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

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Abstract

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.

Objective

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.

Conclusions

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.

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Notes

  1. We do not provide a lengthy discussion on the validity of the reinstatement model, a topic which we and others have discussed in detail in previous reviews (Epstein et al. 2006; Epstein and Preston 2003; Katz and Higgins 2003; Shaham et al. 2003).

References

  • Abercrombie ED, Keller RW Jr, Zigmond MJ (1988) Characterization of hippocampal norepinephrine release as measured by microdialysis perfusion: pharmacological and behavioral studies. Neuroscience 27:897–904

    PubMed  CAS  Google Scholar 

  • Aghajanian GK, VanderMaelen CP (1982) alpha 2-adrenoceptor-mediated hyperpolarization of locus coeruleus neurons: intracellular studies in vivo. Science 215:1394–1396

    PubMed  CAS  Google Scholar 

  • 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 16:261–272

    PubMed  CAS  Google Scholar 

  • Akil H, Watson SJ, Young E, Lewis ME, Khachaturian H, Walker JM (1984) Endogenous opioids: biology and function. Annu Rev Neurosci 7:223–255

    PubMed  CAS  Google Scholar 

  • 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 31:363–374

    PubMed  CAS  Google Scholar 

  • 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 33:2483–2493

    PubMed  CAS  Google Scholar 

  • 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 36:871–878

    PubMed  CAS  Google Scholar 

  • Anderson SM, Bari AA, Pierce RC (2003) Administration of the D1-like dopamine receptor antagonist SCH-23390 into the medial nucleus accumbens shell attenuates cocaine priming-induced reinstatement of drug-seeking behavior in rats. Psychopharmacology 168:132–138

    PubMed  CAS  Google Scholar 

  • 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 30:1104–1110

    PubMed  CAS  Google Scholar 

  • Bachtell RK, Self DW (2009) Effects of adenosine A2A receptor stimulation on cocaine-seeking behavior in rats. Psychopharmacology (Berl) 206:469–478

    CAS  Google Scholar 

  • 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 183:41–53

    PubMed  CAS  Google Scholar 

  • 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 106:21–27

    PubMed  CAS  Google Scholar 

  • Badiani A, Belin D, Epstein D, Calu D, Shaham Y (2011) Opiate versus psychostimulant addiction: the differences do matter. Nat Rev Neurosci 12:685–700

    PubMed  CAS  Google Scholar 

  • 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 6:743–749

    PubMed  CAS  Google Scholar 

  • Bale TL, Vale WW (2004) CRF and CRF receptors: role in stress responsivity and other behaviors. Annu Rev Pharmacol Toxicol 44:525–557

    PubMed  CAS  Google Scholar 

  • 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) 224:377–385

    CAS  Google Scholar 

  • 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 101:288–296

    PubMed  CAS  Google Scholar 

  • Berk M, Malhi GS, Gray LJ, Dean OM (2013) The promise of N-acetylcysteine in neuropsychiatry. Trends Pharmacol Sci (in press)

  • 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 31:11396–11403

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Bossert JM, Liu SY, Lu L, Shaham Y (2004) A role of ventral tegmental area glutamate in contextual cue-induced relapse to heroin seeking. J Neurosci 24:10726–10730

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Bossert JM, Stern AL (2013) Role of ventral subiculum in context-induced reinstatement of heroin seeking in rats. Addict Biol (in press)

  • 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 14:420–422

    PubMed  CAS  Google Scholar 

  • 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 32:4982–4891

    PubMed  CAS  Google Scholar 

  • 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 206:51–60

    PubMed  CAS  Google Scholar 

  • Bouton ME, Swartzentruber D (1991) Sources of relapse after extinction in Pavlovian and instrumental learning. Clin Psychol Rev 11:123–140

    Google Scholar 

  • Bremner JD, Krystal JH, Southwick SM, Charney DS (1996a) Noradrenergic mechanisms in stress and anxiety: I. preclinical studies. Synapse 23:28–38

