, Volume 189, Issue 1, pp 1–16 | Cite as

Toward a model of drug relapse: an assessment of the validity of the reinstatement procedure

  • David H. Epstein
  • Kenzie L. Preston
  • Jane Stewart
  • Yavin Shaham


Background and rationale

The reinstatement model is widely used to study relapse to drug addiction. However, the model’s validity is open to question.


We assess the reinstatement model in terms of criterion and construct validity.

Research highlights and conclusions

We find that the reinstatement model has adequate criterion validity in the broad sense of the term, as evidenced by the fact that reinstatement in laboratory animals is induced by conditions reported to provoke relapse in humans. The model’s criterion validity in the narrower sense, as a medication screen, seems promising for relapse to heroin, nicotine, and alcohol. For relapse to cocaine, criterion validity has not yet been established primarily because clinical studies have examined medication’s effects on reductions in cocaine intake rather than relapse during abstinence. The model’s construct validity faces more substantial challenges and is yet to be established, but we argue that some of the criticisms of the model in this regard may have been overstated.


Conditioned drug cues Drug priming Construct validity Incubation Criterion validity Reinstatement Relapse Review Stress 



D.E., K.P., and Y.S. receive their financial support from the Intramural Research Program of the NIH National Institute on Drug Abuse; J.S. receives her financial support from the Canadian Institutes of Health Research. We thank Roy Wise and the reviewers for critical comments on earlier versions of this paper.


  1. Antelman SM, Levine J, Gershon S (2000) Time-dependent sensitization: the odyssey of a scientific heresy from the laboratory to the door of the clinic. Mol Psychiatry 5:350–356PubMedGoogle Scholar
  2. 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
  3. 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
  4. Bindra D, Cameron L (1953) Changes in experimentally produced anxiety with the passage of time: incubation effect. J Exp Psychol 45:197–203PubMedGoogle Scholar
  5. 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
  6. 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
  7. 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 of heroin seeking. Neuropsychopharmacology 31:2197–3109PubMedGoogle Scholar
  8. Bouton ME (1993) Context, time, and memory retrieval in the interference paradigms of Pavlovian learning. Psychol Bull 114:80–99PubMedGoogle Scholar
  9. Bouton ME, Swartzentruber D (1991) Sources of relapse after extinction in Pavlovian and instrumental learning. Clin Psychol Rev 11:123–140Google Scholar
  10. Brady JV (1951) The effect of electro-convulsive shock on a conditioned emotional response: the permanence of the effect. J Comp Physiol Psychol 44:507–511PubMedGoogle Scholar
  11. Bremner JD, Krystal JH, Southwick SM, Charney DS (1996a) Noradrenergic mechanisms in stress and anxiety: I. preclinical studies. Synapse 23:28–38PubMedGoogle Scholar
  12. Bremner JD, Krystal JH, Southwick SM, Charney DS (1996b) Noradrenergic mechanisms in stress and anxiety: II. clinical studies. Synapse 23:39–51PubMedGoogle Scholar
  13. Burmeister JJ, Lungren EM, Neisewander JL (2003) Effects of fluoxetine and d-fenfluramine on cocaine-seeking behavior in rats. Psychopharmacology (Berl) 168:146–154Google Scholar
  14. Cannon WB (1935) Stresses and strains of homeostasis. Am J Med Sci 189:1–14Google Scholar
  15. Carroll ME (1985) The role of food deprivation in the maintenance and reinstatement of cocaine-seeking behavior in rats. Drug Alcohol Depend 16:95–109PubMedGoogle Scholar
  16. Carter BL, Tiffany ST (1999) Meta-analysis of cue-reactivity in addiction research. Addiction 94:327–340PubMedGoogle Scholar
  17. Childress AR, Ehrman R, Rohsenow DJ, Robbins SJ, O’Brien CP (1992) Classically conditioned factors in drug dependence. In: Lowinson JW, Luiz P, Millman RB, Langard G (eds) Substance abuse: a comprehensive textbook. Williams and Wilkins, Baltimore, pp 56–69Google Scholar
  18. Childress AR, Hole AV, Ehrman RN, Robbins SJ, McLellan AT, O’Brien CP (1993) Cue reactivity and cue reactivity interventions in drug dependence. NIDA Res Monogr 137:73–95PubMedGoogle Scholar
