The Circuitry Underlying the Reinstatement of Cocaine Seeking: Modulation by Deep Brain Stimulation

  • Leonardo A. Guercio
  • R. Christopher PierceEmail author
Part of the Innovations in Cognitive Neuroscience book series (Innovations Cogn.Neuroscience)


Cocaine addiction in humans is characterized by persistent relapse vulnerability following detoxification. Relapse to drug taking can be precipitated by several factors: stress, re-exposure to drug-associated environmental cues, and re-exposure to the drug itself. Preclinical studies have focused on cocaine reinstatement, an animal model of relapse, to achieve a greater understanding of the underlying anatomical, neurobiological, and neurochemical bases of cocaine craving and relapse. Here, we review how changes in dopaminergic and glutamatergic transmission in mesocorticolimbic nuclei contribute to the reinstatement of cocaine seeking. This information can be used to elucidate which nuclei may prove effective therapeutic targets for deep brain stimulation (DBS) as a treatment for cocaine craving and relapse.


Cocaine Drug addiction Drug relapse Dopamine Glutamate Deep-brain stimulation 


  1. Alleweireldt AT, Hobbs RJ, Taylor AR et al (2006) Effects of SCH-23390 infused into the amygdala or adjacent cortex and basal ganglia on cocaine seeking and self-administration in rats. Neuropsychopharmacology 31:363–374. doi: 10.1038/sj.npp.1300794 PubMedCrossRefGoogle Scholar
  2. 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 168:132–138PubMedCrossRefGoogle Scholar
  3. Anderson SM, Schmidt HD, Pierce RC (2005) Administration of the D2 dopamine receptor antagonist sulpiride into the shell, but not the core, of the nucleus accumbens attenuates cocaine priming-induced reinstatement of drug seeking. Neuropsychopharmacology 31:1452–1461. doi: 10.1038/sj.npp.1300922 PubMedCrossRefGoogle Scholar
  4. Anderson SM, Famous KR, Sadri-Vakili G et al (2008) CaMKII: a biochemical bridge linking accumbens dopamine and glutamate systems in cocaine seeking. Nat Neurosci 11:344–353. doi: 10.1038/nn2054 PubMedCrossRefGoogle Scholar
  5. Bachtell RK, Whisler K, Karanian D et al (2005) 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 183:132–138. doi: 10.1007/s00213-005-0133-1 CrossRefGoogle Scholar
  6. Bäckström P, Hyytiä P (2006) Ionotropic and metabotropic glutamate receptor antagonism attenuates cue-induced cocaine seeking. Neuropsychopharmacology 31:778–786PubMedCrossRefGoogle Scholar
  7. 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 192:571–580. doi: 10.1007/s00213-007-0753-8 PubMedCrossRefGoogle Scholar
  8. Baker DA, McFarland K, Lake RW et al (2003) Neuroadaptations in cystine-glutamate exchange underlie cocaine relapse. Nat Neurosci 6:743–749PubMedCrossRefGoogle Scholar
  9. Beaulieu J-M, Gainetdinov RR (2011) The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol Rev 63:182–217. doi: 10.1124/pr.110.002642 PubMedCrossRefGoogle Scholar
  10. Berendse HW, Groenewegen HJ, Lohman AH (1992) Compartmental distribution of ventral striatal neurons projecting to the mesencephalon in the rat. J Neurosci 12:2079–2103PubMedGoogle Scholar
  11. Berglind WJ, Case JM, Parker MP et al (2006) Dopamine D1 or D2 receptor antagonism within the basolateral amygdala differentially alters the acquisition of cocaine-cue associations necessary for cue-induced reinstatement of cocaine-seeking. Neuroscience 137:699–706PubMedCrossRefGoogle Scholar
  12. Blaha CD, Yang CR, Floresco SB et al (1997) Stimulation of the ventral subiculum of the hippocampus evokes glutamate receptor-mediated changes in dopamine efflux in the rat nucleus accumbens. Eur J Neurosci 9:902–911PubMedCrossRefGoogle Scholar
  13. Bossert JM, Ghitza UE, Lu L et al (2005) Neurobiology of relapse to heroin and cocaine seeking: an update and clinical implications. Eur J Pharmacol 526:36–50PubMedCrossRefGoogle Scholar
  14. Bossert JM, Marchant NJ, Calu DJ et al (2013) The reinstatement model of drug relapse: recent neurobiological findings, emerging research topics, and translational research. Psychopharmacology 229:453–476PubMedPubMedCentralCrossRefGoogle Scholar