    PubMed  CAS  Google Scholar 

  • Bremner JD, Krystal JH, Southwick SM, Charney DS (1996b) Noradrenergic mechanisms in stress and anxiety: II. clinical studies. Synapse 23:39–51

    PubMed  CAS  Google Scholar 

  • Bruchas MR, Land BB, Chavkin C (2010) The dynorphin/kappa opioid system as a modulator of stress-induced and pro-addictive behaviors. Brain Res 1314:44–55

    PubMed  CAS  Google Scholar 

  • Bruijnzeel AW (2012) Tobacco addiction and the dysregulation of brain stress systems. Neurosci Biobehav Rev 36:1418–1441

    PubMed  CAS  Google Scholar 

  • 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 213:19–27

    PubMed  CAS  Google Scholar 

  • 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)

  • 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 34:2125–2134

    PubMed  CAS  Google Scholar 

  • Capriles N, Rodaros D, Sorge RE, Stewart J (2003) A role for the prefrontal cortex in stress- and cocaine-induced reinstatement of cocaine seeking in rats. Psychopharmacology 168:66–74

    PubMed  CAS  Google Scholar 

  • 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 569:84–89

    PubMed  CAS  Google Scholar 

  • Carlezon WA Jr, Duman RS, Nestler EJ (2005) The many faces of CREB. Trends Neurosci 28:436–445

    PubMed  CAS  Google Scholar 

  • Chaudhri N, Sahuque LL, Janak PH (2008) Context-induced relapse of conditioned behavioral responding to ethanol cues in rats. Biol Psychiatry 64:203–210

    PubMed  CAS  Google Scholar 

  • 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 207:303–314

    PubMed  CAS  Google Scholar 

  • 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 35:783–791

    PubMed  CAS  Google Scholar 

  • 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 68:303–305

    PubMed  CAS  Google Scholar 

  • Cornish JL, Duffy P, Kalivas PW (1999) A role for nucleus accumbens glutamate transmission in the relapse to cocaine-seeking behavior. Neuroscience 93:1359–1367

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Crombag H, Bossert JM, Koya E, Shaham Y (2008) Context-induced relapse to drug seeking: a review. Trans R Soc Lond B Biol Sci 363:3233–3243

    Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • 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 95:322–327

    PubMed  Google Scholar 

  • 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 10:3565–3571

    PubMed  Google Scholar 

  • de Wit H (1996) Priming effects with drugs and other reinforcers. Exp Clin Psychopharmacol 4:5–10

    Google Scholar 

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

    PubMed  Google Scholar 

  • Diergaarde L, Schoffelmeer AN, De Vries TJ (2008) Pharmacological manipulation of memory reconsolidation: towards a novel treatment of pathogenic memories. Eur J Pharmacol 585:453–457

    PubMed  CAS  Google Scholar 

  • Dudai Y (2006) Reconsolidation: the advantage of being refocused. Curr Opin Neurobiol 16:174–178

    PubMed  CAS  Google Scholar 

  • 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 189:1–16

    PubMed  CAS  Google Scholar 

  • Epstein DH, Preston KL (2003) The reinstatement model and relapse prevention: a clinical perspective. Psychopharmacology 168:31–41

    PubMed  CAS  Google Scholar 

  • 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 23:138–150

    PubMed  CAS  Google Scholar 

  • 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 18:5529–5536

    PubMed  CAS  Google Scholar 

  • 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 4:289–303

    PubMed  CAS  Google Scholar 

  • 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:RC35

    PubMed  CAS  Google Scholar 

  • Ettenberg A (2009) The runway model of drug self-administration. Pharmacol Biochem Behav 91:271–277

    PubMed  CAS  Google Scholar 

  • 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 44:191–198

    PubMed  CAS  Google Scholar 

  • Ettenberg A, MacConell LA, Geist TD (1996) Effects of haloperidol in a response-reinstatement model of heroin relapse. Psychopharmacology 124:205–210

