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Differential involvement of the core and shell subregions of the nucleus accumbens in conditioned cue-induced reinstatement of cocaine seeking in rats

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Abstract

Rationale

The nucleus accumbens (NAC) is theorized to be a critical element of the neural circuitry that mediates relapse to cocaine seeking. Evidence suggests that the NAC is a functionally heterogeneous structure, and the core (NACc) and shell (NACs) regions of the NAC may play a differential role in stimulus-induced motivated behavior. Thus, determination of the involvement of NAC subregions in conditioned cue-induced reinstatement of cocaine seeking is warranted.

Objectives

The present study compared the effects of GABA agonist-induced inactivation of the NACc versus NACs on conditioned cue-induced reinstatement of cocaine seeking behavior.

Methods

Rats were trained to lever press for cocaine infusions (0.20 mg/infusion, IV) paired with presentations of a light-tone stimulus complex. Responding was then allowed to extinguish prior to reinstatement testing. Reinstatement of cocaine seeking (i.e. responses on the previously cocaine-paired lever) was measured in the presence of response-contingent presentation of the light-tone stimulus complex following microinfusion of muscimol+baclofen (Mus+Bac, 0.1/1.0 mM, respectively, 0.3 μl/side) or vehicle into the NACc or NACs. The effects of these manipulations on locomotor activity were also examined.

Results

Mus+Bac-induced inactivation of the NACc abolished, whereas inactivation of the NACs failed to alter, conditioned cue-induced reinstatement of operant responding relative to vehicle pretreatment. Time course analyses of the effects of these manipulations on locomotion versus operant responding confirmed that the effects of Mus+Bac on reinstatement were not due to suppression of general activity.

Conclusions

The functional integrity of the NACc, but not the NACs, is necessary for conditioned cue-induced reinstatement of cocaine seeking behavior.

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References

  • Baker DA, Cornish JL, Kalivas PW (2002) Glutamate and dopamine interactions in the motive circuit. In: Herman BH (ed) Glutamate and addiction. Humana, Totowa, pp 143–156

  • Bradberry CW, Barrett-Larimore RL, Jatlow P, Rubino SR (2000) Impact of self-administered cocaine and cocaine cues on extracellular dopamine in mesolimbic and sensorimotor striatum in rhesus monkeys. J Neurosci 20:3874–3883

    CAS  PubMed  Google Scholar 

  • Brown EE, Fibiger HC (1992) Cocaine-induced conditioned locomotion: absence of associated increases in dopamine release. Neuroscience 48:621–629

    CAS  PubMed  Google Scholar 

  • Burns LH, Everitt BJ, Kelley AE, Robbins TW (1994) Glutamate-dopamine interactions in the ventral striatum: role in locomotor activity and responding with conditioned reinforcement. Psychopharmacology 115:516–528

    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  CAS  PubMed  Google Scholar 

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

    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

    CAS  PubMed  Google Scholar 

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

    Google Scholar 

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

    PubMed  Google Scholar 

  • Di Ciano P, Everitt BJ (2001) Dissociable effects of antagonism of NMDA and AMPA/KA receptors in the nucleus accumbens core and shell on cocaine-seeking behavior. Neuropsychopharmacology 25:341–360

    PubMed  Google Scholar 

  • Duvauchelle CL, Ikegami A, Asami S, Robens J, Kressin K, Castaneda E (2000) Effects of cocaine context on NAcc dopamine and behavioral activity after repeated intravenous cocaine administration. Brain Res 862:49–58

    CAS  PubMed  Google Scholar 

  • Erb S, Salmaso N, Rodaros D, Stewart J (2001) A role for the CRF-containing pathway from central nucleus of the amygdala to bed nucleus of the stria terminalis in the stress-induced reinstatement of cocaine seeking in rats. Psychopharmacology 158:360–365

    Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Fontana DJ, Post RM, Pert A (1993) Conditioned increases in mesolimbic dopamine overflow by stimuli associated with cocaine. Brain Res 629:31–39

    CAS  PubMed  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 160:425–433

    CAS  PubMed  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 135:151–160

    Article  CAS  PubMed  Google Scholar 

  • Ghasemzadeh MB, Nelson LC, Lu XY, Kalivas PW (1999) Neuroadaptations in ionotropic and metabotropic glutamate receptor mRNA produced by cocaine treatment. J Neurochem 72:157–165

    PubMed  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  CAS  PubMed  Google Scholar 

  • Harmer CJ, Phillips GD (1999) Enhanced dopamine efflux in the amygdala by a predictive, but not a non-predictive, stimulus: facilitation by prior repeated d-amphetamine. Neuroscience 90:119–130

    Article  CAS  PubMed  Google Scholar 

  • Hotsenpiller G, Giorgetti M, Wolf ME (2001) Alterations in behaviour and glutamate transmission following presentation of stimuli previously associated with cocaine exposure. Eur J Neurosci 14:1843–1855