  15. Britt JP, Benaliouad F, McDevitt RA et al (2012) Synaptic and behavioral profile of multiple glutamatergic inputs to the nucleus accumbens. Neuron 76:790–803PubMedPubMedCentralCrossRefGoogle Scholar
  16. Brog JS, Salyapongse A, Deutch AY et al (1993) The patterns of afferent innervation of the core and shell in the “accumbens” part of the rat ventral striatum: immunohistochemical detection of retrogradely transported fluoro-gold. J Comp Neurol 338:255–278PubMedCrossRefGoogle Scholar
  17. Capriles N, Rodaros D, Sorge RE et al (2003) A role for the prefrontal cortex in stress- and cocaine-induced reinstatement of cocaine seeking in rats. Psychopharmacology 168:66–74PubMedCrossRefGoogle Scholar
  18. Carlezon WA, Wise RA (1996) Rewarding actions of phencyclidine and related drugs in nucleus accumbens shell and frontal cortex. J Neurosci 16(9):3112–3122PubMedGoogle Scholar
  19. Carroll KM, Rounsaville BJ, Nich C et al (1994) One-year follow-up of psychotherapy and pharmacotherapy for cocaine dependence. Arch Gen Psychiatry 51:989–997PubMedCrossRefGoogle Scholar
  20. Chambers RA, Self DW (2002) Motivational responses to natural and drug rewards in rats with neonatal ventral hippocampal lesions: an animal model of dual diagnosis schizophrenia. Neuropsychopharmacology 27:889–905PubMedPubMedCentralCrossRefGoogle Scholar
  21. 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 U S A 98:1976–1981PubMedPubMedCentralCrossRefGoogle Scholar
  22. Conrad KL, Tseng KY, Uejima JL et al (2008) Formation of accumbens GluR2-lacking AMPA receptors mediates incubation of cocaine craving. Nature 454:118–121PubMedPubMedCentralCrossRefGoogle Scholar
  23. Cornish JL, Kalivas PW (2000) Glutamate transmission in the nucleus accumbens mediates relapse in cocaine addiction. J Neurosci 20:RC89PubMedGoogle Scholar
  24. Cornish JL, Duffy P, Kalivas PW (1999) A role for nucleus accumbens glutamate transmission in the relapse to cocaine-seeking behavior. Neuroscience 93:1359–1367PubMedCrossRefGoogle Scholar
  25. Creed M, Pascoli VJ, Luscher C (2015) Refining deep brain stimulation to emulate optogenetic treatment of synaptic pathology. Science 347:659–664PubMedCrossRefGoogle Scholar
  26. Crombag HS, Shaham Y (2002) Renewal of drug seeking by contextual cues after prolonged extinction in rats. Behav Neurosci 116:169PubMedCrossRefGoogle Scholar
  27. De Vries TJ, Schoffelmeer ANM, Binnekade R et al (2002) Relapse to cocaine- and heroin-seeking behavior mediated by dopamine D2 receptors is time-dependent and associated with behavioral sensitization. Neuropsychopharmacology 26:18–26. doi: 10.1016/s0893-133x(01)00293-7 PubMedCrossRefGoogle Scholar
  28. Di Chiara G, Imperato A (1988) Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci U S A 85:5274–5278PubMedPubMedCentralCrossRefGoogle Scholar
  29. Di Ciano P (2001) Dissociable effects of antagonism of NMDA and AMPA/KA Receptors in the nucleus accumbens core and shell on cocaine-seeking behavior. Neuropsychopharmacology 25:341–360PubMedCrossRefGoogle Scholar
  30. Di Ciano P (2008) Drug seeking under a second-order schedule of reinforcement depends on dopamine D3 receptors in the basolateral amygdala. Behav Neurosci 122:129–139PubMedCrossRefGoogle Scholar
  31. Di Ciano P, Everitt BJ (2004) Conditioned reinforcing properties of stimuli paired with self-administered cocaine, heroin or sucrose: implications for the persistence of addictive behavior. Neuropharmacology 47(Suppl 1):202–213. doi: 10.1016/j.neuropharm.2004.06.005 PubMedCrossRefGoogle Scholar
  32. Ding DC, Gabbott PL, Totterdell S (2001) Differences in the laminar origin of projections from the medial prefrontal cortex to the nucleus accumbens shell and core regions in the rat. Brain Res 917:81–89PubMedCrossRefGoogle Scholar
  33. Fallon JH, Koziell DA, Moore RY (1978) Catecholamine innervation of the basal forebrain. II. Amygdala, suprarhinal cortex and entorhinal cortex. J Comp Neurol 180(3):509–532. doi: 10.1002/cne.901800308 PubMedCrossRefGoogle Scholar