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Everitt BJ, Wolf ME (2002) Psychomotor stimulant addiction: a neural systems perspective. J Neurosci 22:3312–3320

    PubMed  CAS  Google Scholar 

  • Feltenstein MW, See RE (2008) The neurocircuitry of addiction: an overview. Br J Pharmacol 154:261–274

    PubMed  CAS  Google Scholar 

  • 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 20:482–487

    PubMed  CAS  Google Scholar 

  • 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 33:1402–1412

    PubMed  CAS  Google Scholar 

  • Forget B, Pushparaj A, Le Foll B (2010) Granular insular cortex inactivation as a novel therapeutic strategy for nicotine addiction. Biol Psychiatry 68:265–271

    PubMed  CAS  Google Scholar 

  • 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 36:351–360

    PubMed  CAS  Google Scholar 

  • 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 26:958–972

    PubMed  Google Scholar 

  • 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 30:889–900

    PubMed  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • 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)

  • 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 24:6600–6610

    PubMed  CAS  Google Scholar 

  • Fuchs RA, Ramirez DR, Bell GH (2008) Nucleus accumbens shell and core involvement in drug context-induced reinstatement of cocaine seeking in rats. Psychopharmacology 200:545–556

    PubMed  CAS  Google Scholar 

  • 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 1417:27–35

    PubMed  CAS  Google Scholar 

  • Gaffan D, Murray EA, Fabre-Thorpe M (1993) Interaction of the amygdala with the frontal lobe in reward memory. Eur J Neurosci 5:968–975

    PubMed  CAS  Google Scholar 

  • Geisler S, Derst C, Veh RW, Zahm DS (2007) Glutamatergic afferents of the ventral tegmental area in the rat. J Neurosci 27:5730–5743

    PubMed  CAS  Google Scholar 

  • Geyer MA, Markou A (1995) Animal models of psychiatric disorders. In: Bloom FE, Kupfer DJ (eds) Psychopharmacology. Raven Press, New York, pp 787–798

    Google Scholar 

  • 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 77:867–872

    PubMed  CAS  Google Scholar 

  • 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 149–163

    Google Scholar 

  • Grant JE, Odlaug BL, Kim SW (2010) A double-blind, placebo-controlled study of N-acetyl cysteine plus naltrexone for methamphetamine dependence. Eur Neuropsychopharmacol 20:823–828

    PubMed  CAS  Google Scholar 

  • Graziane NM, Polter AM, Briand LA, Pierce RC, Kauer JA (2013) Kappa opioid receptors regulate stress-induced cocaine seeking and synaptic plasticity. Neuron 77:942–954

    PubMed  CAS  Google Scholar 

  • Greenwald MK, Lundahl LH, Steinmiller CL (2013) Yohimbine increases opioid-seeking behavior in heroin-dependent, buprenorphine-maintained individuals. Psychopharmacology (Berl) 225:811–824

    CAS  Google Scholar 

  • Grimm JW, Hope BT, Wise RA, Shaham Y (2001) Incubation of cocaine craving after withdrawal. Nature 412:141–142

    PubMed  CAS  Google Scholar 

  • 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 23:742–747

    PubMed  CAS  Google Scholar 

  • 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 23:103–120

    PubMed  CAS  Google Scholar 

  • Hamlin AS, Clemens KJ, Choi EA, McNally GP (2009) Paraventricular thalamus mediates context-induced reinstatement (renewal) of extinguished reward seeking. Eur J Neurosci 29:802–812

    PubMed  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Hamlin AS, Newby J, McNally GP (2007) The neural correlates and role of D1 dopamine receptors in renewal of extinguished alcohol-seeking. Neuroscience 146:525–536

    PubMed  CAS  Google Scholar 

  • 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 25:320–331

    PubMed  CAS  Google Scholar 

  • Hunt WA, Barnett LW, Branch LG (1971) Relapse rates in addiction programs. J Clin Psychol 27:455–456

