, Volume 229, Issue 3, pp 453–476 | Cite as

The reinstatement model of drug relapse: recent neurobiological findings, emerging research topics, and translational research

  • Jennifer M. BossertEmail author
  • Nathan J. Marchant
  • Donna J. Calu
  • Yavin ShahamEmail author


Background and rationale

Results from many clinical studies suggest that drug relapse and craving are often provoked by acute exposure to the self-administered drug or related drugs, drug-associated cues or contexts, or certain stressors. During the last two decades, this clinical scenario has been studied in laboratory animals by using the reinstatement model. In this model, reinstatement of drug seeking by drug priming, drug cues or contexts, or certain stressors is assessed following drug self-administration training and subsequent extinction of the drug-reinforced responding.


In this review, we first summarize recent (2009–present) neurobiological findings from studies using the reinstatement model. We then discuss emerging research topics, including the impact of interfering with putative reconsolidation processes on cue- and context-induced reinstatement of drug seeking, and similarities and differences in mechanisms of reinstatement across drug classes. We conclude by discussing results from recent human studies that were inspired by results from rat studies using the reinstatement model.


Main conclusions from the studies reviewed highlight: (1) the ventral subiculum and lateral hypothalamus as emerging brain areas important for reinstatement of drug seeking, (2) the existence of differences in brain mechanisms controlling reinstatement of drug seeking across drug classes, (3) the utility of the reinstatement model for assessing the effect of reconsolidation-related manipulations on cue-induced drug seeking, and (4) the encouraging pharmacological concordance between results from rat studies using the reinstatement model and human laboratory studies on cue- and stress-induced drug craving.


Context Craving Cue Extinction Drug priming Drug self-administration Reconsolidation Reinstatement Relapse Review Stress 



This research was supported by the National Institute on Drug Abuse, Intramural Research Program. The authors declare that they do not have any conflicts of interest (financial or otherwise) related to the data presented in this manuscript. We thank Robyn St. Laurent for editorial corrections. The review is dedicated to the Waletzky family.


  1. Abercrombie ED, Keller RW Jr, Zigmond MJ (1988) Characterization of hippocampal norepinephrine release as measured by microdialysis perfusion: pharmacological and behavioral studies. Neuroscience 27:897–904PubMedGoogle Scholar
  2. Aghajanian GK, VanderMaelen CP (1982) alpha 2-adrenoceptor-mediated hyperpolarization of locus coeruleus neurons: intracellular studies in vivo. Science 215:1394–1396PubMedGoogle Scholar
  3. Airavaara M, Pickens CL, Stern AL, Wihbey KA, Harvey BK, Bossert JM, Liu QR, Hoffer BJ, Shaham Y (2011) Endogenous GDNF in ventral tegmental area and nucleus accumbens does not play a role in the incubation of heroin craving. Addict Biol 16:261–272PubMedGoogle Scholar
  4. Akil H, Watson SJ, Young E, Lewis ME, Khachaturian H, Walker JM (1984) Endogenous opioids: biology and function. Annu Rev Neurosci 7:223–255PubMedGoogle Scholar
  5. Alleweireldt AT, Hobbs RJ, Taylor AR, Neisewander JL (2006) Effects of SCH-23390 infused into the amygdala or adjacent cortex and basal ganglia on cocaine seeking and self-administration in rats. Neuropsychopharmacology 31:363–374PubMedGoogle Scholar
  6. Alvarez-Jaimes L, Polis I, Parsons LH (2008) Attenuation of cue-induced heroin-seeking behavior by cannabinoid CB1 antagonist infusions into the nucleus accumbens core and prefrontal cortex, but not basolateral amygdala. Neuropsychopharmacology 33:2483–2493PubMedGoogle Scholar
  7. Amen SL, Piacentine LB, Ahmad ME, Li SJ, Mantsch JR, Risinger RC, Baker DA (2011) Repeated N-acetyl cysteine reduces cocaine seeking in rodents and craving in cocaine-dependent humans. Neuropsychopharmacology 36:871–878PubMedGoogle Scholar
  8. 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 168:132–138PubMedGoogle Scholar
  9. Bachteler D, Economidou D, Danysz W, Ciccocioppo R, Spanagel R (2005) The effects of acamprosate and neramexane on cue-induced reinstatement of ethanol-seeking behavior in rat. Neuropsychopharmacology 30:1104–1110PubMedGoogle Scholar
  10. Bachtell RK, Self DW (2009) Effects of adenosine A2A receptor stimulation on cocaine-seeking behavior in rats. Psychopharmacology (Berl) 206:469–478Google Scholar
  11. Bachtell RK, Whisler K, Karanian D, Self DW (2005) Effects of intranucleus accumbens shell administration of dopamine agonists and antagonists on cocaine-taking and cocaine-seeking behaviors in the rat. Psychopharmacology 183:41–53PubMedGoogle Scholar
  12. Back SE, Hartwell K, DeSantis SM, Saladin M, McRae-Clark AL, Price KL, Moran-Santa Maria MM, Baker NL, Spratt E, Kreek MJ, Brady KT (2010) Reactivity to laboratory stress provocation predicts relapse to cocaine. Drug Alcohol Depend 106:21–27PubMedGoogle Scholar
  13. Badiani A, Belin D, Epstein D, Calu D, Shaham Y (2011) Opiate versus psychostimulant addiction: the differences do matter. Nat Rev Neurosci 12:685–700PubMedGoogle Scholar
  14. Baker DA, McFarland K, Lake RW, Shen H, Tang XC, Toda S, Kalivas PW (2003) Neuroadaptations in cystine-glutamate exchange underlie cocaine relapse. Nat Neurosci 6:743–749PubMedGoogle Scholar
  15. Bale TL, Vale WW (2004) CRF and CRF receptors: role in stress responsivity and other behaviors. Annu Rev Pharmacol Toxicol 44:525–557PubMedGoogle Scholar
  16. Ball KT, Slane M (2012) Differential involvement of prelimbic and infralimbic medial prefrontal cortex in discrete cue-induced reinstatement of 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) seeking in rats. Psychopharmacology (Berl) 224:377–385Google Scholar
  17. Bauzo RM, Kimmel HL, Howell LL (2012) The cystine-glutamate transporter enhancer N-acetyl-L-cysteine attenuates cocaine-induced changes in striatal dopamine but not self-administration in squirrel monkeys. Pharmacol Biochem Behav 101:288–296PubMedGoogle Scholar
  18. Berk M, Malhi GS, Gray LJ, Dean OM (2013) The promise of N-acetylcysteine in neuropsychiatry. Trends Pharmacol Sci (in press)Google Scholar
  19. Blacktop JM, Seubert C, Baker DA, Ferda N, Lee G, Graf EN, Mantsch JR (2011) Augmented cocaine seeking in response to stress or CRF delivered into the ventral tegmental area following long-access self-administration is mediated by CRF receptor type 1 but not CRF receptor type 2. J Neurosci 31:11396–11403PubMedGoogle Scholar