  34. Famous KR, Kumaresan V, Sadri-Vakili G et al (2008) Phosphorylation-dependent trafficking of GluR2-containing AMPA receptors in the nucleus accumbens plays a critical role in the reinstatement of cocaine seeking. J Neurosci 28:11061–11070PubMedPubMedCentralCrossRefGoogle Scholar
  35. Fanselow MS, Dong HW (2010) Are the dorsal and ventral hippocampus functionally distinct structures? Neuron 65:7–19. doi: 10.1016/j.neuron.2009.11.031 PubMedPubMedCentralCrossRefGoogle Scholar
  36. Feltenstein MW, See RE (2007) NMDA receptor blockade in the basolateral amygdala disrupts consolidation of stimulus-reward memory and extinction learning during reinstatement of cocaine-seeking in an animal model of relapse. Neurobiol Learn Mem 88(4):435–444. doi: 10.1016/j.nlm.2007.05.006 PubMedPubMedCentralCrossRefGoogle Scholar
  37. Ferrario CR, Li X, Wang X et al (2010) The role of glutamate receptor redistribution in locomotor sensitization to cocaine. Neuropsychopharmacology 35:818–833PubMedCrossRefGoogle Scholar
  38. Fischer KD, Houston ACW, Rebec GV (2013) Role of the major glutamate transporter GLT1 in nucleus accumbens core versus shell in cue-induced cocaine-seeking behavior. J Neurosci 33:9319–9327PubMedPubMedCentralCrossRefGoogle Scholar
  39. Friedman DP, Aggleton JP, Saunders RC (2002) Comparison of hippocampal, amygdala, and perirhinal projections to the nucleus accumbens: combined anterograde and retrograde tracing study in the Macaque brain. J Comp Neurol 450:345–365PubMedCrossRefGoogle Scholar
  40. Fuchs RA, Evans KA, Parker MC et al (2004) 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. doi: 10.1007/s00213-004-1895-6 PubMedCrossRefGoogle Scholar
  41. Fuchs RA, Evans KA, Ledford CC et al (2005) The role of the dorsomedial prefrontal cortex, basolateral amygdala, and dorsal hippocampus in contextual reinstatement of cocaine seeking in rats. Neuropsychopharmacology 30:296–309PubMedCrossRefGoogle Scholar
  42. Fuchs RA, Feltenstein MW, See RE (2006) The role of the basolateral amygdala in stimulus-reward memory and extinction memory consolidation and in subsequent conditioned cued reinstatement of cocaine seeking. Eur J Neurosci 23:2809–2813PubMedCrossRefGoogle Scholar
  43. Fuchs RA, Eaddy JL, Su ZI et al (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 26:487–498PubMedCrossRefGoogle Scholar
  44. Fuchs RA, Ramirez DR, Bell GH (2008) Nucleus accumbens shell and core involvement in drug context-induced reinstatement of cocaine seeking in rats. Psychopharmacology 200:545–556PubMedPubMedCentralCrossRefGoogle Scholar
  45. Gabriele A, See RE (2010) Reversible inactivation of the basolateral amygdala, but not the dorsolateral caudate putamen, attenuates consolidation of cocaine-cue associative learning in a reinstatement model of drug-seeking. Eur J Neurosci 32:1024–1029. doi: 10.1111/j.1460-9568.2010.07394 PubMedPubMedCentralCrossRefGoogle Scholar
  46. Gasbarri A, Packard MG, Campana E et al (1994a) Anterograde and retrograde tracing of projections from the ventral tegmental area to the hippocampal formation in the rat. Brain Res Bull 33:445–452PubMedCrossRefGoogle Scholar
  47. Gasbarri A, Verney C, Innocenzi R et al (1994b) Mesolimbic dopaminergic neurons innervating the hippocampal formation in the rat: a combined retrograde tracing and immunohistochemical study. Brain Res 668:71–79PubMedCrossRefGoogle Scholar
  48. Gipson CD, Kupchik YM, Shen H et al (2013) Relapse induced by cues predicting cocaine depends on rapid, transient synaptic potentiation. Neuron 77:867–872PubMedPubMedCentralCrossRefGoogle Scholar
  49. Graf EN, Wheeler RA, Baker DA et al (2013) Corticosterone acts in the nucleus accumbens to enhance dopamine signaling and potentiate reinstatement of cocaine seeking. J Neurosci 33:11800–11810PubMedPubMedCentralCrossRefGoogle Scholar
  50. Graybiel AM, Moratalla R, Robertson HA (1990) Amphetamine and cocaine induce drug-specific activation of the c-fos gene in striosome-matrix compartments and limbic subdivisions of the striatum. Proc Natl Acad Sci U S A 87:6912–6916PubMedPubMedCentralCrossRefGoogle Scholar
  51. Grimm J (2000) Dissociation of primary and secondary reward-relevant limbic nuclei in an animal model of relapse. Neuropsychopharmacology 22:473–479PubMedCrossRefGoogle Scholar