    PubMed  CAS  Google Scholar 

  • Hutton-Bedbrook K, McNally GP (2013) The promises and pitfalls of retrieval-extinction procedures in preventing relapse to drug seeking. Front Psychiatry 4:14

    PubMed  Google Scholar 

  • 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 14:684–690

    PubMed  CAS  Google Scholar 

  • Jobes ML, Ghitza UE, Epstein DH, Phillips KA, Heishman SJ, Preston KL (2011) Clonidine blocks stress-induced craving in cocaine users. Psychopharmacology (Berl) 218:83–88

    CAS  Google Scholar 

  • Julius D (1976) NIDA’s naltrexone research program. NIDA Res Monogr 9:5–11

    PubMed  Google Scholar 

  • Kalivas PW, Lalumiere RT, Knackstedt L, Shen H (2009) Glutamate transmission in addiction. Neuropharmacology 56(Suppl 1):169–173

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • 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 107:19567–19572

    PubMed  CAS  Google Scholar 

  • 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 226:347–355

    PubMed  CAS  Google Scholar 

  • Katz J, Higgins S (2003) The validity of the reinstatement model of craving and relapse to drug use. Psychopharmacology 168:21–30

    PubMed  CAS  Google Scholar 

  • Kelley AE, Berridge KC (2002) The neuroscience of natural rewards: relevance to addictive drugs. J Neurosci 22:3306–3311

    PubMed  CAS  Google Scholar 

  • 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 65:841–845

    PubMed  CAS  Google Scholar 

  • 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 12:1069–1073

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • 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 202:238–244

    PubMed  CAS  Google Scholar 

  • 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 71:978–986

    PubMed  CAS  Google Scholar 

  • LaLumiere RT, Kalivas PW (2008) Glutamate release in the nucleus accumbens core is necessary for heroin seeking. J Neurosci 28:3170–3177

    PubMed  CAS  Google Scholar 

  • 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 164:1115–1117

    PubMed  Google Scholar 

  • 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 31:16447–16457

    PubMed  CAS  Google Scholar 

  • 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 30:1370–1381

    PubMed  Google Scholar 

  • 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 36:711–720

    PubMed  CAS  Google Scholar 

  • 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 171:830–839

    PubMed  CAS  Google Scholar 

  • Le A, Shaham Y (2002) Neurobiology of relapse to alcohol in rats. Pharmacol Ther 94:137–156

    PubMed  CAS  Google Scholar 

  • 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)

  • 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 204:477–488

    Google Scholar 

  • 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 218:89–99

    PubMed  CAS  Google Scholar 

  • 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 22:7844–7849

    PubMed  CAS  Google Scholar 

  • 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 179:366–373

    PubMed  CAS  Google Scholar 

  • 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 21:435–444

    PubMed  CAS  Google Scholar 

  • 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 29:686–693

    PubMed  CAS  Google Scholar 

  • Lee JL, Di Ciano P, Thomas KL, Everitt BJ (2005) Disrupting reconsolidation of drug memories reduces cocaine-seeking behavior. Neuron 47:795–801

    PubMed  CAS  Google Scholar 

  • Lee JL, Milton AL, Everitt BJ (2006) Cue-induced cocaine seeking and relapse are reduced by disruption of drug memory reconsolidation. J Neurosci 26:5881–5887

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • 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 29:1312–1320

    PubMed  CAS  Google Scholar 

  • 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 33:1130–1142

    PubMed  CAS  Google Scholar 

  • 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 114:1368–1380

    PubMed  CAS  Google Scholar 

  • 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 146:1677–1688

    PubMed  CAS  Google Scholar 

  • 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) 196:365–375

    CAS  Google Scholar 

  • 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 22:7856–7861

    PubMed  CAS  Google Scholar 

  • 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 24:1604–1611

    PubMed  CAS  Google Scholar 

  • 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 66:137–145

    PubMed  CAS  Google Scholar 

  • 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 333:353–357

    PubMed  CAS  Google Scholar 

  • 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 319:561–569

    PubMed  CAS  Google Scholar 

  • 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 32:13309–13326

    PubMed  CAS  Google Scholar 

  • 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)