  20. 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 526:36–50PubMedGoogle Scholar
  21. 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 31:2197–2209PubMedGoogle Scholar
  22. Bossert JM, Liu SY, Lu L, Shaham Y (2004) A role of ventral tegmental area glutamate in contextual cue-induced relapse to heroin seeking. J Neurosci 24:10726–10730PubMedGoogle Scholar
  23. 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 27:12655–12663PubMedGoogle Scholar
  24. Bossert JM, Stern AL (2013) Role of ventral subiculum in context-induced reinstatement of heroin seeking in rats. Addict Biol (in press)Google Scholar
  25. Bossert JM, Stern AL, Theberge FR, Cifani C, Koya E, Hope BT, Shaham Y (2011) Ventral medial prefrontal cortex neuronal ensembles mediate context-induced relapse to heroin. Nat Neurosci 14:420–422PubMedGoogle Scholar
  26. Bossert JM, Stern AL, Theberge FR, Marchant NJ, Wang HL, Morales M, Shaham Y (2012) Role of projections from ventral medial prefrontal cortex to nucleus accumbens shell in context-induced reinstatement of heroin seeking. J Neurosci 32:4982–4891PubMedGoogle Scholar
  27. Bossert JM, Wihbey KA, Pickens CL, Nair SG, Shaham Y (2009) Role of dopamine D(1)-family receptors in dorsolateral striatum in context-induced reinstatement of heroin seeking in rats. Psychopharmacology 206:51–60PubMedGoogle Scholar
  28. Bouton ME, Swartzentruber D (1991) Sources of relapse after extinction in Pavlovian and instrumental learning. Clin Psychol Rev 11:123–140Google Scholar
  29. Bremner JD, Krystal JH, Southwick SM, Charney DS (1996a) Noradrenergic mechanisms in stress and anxiety: I. preclinical studies. Synapse 23:28–38PubMedGoogle Scholar
  30. Bremner JD, Krystal JH, Southwick SM, Charney DS (1996b) Noradrenergic mechanisms in stress and anxiety: II. clinical studies. Synapse 23:39–51PubMedGoogle Scholar
  31. Bruchas MR, Land BB, Chavkin C (2010) The dynorphin/kappa opioid system as a modulator of stress-induced and pro-addictive behaviors. Brain Res 1314:44–55PubMedGoogle Scholar
  32. Bruijnzeel AW (2012) Tobacco addiction and the dysregulation of brain stress systems. Neurosci Biobehav Rev 36:1418–1441PubMedGoogle Scholar
  33. Buffalari DM, See RE (2011) Inactivation of the bed nucleus of the stria terminalis in an animal model of relapse: effects on conditioned cue-induced reinstatement and its enhancement by yohimbine. Psychopharmacology 213:19–27PubMedGoogle Scholar
  34. Calu DJ, Chen YW, Kawa AB, Nair SG, Shaham Y (2013) The use of the reinstatement model to study relapse to palatable food seeking during dieting. Neuropharmacology (accepted pending minor revisions)Google Scholar
  35. Cannella N, Economidou D, Kallupi M, Stopponi S, Heilig M, Massi M, Ciccocioppo R (2009) Persistent increase of alcohol-seeking evoked by neuropeptide S: an effect mediated by the hypothalamic hypocretin system. Neuropsychopharmacology 34:2125–2134PubMedGoogle Scholar
  36. 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 168:66–74PubMedGoogle Scholar
  37. Carey AN, Borozny K, Aldrich JV, McLaughlin JP (2007) Reinstatement of cocaine place-conditioning prevented by the peptide kappa-opioid receptor antagonist arodyn. Eur J Pharmacol 569:84–89PubMedGoogle Scholar
  38. Carlezon WA Jr, Duman RS, Nestler EJ (2005) The many faces of CREB. Trends Neurosci 28:436–445PubMedGoogle Scholar
  39. Chaudhri N, Sahuque LL, Janak PH (2008) Context-induced relapse of conditioned behavioral responding to ethanol cues in rats. Biol Psychiatry 64:203–210PubMedGoogle Scholar
  40. Chaudhri N, Sahuque LL, Janak PH (2009) Ethanol seeking triggered by environmental context is attenuated by blocking dopamine D1 receptors in the nucleus accumbens core and shell in rats. Psychopharmacology 207:303–314PubMedGoogle Scholar
  41. Chaudhri N, Sahuque LL, Schairer WW, Janak PH (2010) Separable roles of the nucleus accumbens core and shell in context- and cue-induced alcohol-seeking. Neuropsychopharmacology 35:783–791PubMedGoogle Scholar
  42. Conrad KL, McCutcheon JE, Cotterly LM, Ford KA, Beales M, Marinelli M (2010) Persistent increases in cocaine-seeking behavior after acute exposure to cold swim stress. Biol Psychiatry 68:303–305PubMedGoogle Scholar
  43. Cornish JL, Duffy P, Kalivas PW (1999) A role for nucleus accumbens glutamate transmission in the relapse to cocaine-seeking behavior. Neuroscience 93:1359–1367PubMedGoogle Scholar
  44. Cornish JL, Kalivas PW (2000) Glutamate transmission in the nucleus accumbens mediates relapse in cocaine addiction. J Neurosci 20:RC89PubMedGoogle Scholar
  45. Crombag H, Bossert JM, Koya E, Shaham Y (2008) Context-induced relapse to drug seeking: a review. Trans R Soc Lond B Biol Sci 363:3233–3243Google Scholar
  46. Crombag HS, Shaham Y (2002) Renewal of drug seeking by contextual cues after prolonged extinction in rats. Behav Neurosci 116:169–173PubMedGoogle Scholar
  47. de Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE, Fukuhara C, Battenberg EL, Gautvik VT, Bartlett FS 2nd, Frankel WN, van den Pol AN, Bloom FE, Gautvik KM, Sutcliffe JG (1998) The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci USA 95:322–327PubMedGoogle Scholar
  48. De Vries TJ, Schoffelmeer AN, Binnekade R, Mulder AH, Vanderschuren LJ (1998) Drug-induced reinstatement of heroin- and cocaine-seeking behaviour following long-term extinction is associated with expression of behavioural sensitization. Eur J Neurosci 10:3565–3571PubMedGoogle Scholar
  49. de Wit H (1996) Priming effects with drugs and other reinforcers. Exp Clin Psychopharmacol 4:5–10Google Scholar
  50. de Wit H, Stewart J (1981) Reinstatement of cocaine-reinforced responding in the rat. Psychopharmacology 75:134–143PubMedGoogle Scholar
  51. Diergaarde L, Schoffelmeer AN, De Vries TJ (2008) Pharmacological manipulation of memory reconsolidation: towards a novel treatment of pathogenic memories. Eur J Pharmacol 585:453–457PubMedGoogle Scholar
  52. Dudai Y (2006) Reconsolidation: the advantage of being refocused. Curr Opin Neurobiol 16:174–178PubMedGoogle Scholar
  53. Epstein D, Preston K, Stewart J, Shaham Y (2006) Toward a model of drug relapse: an assessment of the validity of the reinstatement procedure. Psychopharmacology 189:1–16PubMedGoogle Scholar
  54. Epstein DH, Preston KL (2003) The reinstatement model and relapse prevention: a clinical perspective. Psychopharmacology 168:31–41PubMedGoogle Scholar
  55. Erb S, Hitchcott PK, Rajabi H, Mueller D, Shaham Y, Stewart J (2000) Alpha-2 adrenergic agonists block stress-induced reinstatement of cocaine seeking. Neuropsychopharmacology 23:138–150PubMedGoogle Scholar