  52. Groenewegen HJ (2003) The basal ganglia and motor control. Neural Plast 10:107–120PubMedPubMedCentralCrossRefGoogle Scholar
  53. Groenewegen HJ, Vermeulen-Van der Zee E, Kortschotte A et al (1987) Organization of the projections from the subiculum to the ventral striatum in the rat. A study using anterograde transport of Phaseolus vulgaris leucoagglutinin. Neuroscience 23:103–120PubMedCrossRefGoogle Scholar
  54. Groenewegen HJ, Wright CI, Beijer AV et al (1999) Convergence and segregation of ventral striatal inputs and outputs. Ann N Y Acad Sci 877:49–63PubMedCrossRefGoogle Scholar
  55. Guercio LA, Schmidt HD, Pierce RC (2015) Deep brain stimulation of the nucleus accumbens shell attenuates cue-induced reinstatement of both cocaine and sucrose seeking in rats. Behav Brain Res 281:125–130PubMedCrossRefGoogle Scholar
  56. Hayes RJ, Vorel SR, Spector J et al (2003) Electrical and chemical stimulation of the basolateral complex of the amygdala reinstates cocaine-seeking behavior in the rat. Psychopharmacology 168:75–83PubMedCrossRefGoogle Scholar
  57. Hearing MC, Schochet TL, See RE et al (2010) Context-driven cocaine-seeking in abstinent rats increases activity-regulated gene expression in the basolateral amygdala and dorsal hippocampus differentially following short and long periods of abstinence. Neuroscience 170:570–579PubMedPubMedCentralCrossRefGoogle Scholar
  58. Hearing M, Kotecki L, de Velasco EMF (2013) Repeated cocaine weakens GABAB-Girk signaling in layer 5/6 pyramidal neurons in the prelimbic cortex. Neuron 80:159–170PubMedPubMedCentralCrossRefGoogle Scholar
  59. Heidbreder CA, Groenewegen HJ, 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 27:555–579PubMedCrossRefGoogle Scholar
  60. Heimer L, Zahm DS, Churchill L et al (1991) Specificity in the projection patterns of accumbal core and shell in the rat. Neuroscience 41:89–125PubMedCrossRefGoogle Scholar
  61. Heimer L, Alheid GF, de Olmos JS et al (1997) The accumbens: beyond the core-shell dichotomy. J Neuropsychiatry Clin Neurosci 9:354–381. doi: 10.1176/jnp.9.3.354 PubMedCrossRefGoogle Scholar
  62. Henke PG (1990) Hippocampal pathway to the amygdala and stress ulcer development. Brain Res Bull 25:691–695PubMedCrossRefGoogle Scholar
  63. Hoover WB, Vertes RP (2007) Anatomical analysis of afferent projections to the medial prefrontal cortex in the rat. Brain Struct Funct 212:149–179. doi: 10.1007/s00429-007-0150-4 PubMedCrossRefGoogle Scholar
  64. 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(11):1843–1855PubMedCrossRefGoogle Scholar
  65. Hume RI, Dingledine R, Heinemann SF (1991) Identification of a site in glutamate receptor subunits that controls calcium permeability. Science 253:1028–1031PubMedCrossRefGoogle Scholar
  66. Ito R, Robbins TW, Everitt BJ (2004) Differential control over cocaine-seeking behavior by nucleus accumbens core and shell. Nat Neurosci 7:389–397PubMedCrossRefGoogle Scholar
  67. Jaffe JH, Cascella NG, Kumor KM et al (1989) Cocaine-induced cocaine craving. Psychopharmacology 97(1):59–64PubMedCrossRefGoogle Scholar
  68. Jones S, Bonci A (2005) Synaptic plasticity and drug addiction. Curr Opin Pharmacol 5(1):20–25. doi: 10.1016/j.coph.2004.08.011 PubMedCrossRefGoogle Scholar
  69. Kalivas PW, O’Brien C (2008) Drug addiction as a pathology of staged neuroplasticity. Neuropsychopharmacology 33:166–180PubMedCrossRefGoogle Scholar
  70. Kantak KM, Black Y, Valencia E et al (2002) Dissociable effects of lidocaine inactivation of the rostral and caudal basolateral amygdala on the maintenance and reinstatement of cocaine-seeking behavior in rats. J Neurosci 22:1126–1136PubMedGoogle Scholar
  71. Karlsson R-M, Kircher DM, Shaham Y, O’Donnell P (2013) Exaggerated cue-induced reinstatement of cocaine seeking but not incubation of cocaine craving in a developmental rat model of schizophrenia. Psychopharmacology 226:45–51PubMedCrossRefGoogle Scholar
  72. Kauer JA, Malenka RC (2007) Synaptic plasticity and addiction. Nat Rev Neurosci 8(11):844–858. doi: 10.1038/nrn2234 PubMedCrossRefGoogle Scholar
  73. Khroyan TV, Barrett-Larimore RL, Rowlett JK et al (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