  • Mahler SV, Smith RJ, Aston-Jones G (2012b) Interactions between VTA orexin and glutamate in cue-induced reinstatement of cocaine seeking in rats. Psychopharmacology 226:687–698

    PubMed  Google Scholar 

  • Marchant NJ, Furlong TM, McNally GP (2010) Medial dorsal hypothalamus mediates the inhibition of reward seeking after extinction. J Neurosci 30:14102–14115

    PubMed  CAS  Google Scholar 

  • Marchant NJ, Hamlin AS, McNally GP (2009) Lateral hypothalamus is required for context-induced reinstatement of extinguished reward seeking. J Neurosci 29:1331–1342

    PubMed  CAS  Google Scholar 

  • Marchant NJ, Li X, Shaham Y (2013) Recent developments in animal models of drug relapse. Curr Opin Neurobiol (in press)

  • Marchant NJ, Millan EZ, McNally GP (2012) The hypothalamus and the neurobiology of drug seeking. Cell Mol Life Sci 69:581–597

    PubMed  CAS  Google Scholar 

  • 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 211:58–63

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • McGaugh JL (1966) Time-dependent processes in memory storage. Science 153:1351–1358

    PubMed  CAS  Google Scholar 

  • McGaugh JL (2000) Memory—a century of consolidation. Science 287:248–251

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • 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 7:754–763

    PubMed  CAS  Google Scholar 

  • Millan EZ, Furlong TM, McNally GP (2010) Accumbens shell–hypothalamus interactions mediate extinction of alcohol seeking. J Neurosci 30:4626–4635

    PubMed  CAS  Google Scholar 

  • Millan EZ, Marchant NJ, McNally GP (2011) Extinction of drug seeking. Behav Brain Res 217:454–462

    PubMed  CAS  Google Scholar 

  • Millan EZ, McNally GP (2011) Accumbens shell AMPA receptors mediate expression of extinguished reward seeking through interactions with basolateral amygdala. Learn Mem 18:414–421

    PubMed  CAS  Google Scholar 

  • Millan EZ, Milligan-Saville J, McNally GP (2013) Memory retrieval, extinction, and reinstatement of alcohol seeking. Neurobiol Learn Mem 101:26–32

    PubMed  CAS  Google Scholar 

  • 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) 156:58–62

    CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Milton AL, Everitt BJ (2012) The persistence of maladaptive memory: addiction, drug memories and anti-relapse treatments. Neurosci Biobehav Rev 36:1119–1139

    PubMed  Google Scholar 

  • 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 28:8230–8237

    PubMed  CAS  Google Scholar 

  • Misanin JR, Miller RR, Lewis DJ (1968) Retrograde amnesia produced by electroconvulsive shock after reactivation of a consolidated memory trace. Science 160:554–555

    PubMed  CAS  Google Scholar 

  • Monfils MH, Cowansage KK, Klann E, LeDoux JE (2009) Extinction-reconsolidation boundaries: key to persistent attenuation of fear memories. Science 324:951–955

    PubMed  CAS  Google Scholar 

  • 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 108:385–390

    PubMed  CAS  Google Scholar 

  • Mueller D, Stewart J (2000) Cocaine-induced conditioned place preference: reinstatement by priming injections of cocaine after extinction. Behav Brain Res 115:39–47

    PubMed  CAS  Google Scholar 

  • Nader K, Schafe GE, LeDoux JE (2000) The labile nature of consolidation theory. Nat Rev Neurosci 1:216–219

    PubMed  CAS  Google Scholar 

  • 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 89:18–45

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • O'Brien CP (2005) Anticraving medications for relapse prevention: a possible new class of psychoactive medications. Am J Psychiatry 162:1423–1431