  19. Childress AR, Mozley PD, McElgin W, Fitzgerald J, Reivich M, O’Brien CP (1999) Limbic activation during cue-induced cocaine craving. Am J Psychiatry 156:11–18PubMedGoogle Scholar
  20. Chrousos GP, Gold PW (1992) The concepts of stress and stress system disorders. Overview of physical and behavioral homeostasis. JAMA 267:1244–1452PubMedGoogle Scholar
  21. Ciccocioppo R, Sanna PP, Weiss F (2001) Cocaine-predictive stimulus induces drug-seeking behavior and neural activation in limbic brain regions after multiple months of abstinence: reversal by D(1) antagonists. Proc Natl Acad Sci USA 98:1976–1981PubMedGoogle Scholar
  22. Ciccocioppo R, Lin D, Martin-Fardon R, Weiss F (2003) Reinstatement of ethanol-seeking behavior by drug cues following single versus multiple ethanol intoxication in the rat: effects of naltrexone. Psychopharmacology (Berl) 168:208–215Google Scholar
  23. Cohen F, Horowitz MJ, Lazarus RS, Moos RH, Robbins LN, Rose RM, Rutter M (1982) Panel report on psychosocial and modifiers of stress. In: Eliott GR, Eisdorfer C (eds) Stress and human health. Springer, Berlin Heidelberg New York, pp 147–188Google Scholar
  24. Cohen S, Evans GW, Stokols D, Krantz DS (1986) Behavior, health, and environmental stress. Plenum, New YorkGoogle Scholar
  25. Comer SD, Sullivan MA, Yu E, Rothenberg JL, Kleber HD, Kampman K, Dackis C, O’Brien CP (2006) Injectable, sustained-release naltrexone for the treatment of opioid dependence: a randomized, placebo-controlled trial. Arch Gen Psychiatry 63:210–218PubMedGoogle Scholar
  26. Crombag HS, Shaham Y (2002) Renewal of drug seeking by contextual cues after prolonged extinction in rats. Behav Neurosci 116:169–173PubMedGoogle Scholar
  27. Cronbach LJ, Meehl PE (1955) Construct validity in psychological tests. Psychol Bull 52:281–302PubMedGoogle Scholar
  28. Curran T, Morgan JI (1995) Fos: an immediate-early transcription factor in neurons. J Neurobiol 26:403–412PubMedGoogle Scholar
  29. Dallman MF, Akana SF, Bhatnagar S, Bell ME, Choi S, Chu A, Horsley C, Levin N, Meijer O, Soriano LR, Strack AM, Viau V (1999) Starvation: early signals, sensors, and sequelae. Endocrinology 140:4015–4023PubMedGoogle Scholar
  30. Davidson JR, Stein DJ, Shalev AY, Yehuda R (2004) Posttraumatic stress disorder: acquisition, recognition, course, and treatment. J Neuropsychiatry Clin Neurosci 16:135–147PubMedGoogle Scholar
  31. Davis WM, Smith SG (1976) Role of conditioned reinforcers in the initiation, maintenance and extinction of drug-seeking behavior. Pavlovian J Biol Sci 11:222–236Google Scholar
  32. Davis M, Myers KM, Chhatwal J, Ressler KJ (2006) Pharmacological treatments that facilitate extinction of fear: relevance to psychotherapy. NeuroRx 3:82–96PubMedGoogle Scholar
  33. 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
  34. De Vries TJ, de Vries W, Janssen MC, Schoffelmeer AN (2005) Suppression of conditioned nicotine and sucrose seeking by the cannabinoid-1 receptor antagonist SR141716A. Behav Brain Res 161:164–168PubMedGoogle Scholar
  35. de Wit H (1996) Priming effects with drugs and other reinforcers. Exp Clin Psychopharmacol 4:5–10Google Scholar
  36. de Wit H, Stewart J (1981) Reinstatement of cocaine-reinforced responding in the rat. Psychopharmacology (Berl) 75:134–143Google Scholar
  37. de Wit H, Stewart J (1983) Drug reinstatement of heroin-reinforced responding in the rat. Psychopharmacology (Berl) 79:29–31Google Scholar
  38. Di Ciano P, Everitt BJ (2004) Conditioned reinforcing properties of stimuli paired with self-administered cocaine, heroin or sucrose: implications for the persistence of addictive behaviour. Neuropharmacology 47(Suppl 1):202–213PubMedGoogle Scholar
  39. Diven K (1937) Certain determinants in the conditioning of anxiety reactions. J Psychol 3:291–308Google Scholar
  40. Dole VP, Nyswander ME, Kreek MJ (1966) Narcotic blockade. Arch Intern Med 118:304–309PubMedGoogle Scholar
  41. Epstein DH, Preston KL (2003) The reinstatement model and relapse prevention: a clinical perspective. Psychopharmacology (Berl) 168:31–41Google Scholar
  42. 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
  43. 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
  44. Erb S, Petrovic A, Yi D, Kayyali H (2006) Central injections of CRF reinstate cocaine seeking in rats after postinjection delays of up to 3 h: an influence of time and environmental context. Psychopharmacology (Berl) 187:112–120Google Scholar