  74. Krettek JE, Price JL (1977) The cortical projections of the mediodorsal nucleus and adjacent thalamic nuclei in the rat. J Comp Neurol 171(2):157–191. doi: 10.1002/cne.901710204 PubMedCrossRefGoogle Scholar
  75. Kufahl PR, Zavala AR, Singh A et al (2009) c-Fos expression associated with reinstatement of cocaine-seeking behavior by response-contingent conditioned cues. Synapse 63:823–835PubMedPubMedCentralCrossRefGoogle Scholar
  76. LaLumiere RT, Niehoff KE, Kalivas PW (2010) The infralimbic cortex regulates the consolidation of extinction after cocaine self-administration. Learn Mem 17:168–175PubMedPubMedCentralCrossRefGoogle Scholar
  77. LaLumiere RT, Smith KC, Kalivas PW (2012) Neural circuit competition in cocaine-seeking: roles of the infralimbic cortex and nucleus accumbens shell. Eur J Neurosci 35:614–622PubMedPubMedCentralCrossRefGoogle Scholar
  78. Lasseter HC, Xie X, Ramirez DR, Fuchs RA (2010) Sub-region specific contribution of the ventral hippocampus to drug context-induced reinstatement of cocaine-seeking behavior in rats. Neuroscience 171:830–839PubMedPubMedCentralCrossRefGoogle Scholar
  79. Lee B, Tiefenbacher S, Platt DM, Spealman RD (2004) Pharmacological blockade of alpha2-adrenoceptors induces reinstatement of cocaine-seeking behavior in squirrel monkeys. Neuropsychopharmacology 29:686–693PubMedCrossRefGoogle Scholar
  80. Lee JLC, Milton AL, Everitt BJ (2006) Cue-induced cocaine seeking and relapse are reduced by disruption of drug memory reconsolidation. J Neurosci 26:5881–5887PubMedCrossRefGoogle Scholar
  81. Lee BR, Ma Y-Y, Huang YH et al (2013) Maturation of silent synapses in amygdala-accumbens projection contributes to incubation of cocaine craving. Nat Neurosci 16:1644–1651PubMedPubMedCentralCrossRefGoogle Scholar
  82. Ma Y-Y, Lee BR, Wang X et al (2014) Bidirectional modulation of incubation of cocaine craving by silent synapse-based remodeling of prefrontal cortex to accumbens projections. Neuron 83:1453–1467PubMedPubMedCentralCrossRefGoogle Scholar
  83. Mameli M, Halbout B, Creton C et al (2009) Cocaine-evoked synaptic plasticity: persistence in the VTA triggers adaptations in the NAc. Nat Neurosci 12:1036–1041PubMedCrossRefGoogle Scholar
  84. Mashhoon Y, Tsikitas LA, Kantak KM (2009) Dissociable effects of cocaine-seeking behavior following D1 receptor activation and blockade within the caudal and rostral basolateral amygdala in rats. Eur J Neurosci 29:1641–1653PubMedPubMedCentralCrossRefGoogle Scholar
  85. Mashhoon Y, Wells AM, Kantak KM (2010) Interaction of the rostral basolateral amygdala and prelimbic prefrontal cortex in regulating reinstatement of cocaine-seeking behavior. Pharmacol Biochem Behav 96:347–353PubMedPubMedCentralCrossRefGoogle Scholar
  86. McCracken CB, Grace AA (2007) High-frequency deep brain stimulation of the nucleus accumbens region suppresses neuronal activity and selectively modulates afferent drive in rat orbitofrontal cortex in vivo. J Neurosci 27:12601–12610PubMedCrossRefGoogle Scholar
  87. McCutcheon JE, Wang X, Tseng KY et al (2011) Calcium-permeable AMPA receptors are present in nucleus accumbens synapses after prolonged withdrawal from cocaine self-administration but not experimenter-administered cocaine. J Neurosci 31:5737–5743PubMedPubMedCentralCrossRefGoogle Scholar
  88. McFarland K, Kalivas PW (2001) The circuitry mediating cocaine-induced reinstatement of drug-seeking behavior. J Neurosci 21:8655–8663PubMedGoogle Scholar
  89. 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 23:3531–3537PubMedGoogle Scholar
  90. McFarland K, Davidge SB, Lapish CC et al (2004) Limbic and motor circuitry underlying footshock-induced reinstatement of cocaine-seeking behavior. J Neurosci 24:1551–1560PubMedCrossRefGoogle Scholar
  91. 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(1-2):57–65. doi: 10.1007/s00213-002-1196-x PubMedCrossRefGoogle Scholar
  92. Meil WM, See RE (1996) Conditioned cued recovery of responding following prolonged withdrawal from self-administered cocaine in rats: an animal model of relapse. Behav Pharmacol 7(8):754–763PubMedGoogle Scholar