    PubMed  Google Scholar 

  • O'Brien CP, Childress AR, McLellan AT, Ehrman R (1992) Classical conditioning in drug-dependent humans. Ann N Y Acad Sci 654:400–415

    PubMed  Google Scholar 

  • 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 208:365–376

    PubMed  Google Scholar 

  • O'Neill CE, LeTendre ML, Bachtell RK (2012) Adenosine A2A receptors in the nucleus accumbens bi-directionally alter cocaine seeking in rats. Neuropsychopharmacology 37:1245–1256

    PubMed  Google Scholar 

  • Paxinos G, Watson C (2005) The rat brain in stereotaxic coordinates, 5th edn. Elsevier Academic Press, Amsterdam

    Google Scholar 

  • 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 35:2037–2048

    PubMed  CAS  Google Scholar 

  • Peters J, Kalivas PW, Quirk GJ (2009) Extinction circuits for fear and addiction overlap in prefrontal cortex. Learn Mem 16:279–288

    PubMed  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Pickens CL, Airavaara M, Theberge F, Fanous S, Hope BT, Shaham Y (2011) Neurobiology of incubation of drug craving. Trends Neurosci 34:411–420

    PubMed  CAS  Google Scholar 

  • 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 213:307–320

    PubMed  CAS  Google Scholar 

  • 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 38:690–698

    PubMed  CAS  Google Scholar 

  • 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 30:901–912

    PubMed  Google Scholar 

  • Redila VA, Chavkin C (2008) Stress-induced reinstatement of cocaine seeking is mediated by the kappa opioid system. Psychopharmacology 200:59–70

    PubMed  CAS  Google Scholar 

  • 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 337:487–493

    PubMed  CAS  Google Scholar 

  • Robinson TE, Berridge KC (1993) The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Rev 18:247–291

    PubMed  CAS  Google Scholar 

  • Rocha A, Kalivas PW (2010) Role of the prefrontal cortex and nucleus accumbens in reinstating methamphetamine seeking. Eur J Neurosci 31:903–909

    PubMed  Google Scholar 

  • Rogers JL, Ghee S, See RE (2008) The neural circuitry underlying reinstatement of heroin-seeking behavior in an animal model of relapse. Neuroscience 151:579–588

    PubMed  CAS  Google Scholar 

  • Sacktor TC (2011) How does PKMzeta maintain long-term memory? Nat Rev Neurosci 12:9–15

    PubMed  CAS  Google Scholar 

  • Sanchez H, Quinn JJ, Torregrossa MM, Taylor JR (2010) Reconsolidation of a cocaine-associated stimulus requires amygdalar protein kinase A. J Neurosci 30:4401–4407

    PubMed  CAS  Google Scholar 

  • 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 1–8

    Google Scholar 

  • 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 526:65–76

    PubMed  CAS  Google Scholar 

  • Schmidt HD, Famous KR, Pierce RC (2009) The limbic circuitry underlying cocaine seeking encompasses the PPTg/LDT. Eur J Neurosci 30:1358–1369

    PubMed  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • 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 12:431–436

    PubMed  CAS  Google Scholar 

  • Self DW (2004) Regulation of drug-taking and -seeking behaviors by neuroadaptations in the mesolimbic dopamine system. Neuropharmacology 47(Suppl 1):242–255

    PubMed  CAS  Google Scholar 

  • Self DW, Genova LM, Hope BT, Barnhart WJ, Spencer JJ, Nestler EJ (1998) Involvement of cAMP-dependent protein kinase in the nucleus accumbens in cocaine self administration and relapse of cocaine-seeking behavior. J Neurosci 18:1848–1859

    PubMed  CAS  Google Scholar 

  • Self DW, Nestler EJ (1998) Relapse to drug-seeking: neural and molecular mechanisms. Drug Alcohol Depend 51:49–69

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Shaham Y, Erb S, Stewart J (2000a) Stress-induced relapse to heroin and cocaine seeking in rats: a review. Brain Res Rev 33:13–33