  45. Everitt BJ, Robbins TW (2000) Second-order schedules of drug reinforcement in rats and monkeys: measurement of reinforcing efficacy and drug-seeking behaviour. Psychopharmacology (Berl) 153:17–30Google Scholar
  46. Eysenck HJ (1968) A theory of the incubation of anxiety–fear responses. Behav Res Ther 6:309–321PubMedGoogle Scholar
  47. Fagerström K, Balfour DJ (2006) Neuropharmacology and potential efficacy of new treatments for tobacco dependence. Expert Opin Investig Drugs 15:107–116PubMedGoogle Scholar
  48. Fuchs RA, Evans KA, Parker MC, See RE (2004) Differential involvement of the core and shell subregions of the nucleus accumbens in conditioned cue-induced reinstatement of cocaine seeking in rats. Psychopharmacology (Berl) 176:459–465Google Scholar
  49. 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
  50. Funk D, Harding S, Juzytsch W, Le AD (2005) Effects of unconditioned and conditioned social defeat on alcohol self-administration and reinstatement of alcohol seeking in rats. Psychopharmacology (Berl) 183:341–349Google Scholar
  51. Garavan H, Pankiewicz J, Bloom A, Cho JK, Sperry L, Ross TJ, Salmeron BJ, Risinger R, Kelley D, Stein EA (2000) Cue-induced cocaine craving: neuroanatomical specificity for drug users and drug stimuli. Am J Psychiatry 157:1789–1798PubMedGoogle Scholar
  52. Gasior M, Paronis CA, Bergman J (2004) Modification by dopaminergic drugs of choice behavior under concurrent schedules of intravenous saline and food delivery in monkeys. J Pharmacol Exp Ther 308:249–259PubMedGoogle Scholar
  53. Geyer MA, Markou A (1995) Animal models of psychiatric disorders. In: Bloom FE, Kupfer DJ (eds) Psychopharmacology: the fourth generation of progress. Raven, New York, pp 787–798Google Scholar
  54. Gilpin EA, Pierce JP, Farkas AJ (1997) Duration of smoking abstinence and success in quitting. J Natl Cancer Inst 89:526–572Google Scholar
  55. 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
  56. Gorelick DA, Wilkins JN (2006) Bromocriptine treatment for cocaine addiction: association with plasma prolactin levels. Drug Alcohol Depend 81:189–195PubMedGoogle Scholar
  57. Gossop M, Green L, Phillips G, Bradley B (1990) Factors predicting outcome among opiate addicts after treatment. Br J Clin Psychol 29(Pt 2):209–216PubMedGoogle Scholar
  58. Grabowski J, Rhoades H, Elk R, Schmitz J, Davis C, Creson D, Kirby K (1995) Fluoxetine is ineffective for treatment of cocaine dependence or concurrent opiate and cocaine dependence: two placebo-controlled double-blind trials. J Clin Psychopharmacol 15:163–174PubMedGoogle Scholar
  59. Grabowski J, Rhoades H, Stotts A, Cowan K, Kopecky C, Dougherty A, Moeller FG, Hassan S, Schmitz J (2004) Agonist-like or antagonist-like treatment for cocaine dependence with methadone for heroin dependence: two double-blind randomized clinical trials. Neuropsychopharmacology 29:969–981PubMedGoogle Scholar
  60. Grant S, London ED, Newlin DB, Villemagne VL, Liu X, Contoreggi C, Phillips RL, Kimes AS, Margolin A (1996) Activation of memory circuits during cue-elicited cocaine craving. Proc Natl Acad Sci USA 93:12040–12045PubMedGoogle Scholar
  61. Griffiths RR, Bigelow GE, Henningfield JE (1980) Similarity in animal and human drug-taking behavior. In: Mello NK (ed) Advances in substance abuse, behavioral and biological research. JAI, Greenwich, pp 1–90Google Scholar
  62. Grimm JW, See RE (2000) Dissociation of primary and secondary reward-relevant limbic nuclei in an animal model of relapse. Neuropsychopharmacology 22:473–479PubMedGoogle Scholar
  63. Grimm JW, Kruzich PJ, See RE (2000) Contingent access to stimuli associated with cocaine self-administration is required for reinstatement of drug-seeking behavior. Psychobiology 28:383–386Google Scholar
  64. Grimm JW, Hope BT, Wise RA, Shaham Y (2001) Incubation of cocaine craving after withdrawal. Nature 412:141–142PubMedGoogle Scholar
  65. Hall SM, Havassy BE, Wassermann DA (1990) Commitment to abstinence and acute stress in relapse to alcohol, opiates and nicotine. J Consult Clin Psychol 58:175–181PubMedGoogle Scholar
  66. Haney M, Ward AS, Foltin RW, Fischman MW (2001) Effects of ecopipam, a selective dopamine D1 antagonist, on smoked cocaine self-administration by humans. Psychopharmacology (Berl) 155:330–337Google Scholar
  67. Higgins ST, Badger GJ, Budney AJ (2000) Initial abstinence and success in achieving longer term cocaine abstinence. Exp Clin Psychopharmacol 8:377–386PubMedGoogle Scholar