  56. Erb S, Shaham Y, Stewart J (1998) The role of corticotropin-releasing factor and corticosterone in stress- and cocaine-induced relapse to cocaine seeking in rats. J Neurosci 18:5529–5536PubMedGoogle Scholar
  57. Erb S, Shaham Y, Stewart J (2001) Stress-induced relapse to drug seeking in the rat: role of the bed nucleus of the stria terminalis and amygdala. Stress 4:289–303PubMedGoogle Scholar
  58. Erb S, Stewart J (1999) A role for the bed nucleus of the stria terminalis, but not the amygdala, in the effects of corticotropin-releasing factor on stress-induced reinstatement of cocaine seeking. J Neurosci 19:RC35PubMedGoogle Scholar
  59. Ettenberg A (2009) The runway model of drug self-administration. Pharmacol Biochem Behav 91:271–277PubMedGoogle Scholar
  60. Ettenberg A, Geist TD (1993) Qualitative and quantitative differences in the operant runway behavior of rats working for cocaine and heroin reinforcement. Pharmacol Biochem Behav 44:191–198PubMedGoogle Scholar
  61. Ettenberg A, MacConell LA, Geist TD (1996) Effects of haloperidol in a response-reinstatement model of heroin relapse. Psychopharmacology 124:205–210PubMedGoogle Scholar
  62. 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 42:1–18PubMedGoogle Scholar
  63. Everitt BJ, Wolf ME (2002) Psychomotor stimulant addiction: a neural systems perspective. J Neurosci 22:3312–3320PubMedGoogle Scholar
  64. Feltenstein MW, See RE (2008) The neurocircuitry of addiction: an overview. Br J Pharmacol 154:261–274PubMedGoogle Scholar
  65. Ferre S, Fredholm BB, Morelli M, Popoli P, Fuxe K (1997) Adenosine-dopamine receptor-receptor interactions as an integrative mechanism in the basal ganglia. Trends Neurosci 20:482–487PubMedGoogle Scholar
  66. Fletcher PJ, Rizos Z, Sinyard J, Tampakeras M, Higgins GA (2008) The 5-HT(2C) receptor agonist Ro60-0175 reduces cocaine self-administration and reinstatement induced by the stressor yohimbine, and contextual cues. Neuropsychopharmacology 33:1402–1412PubMedGoogle Scholar
  67. Forget B, Pushparaj A, Le Foll B (2010) Granular insular cortex inactivation as a novel therapeutic strategy for nicotine addiction. Biol Psychiatry 68:265–271PubMedGoogle Scholar
  68. Fox HC, Anderson GM, Tuit K, Hansen J, Kimmerling A, Siedlarz KM, Morgan PT, Sinha R (2012a) Prazosin effects on stress- and cue-induced craving and stress response in alcohol-dependent individuals: preliminary findings. Alcohol Clin Exp Res 36:351–360PubMedGoogle Scholar
  69. Fox HC, Seo D, Tuit K, Hansen J, Kimmerling A, Morgan PT, Sinha R (2012b) Guanfacine effects on stress, drug craving and prefrontal activation in cocaine dependent individuals: preliminary findings. J Psychopharmacol 26:958–972PubMedGoogle Scholar
  70. Fuchs RA, Bell GH, Ramirez DR, Eaddy JL, Su ZI (2009) Basolateral amygdala involvement in memory reconsolidation processes that facilitate drug context-induced cocaine seeking. Eur J Neurosci 30:889–900PubMedGoogle Scholar
  71. 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 26:3584–3588PubMedGoogle Scholar
  72. 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 26:487–498PubMedGoogle Scholar
  73. 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 30:296–309PubMedGoogle Scholar
  74. Fuchs RA, Evans KA, Parker MC, See RE (2004a) Differential involvement of the core and shell subregions of the nucleus accumbens in conditioned cue-induced reinstatement of cocaine seeking in rats. Psychopharmacology (Berl)Google Scholar
  75. Fuchs RA, Evans KA, Parker MP, See RE (2004b) Differential Involvement of Orbitofrontal Cortex Subregions in Conditioned Cue-Induced and Cocaine-Primed Reinstatement of Cocaine Seeking in Rats. J Neurosci 24:6600–6610PubMedGoogle Scholar
  76. Fuchs RA, Ramirez DR, Bell GH (2008) Nucleus accumbens shell and core involvement in drug context-induced reinstatement of cocaine seeking in rats. Psychopharmacology 200:545–556PubMedGoogle Scholar
  77. Gabriele A, See RE (2011) Lesions and reversible inactivation of the dorsolateral caudate-putamen impair cocaine-primed reinstatement to cocaine-seeking in rats. Brain Res 1417:27–35PubMedGoogle Scholar
  78. Gaffan D, Murray EA, Fabre-Thorpe M (1993) Interaction of the amygdala with the frontal lobe in reward memory. Eur J Neurosci 5:968–975PubMedGoogle Scholar
  79. Geisler S, Derst C, Veh RW, Zahm DS (2007) Glutamatergic afferents of the ventral tegmental area in the rat. J Neurosci 27:5730–5743PubMedGoogle Scholar
  80. Geyer MA, Markou A (1995) Animal models of psychiatric disorders. In: Bloom FE, Kupfer DJ (eds) Psychopharmacology. Raven Press, New York, pp 787–798Google Scholar
  81. Gipson CD, Kupchik YM, Shen H, Reissner KJ, Thomas CA, Kalivas PW (2013) Relapse induced by cues predicting cocaine depends on rapid, transient synaptic potentiation. Neuron 77:867–872PubMedGoogle Scholar
  82. Goldstein JM, Simpson JC (2002) Validity: definition and applications to psychiatric research. In: Tsuang MT, Tohen M (eds) Textbook in psychiatric epidemiology, 2nd edn. Wiley-Liss, New York, pp 149–163Google Scholar
  83. Grant JE, Odlaug BL, Kim SW (2010) A double-blind, placebo-controlled study of N-acetyl cysteine plus naltrexone for methamphetamine dependence. Eur Neuropsychopharmacol 20:823–828PubMedGoogle Scholar
  84. Graziane NM, Polter AM, Briand LA, Pierce RC, Kauer JA (2013) Kappa opioid receptors regulate stress-induced cocaine seeking and synaptic plasticity. Neuron 77:942–954PubMedGoogle Scholar
  85. Greenwald MK, Lundahl LH, Steinmiller CL (2013) Yohimbine increases opioid-seeking behavior in heroin-dependent, buprenorphine-maintained individuals. Psychopharmacology (Berl) 225:811–824Google Scholar
  86. Grimm JW, Hope BT, Wise RA, Shaham Y (2001) Incubation of cocaine craving after withdrawal. Nature 412:141–142PubMedGoogle Scholar
  87. Grimm JW, Lu L, Hayashi T, Hope BT, Su TP, Shaham Y (2003) Time-dependent increases in brain-derived neurotrophic factor protein levels within the mesolimbic dopamine system after withdrawal from cocaine: implications for incubation of cocaine craving. J Neurosci 23:742–747PubMedGoogle Scholar
  88. Groenewegen HJ, Vermeulen-Van der Zee E, te Kortschot A, Witter MP (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 23:103–120PubMedGoogle Scholar
  89. Hamlin AS, Clemens KJ, Choi EA, McNally GP (2009) Paraventricular thalamus mediates context-induced reinstatement (renewal) of extinguished reward seeking. Eur J Neurosci 29:802–812PubMedGoogle Scholar
  90. Hamlin AS, Clemens KJ, McNally GP (2008) Renewal of extinguished cocaine-seeking. Neuroscience 151:659–670PubMedGoogle Scholar