    PubMed  CAS  Google Scholar 

  • 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 17:2605–2614

    PubMed  CAS  Google Scholar 

  • 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 12:292–302

    PubMed  CAS  Google Scholar 

  • Shaham Y, Shalev U, Lu L, de Wit H, Stewart J (2003) The reinstatement model of drug relapse: history, methodology and major findings. Psychopharmacology 168:3–20

    PubMed  CAS  Google Scholar 

  • Shaham Y, Stewart J (1995) Stress reinstates heroin-seeking in drug-free animals: an effect mimicking heroin, not withdrawal. Psychopharmacology 119:334–341

    PubMed  CAS  Google Scholar 

  • Shalev U, Erb S, Shaham Y (2010) Role of CRF and other neuropeptides in stress-induced reinstatement of drug seeking. Brain Res 1314:15–28

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • 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 150:337–346

    PubMed  CAS  Google Scholar 

  • 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 156:98–107

    PubMed  CAS  Google Scholar 

  • 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 108:19407–19412

    PubMed  CAS  Google Scholar 

  • 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 55:1082–1089

    PubMed  CAS  Google Scholar 

  • Simmons D, Self DW (2009) Role of mu- and delta-opioid receptors in the nucleus accumbens in cocaine-seeking behavior. Neuropsychopharmacology 34:1946–1957

    PubMed  CAS  Google Scholar 

  • 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 37:906–918

    PubMed  CAS  Google Scholar 

  • 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 101:329–335

    PubMed  CAS  Google Scholar 

  • Sinha R, Catapano D, O'Mally S (1999) Stress-induced craving and stress responses in cocaine dependent individuals. Psychopharmacology 142:343–351

    PubMed  CAS  Google Scholar 

  • Sinha R, Fuse T, Aubin LR, O'Malley SS (2000) Psychological stress, drug-related cues and cocaine craving. Psychopharmacology 152:140–148

    PubMed  CAS  Google Scholar 

  • 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 63:324–331

    PubMed  Google Scholar 

  • 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 190:569–574

    PubMed  CAS  Google Scholar 

  • Sinha R, Shaham Y, Heilig M (2011) Translational and reverse translational research on the role of stress in drug craving and relapse. Psychopharmacology 218:69–82

    PubMed  CAS  Google Scholar 

  • Smith RJ, Aston-Jones G (2011) alpha(2) Adrenergic and imidazoline receptor agonists prevent cue-induced cocaine seeking. Biol Psychiatry 70:712–719

    PubMed  CAS  Google Scholar 

  • Sorg BA (2012) Reconsolidation of drug memories. Neurosci Biobehav Rev 36:1400–1417

    PubMed  Google Scholar 

  • 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 30:1681–1692

    PubMed  CAS  Google Scholar 

  • Spealman RD, Barrett-Larimore RL, Rowlett JK, Platt DM, Khroyan TV (1999) Pharmacological and environmental determinants of relapse to cocaine-seeking behavior. Pharmacol Biochem Behav 64:327–336

    PubMed  CAS  Google Scholar 

  • 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 18:50–53

    PubMed  CAS  Google Scholar 

  • 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 20:917–923

    PubMed  CAS  Google Scholar 

  • 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 91:251–268

    PubMed  CAS  Google Scholar 

  • 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 457:287–294

    PubMed  CAS  Google Scholar 

  • 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 51:642–651

    PubMed  CAS  Google Scholar 

  • Sun W, Rebec GV (2003) Lidocaine inactivation of ventral subiculum attenuates cocaine-seeking behavior in rats. J Neurosci 23:10258–10264

    PubMed  CAS  Google Scholar 

  • 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)

  • 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 17:444–453

    PubMed  CAS  Google Scholar 

  • 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 224:559–571

    PubMed  CAS  Google Scholar 

  • 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 37:972–981

    PubMed  Google Scholar 

  • Torregrossa MM, Taylor JR (2013) Learning to forget: manipulating extinction and reconsolidation processes to treat addiction. Psychopharmacology (Berl) 226:659–672