  68. 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
  69. Highfield D, Mead A, Grimm JW, Rocha BA, Shaham Y (2002) Reinstatement of cocaine seeking in mice: effects of cocaine priming, cocaine cues and food deprivation. Psychopharmacology (Berl) 161:417–424Google Scholar
  70. Houston FP, Stevenson GD, McNaughton BL, Barnes CA (1999) Effects of age on the generalization and incubation of memory in the F344 rat. Learn Mem 6:111–119PubMedGoogle Scholar
  71. Hughes JR (2002) Is extinction in animals the same as abstinence in humans? Addiction 97:1219PubMedGoogle Scholar
  72. Hunt WA, Barnett LW, Branch LG (1971) Relapse rates in addiction programs. J Clin Psychol 27:455–456PubMedGoogle Scholar
  73. Jaffe JH (1990) Drug addiction and drug abuse. In: Gilman AG, Rall TW, Nies AS, Taylor P (eds) Goodman & Gilman’s the pharmacological basis of therapeutics. Pergamon, New York, pp 522–573Google Scholar
  74. Jaffe JH, Cascell NG, Kumor KM, Sherer MA (1989) Cocaine-induced cocaine craving. Psychopharmacology (Berl) 97:59–64Google Scholar
  75. Jenkins TN, Warner LH, Warden CJ (1926) Standard apparatus for the study of animal motivation. J Comp Psychol 6:361–382Google Scholar
  76. Johanson CE, Fischman MW (1989) The pharmacology of cocaine related to its abuse. Pharmacol Rev 41:3–52PubMedGoogle Scholar
  77. Johnson RE, Chutuape MA, Strain EC, Walsh SL, Stitzer ML, Bigelow GE (2000) A comparison of levomethadyl acetate, buprenorphine, and methadone for opioid dependence. N Engl J Med 343:1290–1297PubMedGoogle Scholar
  78. Kalivas PW, Volkow ND (2005) The neural basis of addiction: a pathology of motivation and choice. Am J Psychiatry 162:1403–1413PubMedGoogle Scholar
  79. Kassel JD, Stroud LR, Paronis CA (2003) Smoking, stress, and negative affect: correlation, causation, and context across stages of smoking. Psychol Bull 129:270–304PubMedGoogle Scholar
  80. Katz JL, Higgins ST (2003) The validity of the reinstatement model of craving and relapse to drug use. Psychopharmacology (Berl) 168:21–30Google Scholar
  81. Katzir AB-Y, N., Levy D, Shaham Y, Zangen A (2006) A novel rat model to assess relapse to cocaine seeking. Soc Neurosci Abstr (in press)Google Scholar
  82. Khroyan TV, Barrett-Larimore RL, Rowlett JK, Spealman RD (2000) Dopamine D1- and D2-like receptor mechanisms in relapse to cocaine-seeking behavior: effects of selective antagonists and agonists. J Pharmacol Exp Ther 294:680–687PubMedGoogle Scholar
  83. Kilts CD, Schweitzer JB, Quinn CK, Gross RE, Faber TL, Muhammad F, Ely TD, Hoffman JM, Drexler KP (2001) Neural activity related to drug craving in cocaine addiction. Arch Gen Psychiatry 58:334–341PubMedGoogle Scholar
  84. Kornetsky C (1977) Animal models: promises and problems. In: Hanin I, Usdin E (eds) Animal models in psychiatry and neurology. Pergamon, Oxford, pp 1–7Google Scholar
  85. Kosten TR, Kosten TA, Poling J, Oliveto A (2005) “Incubation” of cocaine relapse during a disulfiram clinical trial. CPDD, Annual Meeting Abstracts, p 90Google Scholar
  86. Krupitsky EM, Zvartau EE, Masalov DV, Tsoi MV, Burakov AM, Egorova VY, Didenko TY, Romanova TN, Ivanova EB, Bespalov AY, Verbitskaya EV, Neznanov NG, Grinenko AY, O’Brien CP, Woody GE (2004) Naltrexone for heroin dependence treatment in St. Petersburg, Russia. J Subst Abuse Treat 26:285–294PubMedGoogle Scholar
  87. LaRowe SD, Mardikian P, Malcolm R, Myrick H, Kalivas P, McFarland K, Saladin M, McRae A, Brady K (2006) Safety and tolerability of N-acetylcysteine in cocaine-dependent individuals. Am J Addict 15:105–110PubMedGoogle Scholar
  88. Latt NC, Jurd S, Houseman J, Wutzke SE (2002) Naltrexone in alcohol dependence: a randomised controlled trial of effectiveness in a standard clinical setting. Med J Aust 176:530–534PubMedGoogle Scholar
  89. 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
  90. 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
  91. 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 (Berl) 179:366–373Google Scholar
  92. LeDoux JE (2000) Emotion circuits in the brain. Annu Rev Neurosci 23:155–184PubMedGoogle Scholar
  93. Lee B, Tiefenbacher S, Platt DM, Spealman RD (2004) Pharmacological blockade of alpha(2)-adrenoceptors induces reinstatement of cocaine-seeking behavior in squirrel monkeys. Neuropsychopharmacology 29:686–693PubMedGoogle Scholar