  91. Hamlin AS, Newby J, McNally GP (2007) The neural correlates and role of D1 dopamine receptors in renewal of extinguished alcohol-seeking. Neuroscience 146:525–536PubMedGoogle Scholar
  92. Highfield D, Yap J, Grimm J, Shalev U, Shaham Y (2001) Repeated lofexidine treatment attenuates stress-induced, but not drug cues-induced reinstatement of a heroin-cocaine mixture (speedball) seeking in rats. Neuropsychopharmacology 25:320–331PubMedGoogle Scholar
  93. Hunt WA, Barnett LW, Branch LG (1971) Relapse rates in addiction programs. J Clin Psychol 27:455–456PubMedGoogle Scholar
  94. Hutton-Bedbrook K, McNally GP (2013) The promises and pitfalls of retrieval-extinction procedures in preventing relapse to drug seeking. Front Psychiatry 4:14PubMedGoogle Scholar
  95. James MH, Charnley JL, Levi EM, Jones E, Yeoh JW, Smith DW, Dayas CV (2011) Orexin-1 receptor signalling within the ventral tegmental area, but not the paraventricular thalamus, is critical to regulating cue-induced reinstatement of cocaine-seeking. Int J Neuropsychopharmacol 14:684–690PubMedGoogle Scholar
  96. Jobes ML, Ghitza UE, Epstein DH, Phillips KA, Heishman SJ, Preston KL (2011) Clonidine blocks stress-induced craving in cocaine users. Psychopharmacology (Berl) 218:83–88Google Scholar
  97. Julius D (1976) NIDA’s naltrexone research program. NIDA Res Monogr 9:5–11PubMedGoogle Scholar
  98. Kalivas PW, Lalumiere RT, Knackstedt L, Shen H (2009) Glutamate transmission in addiction. Neuropharmacology 56(Suppl 1):169–173PubMedGoogle Scholar
  99. Kalivas PW, McFarland K (2003) Brain circuitry and the reinstatement of cocaine-seeking behavior. Psychopharmacology 168:44–56PubMedGoogle Scholar
  100. Kallupi M, Cannella N, Economidou D, Ubaldi M, Ruggeri B, Weiss F, Massi M, Marugan J, Heilig M, Bonnavion P, de Lecea L, Ciccocioppo R (2010) Neuropeptide S facilitates cue-induced relapse to cocaine seeking through activation of the hypothalamic hypocretin system. Proc Natl Acad Sci USA 107:19567–19572PubMedGoogle Scholar
  101. Kallupi M, de Guglielmo G, Cannella N, Li HW, Calo G, Guerrini R, Ubaldi M, Renger JJ, Uebele VN, Ciccocioppo R (2013) Hypothalamic neuropeptide S receptor blockade decreases discriminative cue-induced reinstatement of cocaine seeking in the rat. Psychopharmacology 226:347–355PubMedGoogle Scholar
  102. Katz J, Higgins S (2003) The validity of the reinstatement model of craving and relapse to drug use. Psychopharmacology 168:21–30PubMedGoogle Scholar
  103. Kelley AE, Berridge KC (2002) The neuroscience of natural rewards: relevance to addictive drugs. J Neurosci 22:3306–3311PubMedGoogle Scholar
  104. Knackstedt LA, LaRowe S, Mardikian P, Malcolm R, Upadhyaya H, Hedden S, Markou A, Kalivas PW (2009) The role of cystine-glutamate exchange in nicotine dependence in rats and humans. Biol Psychiatry 65:841–845PubMedGoogle Scholar
  105. Koya E, Golden SA, Harvey BK, Guez-Barber DH, Berkow A, Simmons DE, Bossert JM, Nair SG, Uejima JL, Marin MT, Mitchell TB, Farquhar D, Ghosh SC, Mattson BJ, Hope BT (2009) Targeted disruption of cocaine-activated nucleus accumbens neurons prevents context-specific sensitization. Nat Neurosci 12:1069–1073PubMedGoogle Scholar
  106. 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:RC155PubMedGoogle Scholar
  107. Kumaresan V, Yuan M, Yee J, Famous KR, Anderson SM, Schmidt HD, Pierce RC (2009) Metabotropic glutamate receptor 5 (mGluR5) antagonists attenuate cocaine priming- and cue-induced reinstatement of cocaine seeking. Behav Brain Res 202:238–244PubMedGoogle Scholar
  108. Kupchik YM, Moussawi K, Tang XC, Wang X, Kalivas BC, Kolokithas R, Ogburn KB, Kalivas PW (2012) The effect of N-acetylcysteine in the nucleus accumbens on neurotransmission and relapse to cocaine. Biol Psychiatry 71:978–986PubMedGoogle Scholar
  109. LaLumiere RT, Kalivas PW (2008) Glutamate release in the nucleus accumbens core is necessary for heroin seeking. J Neurosci 28:3170–3177PubMedGoogle Scholar
  110. LaRowe SD, Myrick H, Hedden S, Mardikian P, Saladin M, McRae A, Brady K, Kalivas PW, Malcolm R (2007) Is cocaine desire reduced by N-acetylcysteine? Am J Psychiatry 164:1115–1117PubMedGoogle Scholar
  111. Larson EB, Graham DL, Arzaga RR, Buzin N, Webb J, Green TA, Bass CE, Neve RL, Terwilliger EF, Nestler EJ, Self DW (2011) Overexpression of CREB in the nucleus accumbens shell increases cocaine reinforcement in self-administering rats. J Neurosci 31:16447–16457PubMedGoogle Scholar
  112. Lasseter HC, Ramirez DR, Xie X, Fuchs RA (2009) Involvement of the lateral orbitofrontal cortex in drug context-induced reinstatement of cocaine-seeking behavior in rats. Eur J Neurosci 30:1370–1381PubMedGoogle Scholar
  113. Lasseter HC, Wells AM, Xie X, Fuchs RA (2011) Interaction of the basolateral amygdala and orbitofrontal cortex is critical for drug context-induced reinstatement of cocaine-seeking behavior in rats. Neuropsychopharmacology 36:711–720PubMedGoogle Scholar
  114. 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 171:830–839PubMedGoogle Scholar
  115. Le A, Shaham Y (2002) Neurobiology of relapse to alcohol in rats. Pharmacol Ther 94:137–156PubMedGoogle Scholar
  116. Le AD, Funk D, Coen K, Li Z, Shaham Y (2012) Role of corticotropin-releasing factor in the median raphe nucleus in yohimbine-induced reinstatement of alcohol seeking in rats. Addict Biol (in press)Google Scholar
  117. Le AD, Funk D, Harding S, Juzytsch W, Fletcher PJ (2009) The role of noradrenaline and 5-hydroxytryptamine in yohimbine-induced increases in alcohol-seeking in rats. Psychopharmacology 204:477–488Google Scholar
  118. Le AD, Funk D, Juzytsch W, Coen K, Navarre BM, Cifani C, Shaham Y (2011) Effect of prazosin and guanfacine on stress-induced reinstatement of alcohol and food seeking in rats. Psychopharmacology 218:89–99PubMedGoogle Scholar
  119. Le AD, Harding S, Juzytsch W, Fletcher PJ, Shaham Y (2002) The role of corticotropin-releasing factor in the median raphe nucleus in relapse to alcohol. J Neurosci 22:7844–7849PubMedGoogle Scholar
  120. Le AD, Harding S, Juzytsch W, Funk D, Shaham Y (2005) Role of alpha-2 adrenoceptors in stress-induced reinstatement of alcohol seeking and alcohol self-administration in rats. Psychopharmacology 179:366–373PubMedGoogle Scholar
  121. Le AD, Poulos CX, Harding S, Watchus W, Juzytsch W, Shaham Y (1999) Effects of naltrexone and fluoxetine on alcohol self-administration and reinstatement of alcohol seeking induced by priming injections of alcohol and exposure to stress in rats. Neuropsychopharmacology 21:435–444PubMedGoogle Scholar
  122. Lee B, Tiefenbacher S, Platt DM, Spealman RD (2004) Pharmacological blockade of alpha(2)-arenoceptors induces reinstatement of cocaine-seeking behavior in squirrel monkeys. Neuropsychopharmacology 29:686–693PubMedGoogle Scholar
