn Mem 87:688–692

    Article  PubMed  CAS  Google Scholar 

  • Sargolini F, Roullet P, Oliverio A, Mele A (2003) Effects of intra-accumbens focal administration of glutamate antagonists on object recognition memory in mice. Behav Brain Res 138:153–63

    Article  PubMed  CAS  Google Scholar 

  • Schmidt HD, Pierce RC (2006) Cooperative activation of D1-like and D2-like dopamine receptors in the nucleus accumbens shell is required for the reinstatement of cocaine-seeking behavior in the rat. Neuroscience 142:451–461

    Article  PubMed  CAS  Google Scholar 

  • Schmidt HD, Anderson SM, Pierce RC (2006) Stimulation of D1-like or D2 dopamine receptors in the shell, but not the core, of the nucleus accumbens reinstates cocaine-seeking behaviour in the rat. Eur J Neurosci 23:219–228

    Article  PubMed  Google Scholar 

  • Schoenbaum G, Setlow B (2003) Lesions of nucleus accumbens disrupt learning about aversive outcomes. J Neurosci 23:9833–9841

    PubMed  CAS  Google Scholar 

  • See RE (2005) Neural substrates of cocaine–cue associations that trigger relapse. Eur J Pharmacol 526:140–146

    Article  PubMed  CAS  Google Scholar 

  • See RE, Elliott JC, Feltenstein MW (2007) The role of dorsal vs ventral striatal pathways in cocaine-seeking behavior after prolonged abstinence in rats. Psychopharmacology (Berl) 194:321–31

    Article  CAS  Google Scholar 

  • Sellings LH, McQuade LE, Clarke PB (2006) Evidence for multiple sites within rat ventral striatum mediating cocaine-conditioned place preference and locomotor activation. J Pharmacol Exp Ther 317:1178–87

    Article  PubMed  CAS  Google Scholar 

  • Sesack SR, Deutch AY, Roth RH, Bunney BS (1989) Topographical organization of the efferent projections of the medial prefrontal cortex in the rat: an anterograde tract-tracing study with Phaseolus vulgaris leucoagglutinin. J Comp Neurol 290:213–242

    Article  PubMed  CAS  Google Scholar 

  • Shalev U, Grimm JW, Shaham Y (2002) Neurobiology of relapse to heroin and cocaine seeking: a review. Pharmacol Rev 54:1–42

    Article  PubMed  CAS  Google Scholar 

  • Sinha R (2001) How does stress increase risk of drug abuse and relapse? Psychopharmacology (Berl) 158:343–359

    Article  CAS  Google Scholar 

  • van Dongen YC, Deniau JM, Pennartz CM, Galis-de Graaf Y, Voorn P, Thierry AM, Groenewegen HJ (2005) Anatomical evidence for direct connections between the shell and core subregions of the rat nucleus accumbens. Neuroscience 136:1049–71

    Article  PubMed  CAS  Google Scholar 

  • van Groen T, Wyss JM (1990) Extrinsic projections from area CA1 of the rat hippocampus: olfactory, cortical, subcortical, and bilateral hippocampal formation projections. J Comp Neurol 302:515–528

    Article  PubMed  Google Scholar 

  • Yun IA, Nicola SM, Fields HL (2004) Contrasting effects of dopamine and glutamate receptor antagonist injection in the nucleus accumbens suggest a neural mechanism underlying cue-evoked goal-directed behavior. Eur J Neurosci 20:249–263

    Article  PubMed  Google Scholar 

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Acknowledgments

The authors would like to thank Heather Lasseter, Stephanie Traina, Dr. Xiaohu Xie, Jessica L. Eaddy, and Zu-In Su for excellent technical assistance and for insightful comments on an earlier version of this manuscript. This work was supported by National Institute on Drug Abuse grant R01 DA017673 (R.A.F), a NIDA R01 grant supplement to promote diversity in health-related research (DA017673-S1, D.R.R.), the University of North Carolina at Chapel Hill Junior Faculty Development Award (R.A.F.), and the Mason and Linda Stephenson Faculty Award (R.A.F.).

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  1. Department of Psychology, University of North Carolina, CB no. 3270, Davie Hall, Chapel Hill, NC, 27599-3270, USA

    Rita A. Fuchs, Donna R. Ramirez & Guinevere H. Bell

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  1. Rita A. Fuchs
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  2. Donna R. Ramirez
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  3. Guinevere H. Bell
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Correspondence to Rita A. Fuchs.

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Fuchs, R.A., Ramirez, D.R. & Bell, G.H. Nucleus accumbens shell and core involvement in drug context-induced reinstatement of cocaine seeking in rats. Psychopharmacology 200, 545–556 (2008). https://doi.org/10.1007/s00213-008-1234-4

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