  94. Leri F, Stewart J (2002) The consequences of different “lapses” on relapse to heroin seeking in rats. Exp Clin Psychopharmacol 10:339–349PubMedGoogle Scholar
  95. 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
  96. Lu L, Shepard JD, Scott Hall F, Shaham Y (2003) Effect of environmental stressors on opiate and psychostimulant reinforcement, reinstatement and discrimination in rats: a review. Neurosci Biobehav Rev 27:457–491PubMedGoogle Scholar
  97. Lu L, Grimm JW, Dempsey J, Shaham Y (2004a) Cocaine seeking over extended withdrawal periods in rats: different time courses of responding induced by cocaine cues versus cocaine priming over the first 6 months. Psychopharmacology 176:101–108PubMedGoogle Scholar
  98. Lu L, Grimm JW, Hope BT, Shaham Y (2004b) Incubation of cocaine craving after withdrawal: a review of preclinical data. Neuropharmacology 47(Suppl 1):214–226PubMedGoogle Scholar
  99. Lu L, Hope BT, Dempsey J, Liu SY, Bossert JM, Shaham Y (2005) Central amygdala ERK signaling pathway is critical to incubation of cocaine craving. Nat Neurosci 8:212–219PubMedGoogle Scholar
  100. Lussier JP, Higgins ST, Badger GJ (2005) Influence of the duration of abstinence on the relative reinforcing effects of cigarette smoking. Psychopharmacology (Berl) 181:486–495Google Scholar
  101. Maas LC, Lukas SE, Kaufman MJ, Weiss RD, Daniels SL, Rogers VW, Kukes TJ, Renshaw PF (1998) Functional magnetic resonance imaging of human brain activation during cue-induced cocaine craving. Am J Psychiatry 155:124–126PubMedGoogle Scholar
  102. Maier SF, Watkins LR (2005) Stressor controllability and learned helplessness: the roles of the dorsal raphe nucleus, serotonin, and corticotropin-releasing factor. Neurosci Biobehav Rev 29:829–841PubMedGoogle Scholar
  103. Markou A, Weiss F, Gold LH, Caine B, Schulteis G, Koob GF (1993) Animal models of drug craving. Psychopharmacology (Berl) 112:163–182Google Scholar
  104. Markou A, Arroyo M, Everitt BJ (1999) Effects of contingent and non-contingent cocaine on drug-seeking behavior measured using a second-order schedule of cocaine reinforcement in rats. Neuropsychopharmacology 20:542–555PubMedGoogle Scholar
  105. Marlatt AG (1996) Models of relapse and relapse prevention: a commentary. Exp Clin Psychopharmacol 4:55–60Google Scholar
  106. Marlatt GA (2002) Do animal models provide a valid analogue for human drug lapse and relapse? Comment on Leri and Stewart (2002). Exp Clin Psychopharmacol 10:359–360PubMedGoogle Scholar
  107. McFarland K, Ettenberg A (1997) Reinstatement of drug-seeking behavior produced by heroin-predictive environmental stimuli. Psychopharmacology (Berl) 131:86–92Google Scholar
  108. McFarlane AC (2000) Posttraumatic stress disorder: a model of the longitudinal course and the role of risk factors. J Clin Psychiatry 61(Suppl 5):15–20; discussion 21–23PubMedGoogle Scholar
  109. McKay JR, Alterman AI, Rutherford MJ, Cacciola JS, McLellan AT (1999) The relationship of alcohol use to cocaine relapse in cocaine dependent patients in an aftercare study. J Stud Alcohol 60:176–180PubMedGoogle Scholar
  110. McKay JR, Merikle E, Mulvaney FD, Weiss RV, Koppenhaver JM (2001) Factors accounting for cocaine use two years following initiation of continuing care. Addiction 96:213–225PubMedGoogle Scholar
  111. McKay JR, Franklin TR, Patapis N, Lynch KG (2006) Conceptual, methodological, and analytical issues in the study of relapse. Clin Psychol Rev 26:109–127PubMedGoogle Scholar
  112. McKinney WT Jr, Bunney WE Jr (1969) Animal model of depression. I. Review of evidence: implications for research. Arch Gen Psychiatry 21:240–248PubMedGoogle Scholar
  113. 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
  114. Mello NK, Negus SS (1996) Preclinical evaluation of pharmacotherapies for treatment of cocaine and opioid abuse using drug self-administration procedures. Neuropsychopharmacology 14:375–424PubMedGoogle Scholar
  115. Miczek KA, Thompson ML, Tornatzky W (1991) Subordinates animals: behavioral and physiological adaptations and opioid tolerance. In: Brown MR, Koob GF, Rivier C (eds) Stress: neurobiology and neuroendocrinology. Marcel Dekker, New York, pp 323–357Google Scholar
  116. Miczek KA, Fish EW, De Bold JF, De Almeida RM (2002) Social and neural determinants of aggressive behavior: pharmacotherapeutic targets at serotonin, dopamine and gamma-aminobutyric acid systems. Psychopharmacology (Berl) 163:434–458Google Scholar
  117. 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