  123. Lee JL, Di Ciano P, Thomas KL, Everitt BJ (2005) Disrupting reconsolidation of drug memories reduces cocaine-seeking behavior. Neuron 47:795–801PubMedGoogle Scholar
  124. Lee JL, Milton AL, Everitt BJ (2006) Cue-induced cocaine seeking and relapse are reduced by disruption of drug memory reconsolidation. J Neurosci 26:5881–5887PubMedGoogle Scholar
  125. 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 22:5713–5718PubMedGoogle Scholar
  126. Leri F, Tremblay A, Sorge RE, Stewart J (2004) Methadone maintenance reduces heroin- and cocaine-induced relapse without affecting stress-induced relapse in a rodent model of poly-drug use. Neuropsychopharmacology 29:1312–1320PubMedGoogle Scholar
  127. Li X, DeJoseph MR, Urban JH, Bahi A, Dreyer JL, Meredith GE, Ford KA, Ferrario CR, Loweth JA, Wolf ME (2013) Different roles of BDNF in nucleus accumbens core versus shell during the incubation of cue-induced cocaine craving and its long-term maintenance. J Neurosci 33:1130–1142PubMedGoogle Scholar
  128. Li X, Li J, Gardner EL, Xi ZX (2010) Activation of mGluR7s inhibits cocaine-induced reinstatement of drug-seeking behavior by a nucleus accumbens glutamate-mGluR2/3 mechanism in rats. J Neurochem 114:1368–1380PubMedGoogle Scholar
  129. Liu S, Bubar MJ, Lanfranco MF, Hillman GR, Cunningham KA (2007) Serotonin2C receptor localization in GABA neurons of the rat medial prefrontal cortex: implications for understanding the neurobiology of addiction. Neuroscience 146:1677–1688PubMedGoogle Scholar
  130. Liu X, Caggiula AR, Palmatier MI, Donny EC, Sved AF (2008) Cue-induced reinstatement of nicotine-seeking behavior in rats: effect of bupropion, persistence over repeated tests, and its dependence on training dose. Psychopharmacology (Berl) 196:365–375Google Scholar
  131. Liu X, Weiss F (2002) Additive effect of stress and drug cues on reinstatement of ethanol seeking: exacerbation by history of dependence and role of concurrent activation of corticotropin-releasing factor and opioid mechanisms. J Neurosci 22:7856–7861PubMedGoogle Scholar
  132. Lu L, Dempsey J, Liu SY, Bossert JM, Shaham Y (2004) A single infusion of brain-derived neurotrophic factor into the ventral tegmental area induces long-lasting potentiation of cocaine seeking after withdrawal. J Neurosci 24:1604–1611PubMedGoogle Scholar
  133. Lu L, Wang X, Wu P, Xu C, Zhao M, Morales M, Harvey BK, Hoffer BJ, Shaham Y (2009) Role of ventral tegmental area glial cell line-derived neurotrophic factor in incubation of cocaine craving. Biol Psychiatry 66:137–145PubMedGoogle Scholar
  134. Luo AH, Tahsili-Fahadan P, Wise RA, Lupica CR, Aston-Jones G (2011) Linking context with reward: a functional circuit from hippocampal CA3 to ventral tegmental area. Science 333:353–357PubMedGoogle Scholar
  135. Madras BK, Xie Z, Lin Z, Jassen A, Panas H, Lynch L, Johnson R, Livni E, Spencer TJ, Bonab AA, Miller GM, Fischman AJ (2006) Modafinil occupies dopamine and norepinephrine transporters in vivo and modulates the transporters and trace amine activity in vitro. J Pharmacol Exp Ther 319:561–569PubMedGoogle Scholar
  136. Mahler SV, Aston-Jones GS (2012) Fos activation of selective afferents to ventral tegmental area during cue-induced reinstatement of cocaine seeking in rats. J Neurosci 32:13309–13326PubMedGoogle Scholar
  137. Mahler SV, Hensley-Simon M, Tahsili-Fahadan P, Lalumiere RT, Thomas C, Fallon RV, Kalivas PW, Aston-Jones G (2012a) Modafinil attenuates reinstatement of cocaine seeking: role for cystine-glutamate exchange and metabotropic glutamate receptors. Addict Biol (in press)Google Scholar
  138. Mahler SV, Smith RJ, Aston-Jones G (2012b) Interactions between VTA orexin and glutamate in cue-induced reinstatement of cocaine seeking in rats. Psychopharmacology 226:687–698PubMedGoogle Scholar
  139. Marchant NJ, Furlong TM, McNally GP (2010) Medial dorsal hypothalamus mediates the inhibition of reward seeking after extinction. J Neurosci 30:14102–14115PubMedGoogle Scholar
  140. Marchant NJ, Hamlin AS, McNally GP (2009) Lateral hypothalamus is required for context-induced reinstatement of extinguished reward seeking. J Neurosci 29:1331–1342PubMedGoogle Scholar
  141. Marchant NJ, Li X, Shaham Y (2013) Recent developments in animal models of drug relapse. Curr Opin Neurobiol (in press)Google Scholar
  142. Marchant NJ, Millan EZ, McNally GP (2012) The hypothalamus and the neurobiology of drug seeking. Cell Mol Life Sci 69:581–597PubMedGoogle Scholar
  143. Marinelli PW, Funk D, Juzytsch W, Le AD (2010) Opioid receptors in the basolateral amygdala but not dorsal hippocampus mediate context-induced alcohol seeking. Behav Brain Res 211:58–63PubMedGoogle Scholar
  144. McFarland K, Davidge SB, Lapish CC, Kalivas PW (2004) Limbic and motor circuitry underlying footshock-induced reinstatement of cocaine-seeking behavior. J Neurosci 24:1551–1560PubMedGoogle Scholar
  145. McFarland K, Kalivas PW (2001) The circuitry mediating cocaine-induced reinstatement of drug-seeking behavior. J Neurosci 21:8655–8663PubMedGoogle Scholar
  146. McGaugh JL (1966) Time-dependent processes in memory storage. Science 153:1351–1358PubMedGoogle Scholar
  147. McGaugh JL (2000) Memory—a century of consolidation. Science 287:248–251PubMedGoogle Scholar
  148. 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 168:57–65PubMedGoogle Scholar
  149. 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 7:754–763PubMedGoogle Scholar
  150. Millan EZ, Furlong TM, McNally GP (2010) Accumbens shell–hypothalamus interactions mediate extinction of alcohol seeking. J Neurosci 30:4626–4635PubMedGoogle Scholar
  151. Millan EZ, Marchant NJ, McNally GP (2011) Extinction of drug seeking. Behav Brain Res 217:454–462PubMedGoogle Scholar
  152. Millan EZ, McNally GP (2011) Accumbens shell AMPA receptors mediate expression of extinguished reward seeking through interactions with basolateral amygdala. Learn Mem 18:414–421PubMedGoogle Scholar
  153. Millan EZ, Milligan-Saville J, McNally GP (2013) Memory retrieval, extinction, and reinstatement of alcohol seeking. Neurobiol Learn Mem 101:26–32PubMedGoogle Scholar
  154. Millan MJ, Newman-Tancredi A, Quentric Y, Cussac D (2001) The "selective" dopamine D1 receptor antagonist, SCH23390, is a potent and high efficacy agonist at cloned human serotonin2C receptors. Psychopharmacology (Berl) 156:58–62Google Scholar
  155. Miller CA, Marshall JF (2005) Molecular substrates for retrieval and reconsolidation of cocaine-associated contextual memory. Neuron 47:873–884PubMedGoogle Scholar