    Article  CAS  PubMed  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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Kaddis FG, Uretsky NJ, Wallace LJ (1995) DNQX in the nucleus accumbens inhibits cocaine-induced conditioned place preference. Brain Res 697:76–82

    CAS  PubMed  Google Scholar 

  • Kalivas PW, McFarland K, Bowers MS, Szumlinski KK, Xi ZX, Baker DA (2003a) Glutamate transmission and addiction to cocaine. Ann N Y Acad Sci 1003:169–175

    Article  CAS  PubMed  Google Scholar 

  • Kalivas PW, McFarland K, See RE (2003b) Psychiatric pathophysiology: addiction. In: Tasman A, Kay J, Lieberman JA (eds) Psychiatry. Wiley, Chichester, pp 330–337

  • Kruzich PJ, See RE (2001) Differential contributions of the basolateral and central amygdala in the acquisition and expression of conditioned relapse to cocaine-seeking behavior. J Neurosci 21:RC155:1–5

    Google Scholar 

  • Leri F, Flores J, Rodaros D, Stewart J (2002) Blockade of stress-induced but not cocaine-induced reinstatement by infusion of noradrenergic antagonists into the bed nucleus of the stria terminalis or the central nucleus of the amygdala. J Neurosci 22:5713–5718

    CAS  PubMed  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 

  • Lu L, Grimm JW, Shaham Y, Hope BT (2003) Molecular neuroadaptations in the accumbens and ventral tegmental area during the first 90 days of forced abstinence from cocaine self-administration in rats. J Neurochem 85:1604–1613

    Article  CAS  PubMed  Google Scholar 

  • Martin JH (1989) Neuroanatomy text and atlas. Elsevier, Amsterdam

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • McFarland K, Lapish CC, Kalivas PW (2003) Prefrontal glutamate release into the core of the nucleus accumbens mediates cocaine-induced reinstatement of drug-seeking behavior. J Neurosci 23:3531–3537

    CAS  PubMed  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  CAS  PubMed  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 168:57–65

    Article  CAS  PubMed  Google Scholar 

  • Meil WM, See RE (1997) Lesions of the basolateral amygdala abolish the ability of drug associated cues to reinstate responding during withdrawal from self-administered cocaine. Behav Brain Res 87:139–148

    CAS  PubMed  Google Scholar 

  • Neisewander JL, O’Dell LE, Tran-Nguyen LT, Castaneda E, Fuchs RA (1996) Dopamine overflow in the nucleus accumbens during extinction and reinstatement of cocaine self-administration behavior. Neuropsychopharmacology 15:506–514

    CAS  PubMed  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

    CAS  PubMed  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

    CAS  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

    CAS  PubMed  Google Scholar 

  • Parkinson JA, Olmstead MC, Burns LH, Robbins TW, Everitt BJ (1999) Dissociation in effects of lesions of the nucleus accumbens core and shell on appetitive pavlovian approach behavior and the potentiation of conditioned reinforcement and locomotor activity by d-amphetamine. J Neurosci 19:2401–2411

    CAS  PubMed  Google Scholar 

  • Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates. Academic, New York

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

    Google Scholar 

  • Swanson CJ, Baker DA, Carson D, Worley PF, Kalivas PW (2001) Repeated cocaine administration attenuates group I metabotropic glutamate receptor-mediated glutamate release and behavioral activation: a potential role for Homer. J Neurosci 21:9043–9052

    CAS  PubMed  Google Scholar 

  • Taylor JR, Robbins TW (1984) Enhanced behavioural control by conditioned reinforcers following microinjections of d-amphetamine into the nucleus accumbens. Psychopharmacology 84:405–412

    CAS  PubMed  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 USA 97:4321–4326

    CAS  PubMed  Google Scholar 

  • Xi ZX, Ramamoorthy S, Baker DA, Shen H, Samuvel DJ, Kalivas PW (2002) Modulation of group II metabotropic glutamate receptor signaling by chronic cocaine. J Pharmacol Exp Ther 303:608–615

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The experiments described herein conform to the ethical standards outlined in “Principles of laboratory animal care” (NIH publication no. 80-23, revised 1996). The authors would like to thank the technical assistance of J. Matthew Edwards and William Berglind. This research was supported by National Institute on Drug Abuse grant DA10462 (R.E.S.).

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Correspondence to Rita A. Fuchs.

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Fuchs, R.A., Evans, K.A., Parker, M.C. et al. Differential involvement of the core and shell subregions of the nucleus accumbens in conditioned cue-induced reinstatement of cocaine seeking in rats. Psychopharmacology 176, 459–465 (2004). https://doi.org/10.1007/s00213-004-1895-6

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  • DOI: https://doi.org/10.1007/s00213-004-1895-6

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