  118. Nann-Vernotica E, Donny EC, Bigelow GE, Walsh SL (2001) Repeated administration of the D1/5 antagonist ecopipam fails to attenuate the subjective effects of cocaine. Psychopharmacology (Berl) 155:338–347Google Scholar
  119. 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
  120. Nunnally JC, Bernstein IH (1994) Psychometric theory, 3rd edn. McGraw-Hill, New YorkGoogle Scholar
  121. O’Brien CP (1997) A range of research-based pharmacotherapies for addiction. Science 278:66–70PubMedGoogle Scholar
  122. O’Brien CP (2005) Anticraving medications for relapse prevention: a possible new class of psychoactive medications. Am J Psychiatry 162:1423–1431PubMedGoogle Scholar
  123. O’Brien CP, Gardner EL (2005a) Critical assessment of how to study addiction and its treatment: human and non-human animal models. Pharmacol Ther 108:18–58PubMedGoogle Scholar
  124. O’Brien CP, Gardner EL (2005b) Critical assessment of how to study addiction and its treatment: human and non-human animal models. Pharmacol Ther 108:18–58PubMedGoogle Scholar
  125. O’Brien CP, Ehrman RN, Ternes JW (1986) Classical conditioning in human opioid dependence. In: Goldberg S, Stolerman I (eds) Behavioral analysis of drug dependence. Academic, Orlando, pp 329–356Google Scholar
  126. O’Brien CP, Childress AR, Mclellan TA, Ehrman R (1992) Classical conditioning in drug dependent humans. Ann N Y Acad Sci 654:400–415PubMedGoogle Scholar
  127. O’Malley SS, Jaffe JH, Chang G, Schottenfeld RS, Meyer RE, Rounsaville BJ (1992) Naltrexone and coping skills therapy for alcohol dependence: a controlled study. Arch Gen Psychiatry 49:881–887PubMedGoogle Scholar
  128. Panlilio LV, Thorndike EB, Schindler CW (2003) Reinstatement of punishment-suppressed opioid self-administration in rats: an alternative model of relapse to drug abuse. Psychopharmacology (Berl) 168:229–235Google Scholar
  129. Panlilio LV, Thorndike EB, Schindler CW (2005) Lorazepam reinstates punishment-suppressed remifentanil self-administration in rats. Psychopharmacology (Berl) 179:374–382Google Scholar
  130. Pavlov IP (1927) Conditioned reflexes. Oxford University Press, LondonGoogle Scholar
  131. Piasecki TM, Fiore MC, Baker TB (1998) Profiles in discouragement: two studies of variability in the time course of smoking withdrawal symptoms. J Abnorm Psychol 107:238–251PubMedGoogle Scholar
  132. Piazza PV, Le Moal M (1998) The role of stress in drug self-administration. Trends Pharmacol Sci 19:67–74PubMedGoogle Scholar
  133. Rebec GV, Sun W (2005) Neuronal substrates of relapse to cocaine-seeking behavior: role of prefrontal cortex. J Exp Anal Behav 84:653–666PubMedGoogle Scholar
  134. Ribeiro Do Couto B, Aguilar MA, Manzanedo C, Rodriguez-Arias M, Armario A, Minarro J (2006) Social stress is as effective as physical stress in reinstating morphine-induced place preference in mice. Psychopharmacology (Berl) 185:459–470Google Scholar
  135. Romach MK, Glue P, Kampman K, Kaplan HL, Somer GR, Poole S, Clarke L, Coffin V, Cornish J, O’Brien CP, Sellers EM (1999) Attenuation of the euphoric effects of cocaine by the dopamine D1/D5 antagonist ecopipam (SCH 39166). Arch Gen Psychiatry 56:1101–1106PubMedGoogle Scholar
  136. Rose JE (1996) Nicotine addiction and treatment. Annu Rev Med 47:493–507PubMedGoogle Scholar
  137. Russell RW (1964) Extrapolation from animals to man. In: Steinberg AH (ed) Animal behaviour and drug action. Little, Brown, Boston, pp 410–418Google Scholar
  138. Sanchez CJ, Sorg BA (2001) Conditioned fear stimuli reinstate cocaine-induced conditioned place preference. Brain Res 908:86–92PubMedGoogle Scholar
  139. Sarter M, Bruno JP (2002) Animal models in biological psychiatry. In: D’haenen H, den Boer JA, Willner P (eds) Biological psychiatry. Wiley and Sons, Hoboken, NJ pp 1–8Google Scholar
  140. Sass H, Soyka M, Mann K, Zieglgansberger W (1996) Relapse prevention by acamprosate. Results from a placebo-controlled study on alcohol dependence. Arch Gen Psychiatry 53:673–680PubMedGoogle Scholar
  141. Schenk S, Partridge B (1999) Cocaine-seeking produced by experimenter-administered drug injections: dose–effect relationships in rats. Psychopharmacology (Berl) 147:285–290Google Scholar
  142. Schubiner H, Saules KK, Arfken CL, Johanson CE, Schuster CR, Lockhart N, Edwards A, Donlin J, Pihlgren E (2002) Double-blind placebo-controlled trial of methylphenidate in the treatment of adult ADHD patients with comorbid cocaine dependence. Exp Clin Psychopharmacol 10:286–294PubMedGoogle Scholar