  156. Milton AL, Everitt BJ (2012) The persistence of maladaptive memory: addiction, drug memories and anti-relapse treatments. Neurosci Biobehav Rev 36:1119–1139PubMedGoogle Scholar
  157. Milton AL, Lee JL, Butler VJ, Gardner R, Everitt BJ (2008) Intra-amygdala and systemic antagonism of NMDA receptors prevents the reconsolidation of drug-associated memory and impairs subsequently both novel and previously acquired drug-seeking behaviors. J Neurosci 28:8230–8237PubMedGoogle Scholar
  158. Misanin JR, Miller RR, Lewis DJ (1968) Retrograde amnesia produced by electroconvulsive shock after reactivation of a consolidated memory trace. Science 160:554–555PubMedGoogle Scholar
  159. Monfils MH, Cowansage KK, Klann E, LeDoux JE (2009) Extinction-reconsolidation boundaries: key to persistent attenuation of fear memories. Science 324:951–955PubMedGoogle Scholar
  160. Moussawi K, Zhou W, Shen H, Reichel CM, See RE, Carr DB, Kalivas PW (2011) Reversing cocaine-induced synaptic potentiation provides enduring protection from relapse. Proc Natl Acad Sci U S A 108:385–390PubMedGoogle Scholar
  161. Mueller D, Stewart J (2000) Cocaine-induced conditioned place preference: reinstatement by priming injections of cocaine after extinction. Behav Brain Res 115:39–47PubMedGoogle Scholar
  162. Nader K, Schafe GE, LeDoux JE (2000) The labile nature of consolidation theory. Nat Rev Neurosci 1:216–219PubMedGoogle Scholar
  163. Nair SG, Adams-Deutsch T, Epstein DH, Shaham Y (2009) The neuropharmacology of relapse to food seeking: methodology, main findings, and comparison with relapse to drug seeking. Prog Neurobiol 89:18–45PubMedGoogle Scholar
  164. 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 20:798–805PubMedGoogle Scholar
  165. O'Brien CP (2005) Anticraving medications for relapse prevention: a possible new class of psychoactive medications. Am J Psychiatry 162:1423–1431PubMedGoogle Scholar
  166. O'Brien CP, Childress AR, McLellan AT, Ehrman R (1992) Classical conditioning in drug-dependent humans. Ann N Y Acad Sci 654:400–415PubMedGoogle Scholar
  167. O'Connor EC, Parker D, Rollema H, Mead AN (2010) The alpha4beta2 nicotinic acetylcholine-receptor partial agonist varenicline inhibits both nicotine self-administration following repeated dosing and reinstatement of nicotine seeking in rats. Psychopharmacology 208:365–376PubMedGoogle Scholar
  168. O'Neill CE, LeTendre ML, Bachtell RK (2012) Adenosine A2A receptors in the nucleus accumbens bi-directionally alter cocaine seeking in rats. Neuropsychopharmacology 37:1245–1256PubMedGoogle Scholar
  169. Paxinos G, Watson C (2005) The rat brain in stereotaxic coordinates, 5th edn. Elsevier Academic Press, AmsterdamGoogle Scholar
  170. Pentkowski NS, Duke FD, Weber SM, Pockros LA, Teer AP, Hamilton EC, Thiel KJ, Neisewander JL (2010) Stimulation of medial prefrontal cortex serotonin 2C (5-HT(2C)) receptors attenuates cocaine-seeking behavior. Neuropsychopharmacology 35:2037–2048PubMedGoogle Scholar
  171. Peters J, Kalivas PW, Quirk GJ (2009) Extinction circuits for fear and addiction overlap in prefrontal cortex. Learn Mem 16:279–288PubMedGoogle Scholar
  172. Peters J, LaLumiere RT, Kalivas PW (2008) Infralimbic prefrontal cortex is responsible for inhibiting cocaine seeking in extinguished rats. J Neurosci 28:6046–6053PubMedGoogle Scholar
  173. Pickens CL, Airavaara M, Theberge F, Fanous S, Hope BT, Shaham Y (2011) Neurobiology of incubation of drug craving. Trends Neurosci 34:411–420PubMedGoogle Scholar
  174. Pockros LA, Pentkowski NS, Swinford SE, Neisewander JL (2011) Blockade of 5-HT2A receptors in the medial prefrontal cortex attenuates reinstatement of cue-elicited cocaine-seeking behavior in rats. Psychopharmacology 213:307–320PubMedGoogle Scholar
  175. Pushparaj A, Hamani C, Yu W, Shin DS, Kang B, Nobrega JN, Le Foll B (2013) Electrical stimulation of the insular region attenuates nicotine-taking and nicotine-seeking behaviors. Neuropsychopharmacology 38:690–698PubMedGoogle Scholar
  176. Ramirez DR, Bell GH, Lasseter HC, Xie X, Traina SA, Fuchs RA (2009) Dorsal hippocampal regulation of memory reconsolidation processes that facilitate drug context-induced cocaine-seeking behavior in rats. Eur J Neurosci 30:901–912PubMedGoogle Scholar
  177. Redila VA, Chavkin C (2008) Stress-induced reinstatement of cocaine seeking is mediated by the kappa opioid system. Psychopharmacology 200:59–70PubMedGoogle Scholar
  178. Reichel CM, Moussawi K, Do PH, Kalivas PW, See RE (2011) Chronic N-acetylcysteine during abstinence or extinction after cocaine self-administration produces enduring reductions in drug seeking. J Pharmacol Exp Ther 337:487–493PubMedGoogle Scholar
  179. Robinson TE, Berridge KC (1993) The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Rev 18:247–291PubMedGoogle Scholar
  180. Rocha A, Kalivas PW (2010) Role of the prefrontal cortex and nucleus accumbens in reinstating methamphetamine seeking. Eur J Neurosci 31:903–909PubMedGoogle Scholar
  181. Rogers JL, Ghee S, See RE (2008) The neural circuitry underlying reinstatement of heroin-seeking behavior in an animal model of relapse. Neuroscience 151:579–588PubMedGoogle Scholar
  182. Sacktor TC (2011) How does PKMzeta maintain long-term memory? Nat Rev Neurosci 12:9–15PubMedGoogle Scholar
  183. Sanchez H, Quinn JJ, Torregrossa MM, Taylor JR (2010) Reconsolidation of a cocaine-associated stimulus requires amygdalar protein kinase A. J Neurosci 30:4401–4407PubMedGoogle Scholar
  184. Sarter M, Bruno JP (2002) Animal models in biological psychiatry. In: D'haenen H, den Boer JA, Willner P (eds) Biological psychiatry. Willey, Hoboken, pp 1–8Google Scholar
  185. Schmidt HD, Anderson SM, Famous KR, Kumaresan V, Pierce RC (2005) Anatomy and pharmacology of cocaine priming-induced reinstatement of drug seeking. Eur J Pharmacol 526:65–76PubMedGoogle Scholar
  186. Schmidt HD, Famous KR, Pierce RC (2009) The limbic circuitry underlying cocaine seeking encompasses the PPTg/LDT. Eur J Neurosci 30:1358–1369PubMedGoogle Scholar
  187. See RE (2005) Neural substrates of cocaine-cue associations that trigger relapse. Eur J Pharmacol 526:140–146PubMedGoogle Scholar
  188. See RE (2009) Dopamine D1 receptor antagonism in the prelimbic cortex blocks the reinstatement of heroin-seeking in an animal model of relapse. Int J Neuropsychopharmacol 12:431–436PubMedGoogle Scholar
  189. Self DW (2004) Regulation of drug-taking and -seeking behaviors by neuroadaptations in the mesolimbic dopamine system. Neuropharmacology 47(Suppl 1):242–255PubMedGoogle Scholar
  190. Self DW, Genova LM, Hope BT, Barnhart WJ, Spencer JJ, Nestler EJ (1998) Involvement of cAMP-dependent protein kinase in the nucleus accumbens in cocaine self administration and relapse of cocaine-seeking behavior. J Neurosci 18:1848–1859PubMedGoogle Scholar