  93. 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(2):139–148PubMedCrossRefGoogle Scholar
  94. Marchant NJ, Kaganovsky K, Shaham Y, Bossert JM (2015) Role of corticostriatal circuits in contextinduced reinstatement of drug seeking. Brain Res 1628A: 219–232.Google Scholar
  95. Meredith GE, Agolia R, Arts MP et al (1992) Morphological differences between projection neurons of the core and shell in the nucleus accumbens of the rat. Neuroscience 50:149–162PubMedCrossRefGoogle Scholar
  96. Missale C, Nash SR, Robinson SW et al (1998) Dopamine receptors: from structure to function. Physiol Rev 78(1):189–225PubMedGoogle Scholar
  97. Moser MB, Moser EI (1998) Functional differentiation in the hippocampus. Hippocampus 8:608–619PubMedCrossRefGoogle Scholar
  98. Moser MB, Moser EI, Forrest E et al (1995) Spatial learning with a minislab in the dorsal hippocampus. Proc Natl Acad Sci U S A 92:9697–9701PubMedPubMedCentralCrossRefGoogle Scholar
  99. Neisewander JL, Baker DA, Fuchs RA et al (2000) Fos protein expression and cocaine-seeking behavior in rats after exposure to a cocaine self-administration environment. J Neurosci 20:798–805PubMedGoogle Scholar
  100. O’Brien CP (1997) A range of research-based pharmacotherapies for addiction. Science 278(5335):66–70PubMedCrossRefGoogle Scholar
  101. O’Brien CP, Childress AR, McLellan AT et al (1992) Classical conditioning in drug-dependent humans. Ann N Y Acad Sci 654:400–415PubMedCrossRefGoogle Scholar
  102. Park W-K, Bari AA, Jey AR et al (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
  103. Pascoli V, Terrier J, Espallergues J et al (2014) Contrasting forms of cocaine-evoked plasticity control components of relapse. Nature 509:459–464PubMedCrossRefGoogle Scholar
  104. Peters J, LaLumiere RT, Kalivas PW (2008) Infralimbic prefrontal cortex is responsible for inhibiting cocaine seeking in extinguished rats. J Neurosci 28:6046–6053PubMedPubMedCentralCrossRefGoogle Scholar
  105. Phillipson OT, Griffiths AC (1985) The topographic order of inputs to nucleus accumbens in the rat. Neuroscience 16:275–296PubMedCrossRefGoogle Scholar
  106. Pierce RC, Kumaresan V (2006) The mesolimbic dopamine system: the final common pathway for the reinforcing effect of drugs of abuse? Neurosci Biobehav Rev 30:215–238PubMedCrossRefGoogle Scholar
  107. Pierce RC, Bell K, Duffy P et al (1996) Repeated cocaine augments excitatory amino acid transmission in the nucleus accumbens only in rats having developed behavioral sensitization. J Neurosci 16:1550–1560PubMedGoogle Scholar
  108. Ping A, Xi J, Prasad BM, Wang MH et al (2008) Contributions of nucleus accumbens core and shell GluR1 containing AMPA receptors in AMPA- and cocaine-primed reinstatement of cocaine-seeking behavior. Brain Res 1215:173–182. doi: 10.1016/j.brainres.2008.03.088 PubMedPubMedCentralCrossRefGoogle Scholar
  109. 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 92:12304–12308PubMedPubMedCentralCrossRefGoogle Scholar
  110. Raybuck JD, Lattal KM (2014) Differential effects of dorsal hippocampal inactivation on expression of recent and remote drug and fear memory. Neurosci Lett 569:1–5. doi: 10.1016/j.neulet.2014.02.063 PubMedPubMedCentralCrossRefGoogle Scholar
  111. Ritz MC, Cone EJ, Kuhar MJ (1990) Cocaine inhibition of ligand binding at dopamine, norepinephrine and serotonin transporters: a structure-activity study. Life Sci 46:635–645PubMedCrossRefGoogle Scholar
  112. 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 87:688–692PubMedPubMedCentralCrossRefGoogle Scholar
  113. Rueter SM, Burns CM, Coode SA et al (1995) Glutamate receptor RNA editing in vitro by enzymatic conversion of adenosine to inosine. Science 267:1491–1494PubMedCrossRefGoogle Scholar
  114. SAMHSA (2012) Results from the 2011 National Survey on Drug Use and Health: National Findings. Office of Applied Studies, NSDUH Series H-44, RockvilleGoogle Scholar
  115. Sari Y, Smith KD, Ali PK, Rebec GV (2009) Upregulation of GLT1 attenuates cue-induced reinstatement of cocaine-seeking behavior in rats. J Neurosci 29:9239–9243PubMedPubMedCentralCrossRefGoogle Scholar