  143. See RE (2002) Neural substrates of conditioned-cued relapse to drug-seeking behavior. Pharmacol Biochem Behav 71:517–529PubMedGoogle Scholar
  144. See RE (2005) Neural substrates of cocaine-cue associations that trigger relapse. Eur J Pharmacol 526:140–146PubMedGoogle Scholar
  145. Self DW, Nestler EJ (1998) Relapse to drug-seeking: neural and molecular mechanisms. Drug Alcohol Depend 51:49–69PubMedGoogle Scholar
  146. Self DW, Choi KH, Simmons D, Walker JR, Smagula CS (2004) Extinction training regulates neuroadaptive responses to withdrawal from chronic cocaine self-administration. Learn Mem 11:648–657PubMedGoogle Scholar
  147. Selye H (1956) The stress of life. McGraw-Hill, New YorkGoogle Scholar
  148. Shaham Y (1996) Effect of stress on opioid-seeking behavior: evidence from studies with rats. Ann Behav Med 18:255–263CrossRefPubMedGoogle Scholar
  149. Shaham Y, Stewart J (1995) Stress reinstates heroin self-administration behavior in drug-free animals: an effect mimicking heroin, not withdrawal. Psychopharmacology (Berl) 119:334–341Google Scholar
  150. Shaham Y, Stewart J (1996) Effects of opioid and dopamine receptor antagonists on relapse induced by stress and reexposure to heroin in rats. Psychopharmacology (Berl) 125:385–391Google Scholar
  151. Shaham Y, Rajabi H, Stewart J (1996) Relapse to heroin-seeking under opioid maintenance: the effects of opioid withdrawal, heroin priming and stress. J Neurosci 16:1957–1963PubMedGoogle Scholar
  152. Shaham Y, Adamson LK, Grocki S, Corrigall WA (1997a) Reinstatement and spontaneous recovery of nicotine-seeking in rats. Psychopharmacology (Berl) 130:396–403Google Scholar
  153. Shaham Y, Funk D, Erb S, Brown TJ, Walker CD, Stewart J (1997b) Corticotropin-releasing factor, but not corticosterone, is involved in stress-induced relapse to heroin-seeking in rats. J Neurosci 17:2605–2614PubMedGoogle Scholar
  154. Shaham Y, Erb S, Stewart J (2000a) Stress-induced relapse to heroin and cocaine seeking in rats: a review. Brain Res Brain Res Rev 33:13–33PubMedGoogle Scholar
  155. 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
  156. Shaham Y, Shalev U, Lu L, De Wit H, Stewart J (2003) The reinstatement model of drug relapse: history, methodology and major findings. Psychopharmacology (Berl) 168:3–20Google Scholar
  157. 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 (Berl) 150:337–346Google Scholar
  158. Shalev U, Morales M, Hope B, Yap J, Shaham Y (2001a) Time-dependent changes in extinction behavior and stress-induced reinstatement of drug seeking following withdrawal from heroin in rats. Psychopharmacology (Berl) 156:98–107Google Scholar
  159. Shalev U, Yap J, Shaham Y (2001b) Leptin attenuates food deprivation-induced relapse to heroin seeking. J Neurosci 21:RC129PubMedGoogle Scholar
  160. Shalev U, Grimm JW, Shaham Y (2002) Neurobiology of relapse to heroin and cocaine seeking: a review. Pharmacol Rev 54:1–42PubMedGoogle Scholar
  161. Shalev U, Finnie PS, Quinn T, Tobin S, Wahi P (2006) A role for corticotropin-releasing factor, but not corticosterone, in acute food-deprivation-induced reinstatement of heroin seeking in rats. Psychopharmacology (Berl) 187:376–384Google Scholar
  162. 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
  163. Shiffman S (2005) Dynamic influences on smoking relapse process. J Pers 73:1715–1748PubMedGoogle Scholar
  164. Shiffman S, Waters AJ (2004) Negative affect and smoking lapses: a prospective analysis. J Consult Clin Psychol 72:192–201PubMedGoogle Scholar
  165. Shiffman S, Paty JA, Gnys M, Kassel JA, Hickcox M (1996) First lapses to smoking: within-subjects analysis of real-time reports. J Consult Clin Psychol 64:366–379PubMedGoogle Scholar
  166. Shiffman S, Hufford M, Hickcox M, Paty JA, Gnys M, Kassel JD (1997) Remember that? A comparison of real-time versus retrospective recall of smoking lapses. J Consult Clin Psychol 65:292–300PubMedGoogle Scholar
  167. Shiffman S, Ferguson SG, Gwaltney CJ (2006a) Immediate hedonic response to smoking lapses: relationship to smoking relapse, and effects of nicotine replacement therapy. Psychopharmacology (Berl) 184:608–618Google Scholar
  168. Shiffman S, Scharf DM, Shadel WG, Gwaltney CJ, Dang Q, Paton SM, Clark DB (2006b) Analyzing milestones in smoking cessation: illustration in a nicotine patch trial in adult smokers. J Consult Clin Psychol 74:276–285PubMedGoogle Scholar