  191. Self DW, Nestler EJ (1998) Relapse to drug-seeking: neural and molecular mechanisms. Drug Alcohol Depend 51:49–69PubMedGoogle Scholar
  192. 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 290:213–242PubMedGoogle Scholar
  193. Shaham Y, Erb S, Stewart J (2000a) Stress-induced relapse to heroin and cocaine seeking in rats: a review. Brain Res Rev 33:13–33PubMedGoogle Scholar
  194. Shaham Y, Funk D, Erb S, Brown TJ, Walker CD, Stewart J (1997) Corticotropin-releasing factor, but not corticosterone, is involved in stress-induced relapse to heroin-seeking in rats. J Neurosci 17:2605–2614PubMedGoogle Scholar
  195. Shaham Y, Highfield D, Delfs JM, Leung S, Stewart J (2000b) Clonidine blocks stress-induced reinstatement of heroin seeking in rats: an effect independent of the locus coeruleus noradrenergic neurons. Eur J Neurosci 12:292–302PubMedGoogle Scholar
  196. Shaham Y, Shalev U, Lu L, de Wit H, Stewart J (2003) The reinstatement model of drug relapse: history, methodology and major findings. Psychopharmacology 168:3–20PubMedGoogle Scholar
  197. Shaham Y, Stewart J (1995) Stress reinstates heroin-seeking in drug-free animals: an effect mimicking heroin, not withdrawal. Psychopharmacology 119:334–341PubMedGoogle Scholar
  198. Shalev U, Erb S, Shaham Y (2010) Role of CRF and other neuropeptides in stress-induced reinstatement of drug seeking. Brain Res 1314:15–28PubMedGoogle Scholar
  199. Shalev U, Grimm JW, Shaham Y (2002) Neurobiology of relapse to heroin and cocaine seeking: a review. Pharmacol Rev 54:1–42PubMedGoogle Scholar
  200. 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 150:337–346PubMedGoogle Scholar
  201. Shalev U, Morales M, Hope B, Yap J, Shaham Y (2001) Time-dependent changes in extinction behavior and stress-induced reinstatement of drug seeking following withdrawal from heroin in rats. Psychopharmacology 156:98–107PubMedGoogle Scholar
  202. Shen H, Moussawi K, Zhou W, Toda S, Kalivas PW (2011) Heroin relapse requires long-term potentiation-like plasticity mediated by NMDA2b-containing receptors. Proc Natl Acad Sci U S A 108:19407–19412PubMedGoogle Scholar
  203. Shepard JD, Bossert JM, Liu SY, Shaham Y (2004) The anxiogenic drug yohimbine reinstates methamphetamine seeking in a rat model of drug relapse. Biol Psychiatry 55:1082–1089PubMedGoogle Scholar
  204. Simmons D, Self DW (2009) Role of mu- and delta-opioid receptors in the nucleus accumbens in cocaine-seeking behavior. Neuropsychopharmacology 34:1946–1957PubMedGoogle Scholar
  205. Simms JA, Haass-Koffler CL, Bito-Onon J, Li R, Bartlett SE (2012) Mifepristone in the central nucleus of the amygdala reduces yohimbine stress-induced reinstatement of ethanol-seeking. Neuropsychopharmacology 37:906–918PubMedGoogle Scholar
  206. Sinclair CM, Cleva RM, Hood LE, Olive MF, Gass JT (2012) mGluR5 receptors in the basolateral amygdala and nucleus accumbens regulate cue-induced reinstatement of ethanol-seeking behavior. Pharmacol Biochem Behav 101:329–335PubMedGoogle Scholar
  207. Sinha R, Catapano D, O'Mally S (1999) Stress-induced craving and stress responses in cocaine dependent individuals. Psychopharmacology 142:343–351PubMedGoogle Scholar
  208. Sinha R, Fuse T, Aubin LR, O'Malley SS (2000) Psychological stress, drug-related cues and cocaine craving. Psychopharmacology 152:140–148PubMedGoogle Scholar
  209. Sinha R, Garcia M, Paliwal P, Kreek MJ, Rounsaville BJ (2006) Stress-induced cocaine craving and hypothalamic-pituitary-adrenal responses are predictive of cocaine relapse outcomes. Arch Gen Psychiatry 63:324–331PubMedGoogle Scholar
  210. Sinha R, Kimmerling A, Doebrick C, Kosten TR (2007) Effects of lofexidine on stress-induced and cue-induced opioid craving and opioid abstinence rates: preliminary findings. Psychopharmacology 190:569–574PubMedGoogle Scholar
  211. Sinha R, Shaham Y, Heilig M (2011) Translational and reverse translational research on the role of stress in drug craving and relapse. Psychopharmacology 218:69–82PubMedGoogle Scholar
  212. Smith RJ, Aston-Jones G (2011) alpha(2) Adrenergic and imidazoline receptor agonists prevent cue-induced cocaine seeking. Biol Psychiatry 70:712–719PubMedGoogle Scholar
  213. Sorg BA (2012) Reconsolidation of drug memories. Neurosci Biobehav Rev 36:1400–1417PubMedGoogle Scholar
  214. Sorge RE, Rajabi H, Stewart J (2005) Rats maintained chronically on buprenorphine show reduced heroin and cocaine seeking in tests of extinction and drug-induced reinstatement. Neuropsychopharmacology 30:1681–1692PubMedGoogle Scholar
  215. 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 64:327–336PubMedGoogle Scholar
  216. 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 18:50–53PubMedGoogle Scholar
  217. Stewart J (1984) Reinstatement of heroin and cocaine self-administration behavior in the rat by intracerebral application of morphine in the ventral tegmental area. Pharmacol Biochem Behav 20:917–923PubMedGoogle Scholar
  218. Stewart J, de Wit H, Eikelboom R (1984) Role of unconditioned and conditioned drug effects in the self-administration of opiates and stimulants. Psychol Rev 91:251–268PubMedGoogle Scholar
  219. Stewart J, Vezina P (1988) A comparison of the effects of intra-accumbens injections of amphetamine and morphine on reinstatement of heroin intravenous self-administration behavior. Brain Res 457:287–294PubMedGoogle Scholar
  220. Stine SM, Southwick SM, Petrakis IL, Kosten TR, Charney DS, Krystal JH (2002) Yohimbine-induced withdrawal and anxiety symptoms in opioid-dependent patients. Biol Psychiatry 51:642–651PubMedGoogle Scholar
  221. Sun W, Rebec GV (2003) Lidocaine inactivation of ventral subiculum attenuates cocaine-seeking behavior in rats. J Neurosci 23:10258–10264PubMedGoogle Scholar
  222. Theberge FR, Li X, Kambhampati, S. , Pickens CL, Bossert JM, Baumann MH, Hutchinson MR, Rice RC, Watkins LR, Shaham Y (2013) Effect of chronic delivery of the Toll-like receptor 4 antagonist (+)-Naltrexone on incubation of heroin craving. Biol Psychiatry (in press)Google Scholar
  223. Theberge FR, Milton AL, Belin D, Lee JL, Everitt BJ (2010) The basolateral amygdala and nucleus accumbens core mediate dissociable aspects of drug memory reconsolidation. Learn Mem 17:444–453PubMedGoogle Scholar
  224. Theberge FR, Pickens CL, Goldart E, Fanous S, Hope BT, Liu QR, Shaham Y (2012) Association of time-dependent changes in mu opioid receptor mRNA, but not BDNF, TrkB, or MeCP2 mRNA and protein expression in the rat nucleus accumbens with incubation of heroin craving. Psychopharmacology 224:559–571PubMedGoogle Scholar