  116. Schenk S (2002) Effects of GBR 12909, WIN 35,428 and indatraline on cocaine self-administration and cocaine seeking in rats. Psychopharmacology 160:263–270PubMedCrossRefGoogle Scholar
  117. 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 142:451–461PubMedCrossRefGoogle Scholar
  118. Schmidt HD, Pierce RC (2010) Cocaine-induced neuroadaptations in glutamate transmission. Ann N Y Acad Sci 1187:35–75. doi: 10.1111/j.1749-6632.2009.05144.x PubMedCrossRefGoogle Scholar
  119. 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. doi: 10.1111/j.1460-9568.2005.04524.x PubMedCrossRefGoogle Scholar
  120. See RE (2005) Neural substrates of cocaine-cue associations that trigger relapse. Eur J Pharmacol 526:140–146PubMedCrossRefGoogle Scholar
  121. 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 154:301–310PubMedCrossRefGoogle Scholar
  122. Self DW, Barnhart WJ, Lehman DA et al (1996) Opposite modulation of cocaine-seeking behavior by D1- and D2-like dopamine receptor agonists. Science 271(5255):1586–1589PubMedCrossRefGoogle Scholar
  123. Self DW, Karanian DA, Spencer JJ (2000) Effects of the novel D1 dopamine receptor agonist ABT-431 on cocaine self-administration and reinstatement. Ann N Y Acad Sci 909:133–144PubMedCrossRefGoogle Scholar
  124. Shaham Y, Hope BT (2005) The role of neuroadaptations in relapse to drug seeking. Nat Neurosci 8(11):1437–1439. doi: 10.1038/nn1105-1437 PubMedCrossRefGoogle Scholar
  125. Shaham Y, Stewart J (1995) Stress reinstates heroin-seeking in drug-free animals: an effect mimicking heroin, not withdrawal. Psychopharmacology 119:334–341PubMedCrossRefGoogle Scholar
  126. Shalev U, Highfield D, Yap J, Shaham Y (2000) Stress and relapse to drug seeking in rats: studies on the generality of the effect. Psychopharmacology 150:337–346PubMedCrossRefGoogle Scholar
  127. Shalev U, Grimm JW, Shaham Y (2002) Neurobiology of relapse to heroin and cocaine seeking: a review. Pharmacol Rev 54(1):1–42PubMedCrossRefGoogle Scholar
  128. Sinha R, Catapano D, O’Malley S (1999) Stress-induced craving and stress response in cocaine dependent individuals. Psychopharmacology 142:343–351PubMedCrossRefGoogle Scholar
  129. Sondheimer I, Knackstedt LA (2011) Ceftriaxone prevents the induction of cocaine sensitization and produces enduring attenuation of cue- and cocaine-primed reinstatement of cocaine-seeking. Behav Brain Res 225(1):252–258. doi: 10.1016/j.bbr.2011.07.041 PubMedPubMedCentralCrossRefGoogle Scholar
  130. Stefanik MT, Kalivas PW (2013) Optogenetic dissection of basolateral amygdala projections during cue-induced reinstatement of cocaine seeking. Front Behav Neurosci 7:213PubMedPubMedCentralCrossRefGoogle Scholar
  131. Stefanik MT, Moussawi K, Kupchik YM, Smith KC, Miller RL, Huff ML, Deisseroth K, Kalivas PW, LaLumiere RT (2013) Optogenetic inhibition of cocaine seeking in rats. Addict Biol 18:50–53PubMedCrossRefGoogle Scholar
  132. Steketee JD (2003) Neurotransmitter systems of the medial prefrontal cortex: potential role in sensitization to psychostimulants. Brain Res Brain Res Rev 41:203–228PubMedCrossRefGoogle Scholar
  133. Stuber GD, Sparta DR, Stamatakis AM et al (2011) Excitatory transmission from the amygdala to nucleus accumbens facilitates reward seeking. Nature 475:377–380PubMedPubMedCentralCrossRefGoogle Scholar
  134. Sun W, Rebec GV (2003) Lidocaine inactivation of ventral subiculum attenuates cocaine-seeking behavior in rats. J Neurosci 23:10258–10264PubMedGoogle Scholar
  135. Sun W, Rebec GV (2006) Repeated cocaine self-administration alters processing of cocaine-related information in rat prefrontal cortex. J Neurosci 26:8004–8008PubMedCrossRefGoogle Scholar
  136. Swanson LW, Cowan WM (1977) An autoradiographic study of the organization of the efferent connections of the hippocampal formation in the rat. J Comp Neurol 172(1):49–84. doi: 10.1002/cne.901720104 PubMedCrossRefGoogle Scholar
  137. Taepavarapruk P, Floresco SB, Phillips AG (2000) Hyperlocomotion and increased dopamine efflux in the rat nucleus accumbens evoked by electrical stimulation of the ventral subiculum: role of ionotropic glutamate and dopamine D1 receptors. Psychopharmacology 151:242–251PubMedCrossRefGoogle Scholar