    CAS  Google Scholar 

  • 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)

  • Ungerstedt U (1971) Stereotaxic mapping of the monoamine pathways in the rat brain. Acta Physiol Scand Suppl 367:1–48

    PubMed  CAS  Google Scholar 

  • 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 323:525–533

    PubMed  CAS  Google Scholar 

  • 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 428:191–212

    PubMed  Google Scholar 

  • Vorel SR, Liu X, Hayes RJ, Spector JA, Gardner EL (2001) Relapse to cocaine-seeking after hippocampal theta burst stimulation. Science 292:1175–1178

    PubMed  CAS  Google Scholar 

  • 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 25:5389–5396

    PubMed  CAS  Google Scholar 

  • 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 193:283–294

    PubMed  CAS  Google Scholar 

  • 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 65:857–862

    PubMed  CAS  Google Scholar 

  • 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)

  • 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 30:12632–12641

    PubMed  CAS  Google Scholar 

  • Wang X, Moussawi K, Knackstedt L, Shen H, Kalivas PW (2013) Role of mGluR5 neurotransmission in reinstated cocaine-seeking. Addict Biol 18:40–49

    PubMed  Google Scholar 

  • Weiss F (2005) Neurobiology of craving, conditioned reward and relapse. Curr Opin Pharmacol 5:9–19

    PubMed  CAS  Google Scholar 

  • 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 97:4321–4326

    PubMed  CAS  Google Scholar 

  • 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)

  • 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 18:693–702

    PubMed  CAS  Google Scholar 

  • Wiggins A, Smith RJ, Shen HW, Kalivas PW (2011) Integrins modulate relapse to cocaine-seeking. J Neurosci 31:16177–16184

    PubMed  CAS  Google Scholar 

  • Willcocks AL, McNally GP (2013) The role of medial prefrontal cortex in extinction and reinstatement of alcohol-seeking in rats. Eur J Neurosci 37:259–268

    PubMed  Google Scholar 

  • Willins DL, Deutch AY, Roth BL (1997) Serotonin 5-HT2A receptors are expressed on pyramidal cells and interneurons in the rat cortex. Synapse 27:79–82

    PubMed  CAS  Google Scholar 

  • Wise RA, Bozarth MA (1987) A psychomotor stimulant theory of addiction. Psychol Rev 94:469–492

    PubMed  CAS  Google Scholar 

  • 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 176:57–65

    PubMed  CAS  Google Scholar 

  • 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 17:287–299

    PubMed  CAS  Google Scholar 

  • 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 208:1–11

    PubMed  CAS  Google Scholar 

  • 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 43:487–497

    PubMed  CAS  Google Scholar 

  • 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 336:241–245

    PubMed  CAS  Google Scholar 

  • 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 60:303–311

    PubMed  CAS  Google Scholar 

  • Yun IA, Fields HL (2003) Basolateral amygdala lesions impair both cue- and cocaine-induced reinstatement in animals trained on a discriminative stimulus task. Neuroscience 121:747–757

    PubMed  CAS  Google Scholar 

  • 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 53:958–966

    PubMed  CAS  Google Scholar 

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Acknowledgments

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.

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  1. Behavioral Neuroscience Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD, USA

    Jennifer M. Bossert, Nathan J. Marchant, Donna J. Calu & Yavin Shaham

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  1. Jennifer M. Bossert
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  2. Nathan J. Marchant
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  3. Donna J. Calu
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  4. Yavin Shaham
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Correspondence to Jennifer M. Bossert or Yavin Shaham.

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Bossert, J.M., Marchant, N.J., Calu, D.J. et al. The reinstatement model of drug relapse: recent neurobiological findings, emerging research topics, and translational research. Psychopharmacology 229, 453–476 (2013). https://doi.org/10.1007/s00213-013-3120-y

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  • DOI: https://doi.org/10.1007/s00213-013-3120-y

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