  225. Tobin S, Sedki F, Abbas Z, Shalev U (2013) Antagonism of the dopamine D1-like receptor in mesocorticolimbic nuclei attenuates acute food deprivation-induced reinstatement of heroin seeking in rats. Eur J Neurosci 37:972–981PubMedGoogle Scholar
  226. Torregrossa MM, Taylor JR (2013) Learning to forget: manipulating extinction and reconsolidation processes to treat addiction. Psychopharmacology (Berl) 226:659–672Google Scholar
  227. Umhau JC, Schwandt ML, Usala J, Geyer C, Singley E, George DT, Heilig M (2011) Pharmacologically induced alcohol craving in treatment seeking alcoholics correlates with alcoholism severity, but is insensitive to acamprosate. Neuropsychopharmacology (in press)Google Scholar
  228. Ungerstedt U (1971) Stereotaxic mapping of the monoamine pathways in the rat brain. Acta Physiol Scand Suppl 367:1–48PubMedGoogle Scholar
  229. Valdez GR, Platt DM, Rowlett JK, Ruedi-Bettschen D, Spealman RD (2007) Kappa agonist-induced reinstatement of cocaine seeking in squirrel monkeys: a role for opioid and stress-related mechanisms. J Pharmacol Exp Ther 323:525–533PubMedGoogle Scholar
  230. Van Pett K, Viau V, Bittencourt JC, Chan RK, Li HY, Arias C, Prins GS, Perrin M, Vale W, Sawchenko PE (2000) Distribution of mRNAs encoding CRF receptors in brain and pituitary of rat and mouse. J Comp Neurol 428:191–212PubMedGoogle Scholar
  231. Vorel SR, Liu X, Hayes RJ, Spector JA, Gardner EL (2001) Relapse to cocaine-seeking after hippocampal theta burst stimulation. Science 292:1175–1178PubMedGoogle Scholar
  232. Wang B, Shaham Y, Zitzman D, Azari S, Wise RA, You ZB (2005) Cocaine experience establishes control of midbrain glutamate and dopamine by corticotropin-releasing factor: a role in stress-induced relapse to drug seeking. J Neurosci 25:5389–5396PubMedGoogle Scholar
  233. Wang B, You ZB, Rice KC, Wise RA (2007) Stress-induced relapse to cocaine seeking: roles for the CRF(2) receptor and CRF-binding protein in the ventral tegmental area of the rat. Psychopharmacology 193:283–294PubMedGoogle Scholar
  234. Wang B, You ZB, Wise RA (2009) Reinstatement of cocaine seeking by hypocretin (orexin) in the ventral tegmental area: independence from the local corticotropin-releasing factor network. Biol Psychiatry 65:857–862PubMedGoogle Scholar
  235. Wang B, You ZB, Wise RA (2012) Heroin self-administration experience establishes control of ventral tegmental glutamate release by stress and environmental Stimuli. Neuropsychopharmacology (in press)Google Scholar
  236. Wang X, Luo YX, He YY, Li FQ, Shi HS, Xue LF, Xue YX, Lu L (2010) Nucleus accumbens core mammalian target of rapamycin signaling pathway is critical for cue-induced reinstatement of cocaine seeking in rats. J Neurosci 30:12632–12641PubMedGoogle Scholar
  237. Wang X, Moussawi K, Knackstedt L, Shen H, Kalivas PW (2013) Role of mGluR5 neurotransmission in reinstated cocaine-seeking. Addict Biol 18:40–49PubMedGoogle Scholar
  238. Weiss F (2005) Neurobiology of craving, conditioned reward and relapse. Curr Opin Pharmacol 5:9–19PubMedGoogle Scholar
  239. Weiss F, Maldonado-Vlaar CS, Parsons LH, Kerr TM, Smit 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 97:4321–4326PubMedGoogle Scholar
  240. Wells AM, Arguello AA, Xie X, Blanton MA, Lasseter HC, Reittinger AM, Fuchs RA (2012) Extracellular signal-regulated kinase in the basolateral amygdala, but not the nucleus accumbens core, is critical for context-response-cocaine memory reconsolidation in rats. Neuropsychopharmacology (in press)Google Scholar
  241. Wells AM, Lasseter HC, Xie X, Cowhey KE, Reittinger AM, Fuchs RA (2011) Interaction between the basolateral amygdala and dorsal hippocampus is critical for cocaine memory reconsolidation and subsequent drug context-induced cocaine-seeking behavior in rats. Learn Mem 18:693–702PubMedGoogle Scholar
  242. Wiggins A, Smith RJ, Shen HW, Kalivas PW (2011) Integrins modulate relapse to cocaine-seeking. J Neurosci 31:16177–16184PubMedGoogle Scholar
  243. Willcocks AL, McNally GP (2013) The role of medial prefrontal cortex in extinction and reinstatement of alcohol-seeking in rats. Eur J Neurosci 37:259–268PubMedGoogle Scholar
  244. Willins DL, Deutch AY, Roth BL (1997) Serotonin 5-HT2A receptors are expressed on pyramidal cells and interneurons in the rat cortex. Synapse 27:79–82PubMedGoogle Scholar
  245. Wise RA, Bozarth MA (1987) A psychomotor stimulant theory of addiction. Psychol Rev 94:469–492PubMedGoogle Scholar
  246. Xi ZX, Gilbert J, Campos AC, Kline N, Ashby CR Jr, Hagan JJ, Heidbreder CA, Gardner EL (2004) Blockade of mesolimbic dopamine D3 receptors inhibits stress-induced reinstatement of cocaine-seeking in rats. Psychopharmacology 176:57–65PubMedGoogle Scholar
  247. Xie X, Lasseter HC, Ramirez DR, Ponds KL, Wells AM, Fuchs RA (2012) Subregion-specific role of glutamate receptors in the nucleus accumbens on drug context-induced reinstatement of cocaine-seeking behavior in rats. Addict Biol 17:287–299PubMedGoogle Scholar
  248. Xie X, Ramirez DR, Lasseter HC, Fuchs RA (2010) Effects of mGluR1 antagonism in the dorsal hippocampus on drug context-induced reinstatement of cocaine-seeking behavior in rats. Psychopharmacology 208:1–11PubMedGoogle Scholar
  249. Xu YL, Reinscheid RK, Huitron-Resendiz S, Clark SD, Wang Z, Lin SH, Brucher FA, Zeng J, Ly NK, Henriksen SJ, de Lecea L, Civelli O (2004) Neuropeptide S: a neuropeptide promoting arousal and anxiolytic-like effects. Neuron 43:487–497PubMedGoogle Scholar
  250. Xue YX, Luo YX, Wu P, Shi HS, Xue LF, Chen C, Zhu WL, Ding ZB, Bao YP, Shi J, Epstein DH, Shaham Y, Lu L (2012) A memory retrieval-extinction procedure to prevent drug craving and relapse. Science 336:241–245PubMedGoogle Scholar
  251. Yamada H, Bruijnzeel AW (2011) Stimulation of alpha2-adrenergic receptors in the central nucleus of the amygdala attenuates stress-induced reinstatement of nicotine seeking in rats. Neuropharmacology 60:303–311PubMedGoogle Scholar
  252. Yun IA, Fields HL (2003) Basolateral amygdala lesions impair both cue- and cocaine-induced reinstatement in animals trained on a discriminative stimulus task. Neuroscience 121:747–757PubMedGoogle Scholar
  253. Zislis G, Desai TV, Prado M, Shah HP, Bruijnzeel AW (2007) Effects of the CRF receptor antagonist D-Phe CRF(12–41) and the alpha2-adrenergic receptor agonist clonidine on stress-induced reinstatement of nicotine-seeking behavior in rats. Neuropharmacology 53:958–966PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg (outside the USA) 2013

Authors and Affiliations

  1. 1.Behavioral Neuroscience Branch, Intramural Research ProgramNational Institute on Drug AbuseBaltimoreUSA

Personalised recommendations