  138. Tanaka H, Grooms SY, Bennett MV et al (2000) The AMPAR subunit GluR2: still front and center-stage. Brain Res 886:190–207PubMedCrossRefGoogle Scholar
  139. Vassoler FM, Schmidt HD, Gerard ME et al (2008) Deep brain stimulation of the nucleus accumbens shell attenuates cocaine priming-induced reinstatement of drug seeking in rats. J Neurosci 28:8735–8739PubMedPubMedCentralCrossRefGoogle Scholar
  140. Vassoler FM, Schmidt HD, Pierce RC (2009) Examination of the behavioral effects of deep brain stimulation of limbic nuclei in cocaine reinstatement. In: Society for neuroscience, 39th annual meeting, Chicago, Oct 2009Google Scholar
  141. Vassoler FM, White SL, Hopkins TJ et al (2013) Deep brain stimulation of the nucleus accumbens shell attenuates cocaine reinstatement through local and antidromic activation. J Neurosci 33:14446–14454PubMedPubMedCentralCrossRefGoogle Scholar
  142. Vinogradova OS (1995) Expression, control, and probable functional significance of the neuronal theta-rhythm. Prog Neurobiol 45:523–583PubMedCrossRefGoogle Scholar
  143. Vorel SR (2001) Relapse to cocaine-seeking after hippocampal theta burst stimulation. Science 292:1175–1178PubMedCrossRefGoogle Scholar
  144. Vorel SR, Ashby CR, Paul M et al (2002) Dopamine D3 receptor antagonism inhibits cocaine-seeking and cocaine-enhanced brain reward in rats. J Neurosci 22:9595–9603PubMedGoogle Scholar
  145. Weiss F, Maldonado-Vlaar CS, Parsons LH et al (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 97:4321–4326PubMedPubMedCentralCrossRefGoogle Scholar
  146. Wit H, Stewart J (1981) Reinstatement of cocaine-reinforced responding in the rat. Psychopharmacology 75(2):134–143PubMedCrossRefGoogle Scholar
  147. Wright CI, Groenewegen HJ (1995) Patterns of convergence and segregation in the medial nucleus accumbens of the rat: relationships of prefrontal cortical, midline thalamic, and basal amygdaloid afferents. J Comp Neurol 361(3):383–403. doi: 10.1002/cne.903610304 PubMedCrossRefGoogle Scholar
  148. Xie X, Ramirez DR, Lasseter HC et al (2010) Effects of mGluR1 antagonism in the dorsal hippocampus on drug context-induced reinstatement of cocaine-seeking behavior in rats. Psychopharmacology 208:1–11PubMedCrossRefGoogle Scholar
  149. Xie X, Lasseter HC, Ramirez DR et al (2012) Subregion-specific role of glutamate receptors in the nucleus accumbens on drug context-induced reinstatement of cocaine-seeking behavior in rats. Addict Biol 17:287–299PubMedCrossRefGoogle Scholar
  150. Xie X, Arguello AA, Wells AM et al (2013) Role of a hippocampal SRC-family kinase-mediated glutamatergic mechanism in drug context-induced cocaine seeking. Neuropsychopharmacology 38:2657–2665PubMedPubMedCentralCrossRefGoogle Scholar
  151. Xue Y-X, Xue L-F, Liu J-F et al (2014) Depletion of perineuronal nets in the amygdala to enhance the erasure of drug memories. J Neurosci 34:6647–6658PubMedCrossRefGoogle Scholar
  152. Yun IA, Fields HL (2003) Basolateral amygdala lesions impair both cue- and cocaine-induced reinstatement in animals trained on a discriminative stimulus task. Neuroscience 121(3):747–757PubMedCrossRefGoogle Scholar
  153. Zavala AR, Browning JR, Dickey ED et al (2008) Region-specific involvement of AMPA/Kainate receptors in Fos protein expression induced by cocaine-conditioned cues. Eur Neuropsychopharmacol 18:600–611PubMedPubMedCentralCrossRefGoogle Scholar
  154. Zhou L, Pruitt C, Shin CB et al (2014) Fos expression induced by cocaine-conditioned cues in male and female rats. Brain Struct Funct 219:1831–1840PubMedCrossRefGoogle Scholar
  155. Ziółkowska B, Kiełbiński M, Gieryk A et al (2011) Regulation of the immediate-early genes arc and zif268 in a mouse operant model of cocaine seeking reinstatement. J Neural Transm 118:877–887PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Neuroscience Graduate GroupPerelman School of Medicine, University of PennsylvaniaPhiladelphiaUSA
  2. 2.Department of PsychiatryCenter for Neurobiology and Behavior, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUSA

Personalised recommendations