  169. Shufman EN, Porat S, Witztum E, Gandacu D, Bar-Hamburger R, Ginath Y (1994) The efficacy of naltrexone in preventing reabuse of heroin after detoxification. Biol Psychiatry 35:935–945PubMedGoogle Scholar
  170. Sinha R (2001) How does stress increase risk of drug abuse and relapse? Psychopharmacology (Berl) 158:343–359Google Scholar
  171. Sinha R, Fuse T, Aubin LR, O’Malley SS (2000) Psychological stress, drug-related cues and cocaine craving. Psychopharmacology (Berl) 152:140–148Google Scholar
  172. Sinha R, Kimmerling A, Doebrick C, Kosten TR (2006) Effects of lofexidine on stress-induced and cue-induced opioid craving and opioid abstinence rates: preliminary findings. Biol Psychiatry (under review)Google Scholar
  173. Skinner BF (1953) Science and human behavior. Free Press, New YorkGoogle Scholar
  174. Smith SG, Davis WM (1974) Punishment of amphetamine and morphine self-administration behavior. Psychol Rec 24:477–480Google Scholar
  175. 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
  176. Stewart J (2000) Pathways to relapse: the neurobiology of drug- and stress-induced relapse to drug-taking. J Psychiatry Neurosci 25:125–136PubMedGoogle Scholar
  177. Streeton C, Whelan G (2001) Naltrexone, a relapse prevention maintenance treatment of alcohol dependence: a meta-analysis of randomized controlled trials. Alcohol Alcohol 36:544–552PubMedGoogle Scholar
  178. Stretch R, Gerber GJ, Wood SM (1971) Factors affecting behavior maintained by response-contingent intravenous infusions of amphetamine in squirrel monkeys. Can J Physiol Pharmacol 49:581–589PubMedGoogle Scholar
  179. Tempesta E, Janiri L, Bignamini A, Chabac S, Potgieter A (2000) Acamprosate and relapse prevention in the treatment of alcohol dependence: a placebo-controlled study. Alcohol Alcohol 35:202–209PubMedGoogle Scholar
  180. Tiffany ST, Carter BL (1998) Is craving the source of compulsive drug use? J Psychopharmacol 12:23–30PubMedGoogle Scholar
  181. Tiffany ST, Conklin CA (2000) A cognitive processing model of alcohol craving and compulsive alcohol use. Addiction 95(Suppl 2):S145–153PubMedGoogle Scholar
  182. Tran-Nguyen TL, Fuchs RA, Coffey GP, O’Dell LE, Baker DA, Neisewander JL (1998) Time-dependent changes in cocaine-seeking behavior and dopamine overflow in the amygdala during cocaine withdrawal. Neuropsychopharmacology 19:48–59PubMedGoogle Scholar
  183. Vaillant GE (1988) What can long-term follow-up teach us about relapse and prevention of relapse in addiction? Br J Addict 83:1147–1157PubMedGoogle Scholar
  184. Vanderschuren LJ, Di Ciano P, Everitt BJ (2005) Involvement of the dorsal striatum in cue-controlled cocaine seeking. J Neurosci 25:8665–8870PubMedGoogle Scholar
  185. Vocci F, Ling W (2005) Medications development: successes and challenges. Pharmacol Ther 108:94–108PubMedGoogle Scholar
  186. Volpicelli JR, Anterman AI, Hayashida M, O’Brien CP (1992) Naltrexone in the treatment of alcohol dependence. Arch Gen Psychiatry 49:876–880PubMedGoogle Scholar
  187. Waldorf D, Reinarman C, Murphy S (1992) Cocaine changes: the experience of using and quitting. Temple University Press, PhiladelphiaGoogle Scholar
  188. 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
  189. Wang J, Fang Q, Liu Z, Lu L (2006) Region-specific effects of brain corticotropin-releasing factor receptor type 1 blockade on footshock-stress- or drug-priming-induced reinstatement of morphine conditioned place preference in rats. Psychopharmacology (Berl) 185:19–28Google Scholar
  190. Warden CJ (1931) Animal motivation: experimental studies on the albino rat. Columbia University Press, New YorkGoogle Scholar
  191. Wasserman DA, Weinstein MG, Havassy BE, Hall SM (1998) Factors associated with lapses to heroin use during methadone maintenance. Drug Alcohol Depend 52:183–192PubMedGoogle Scholar
  192. Weiss F (2005) Neurobiology of craving, conditioned reward and relapse. Curr Opin Pharmacol 5:9–19PubMedGoogle Scholar
  193. 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
  194. Wexler BE, Gottschalk CH, Fulbright RK, Prohovnik I, Lacadie CM, Rounsaville BJ, Gore JC (2001) Functional magnetic resonance imaging of cocaine craving. Am J Psychiatry 158:86–95PubMedGoogle Scholar
  195. Wikler A (1973) Dynamics of drug dependence, implication of a conditioning theory for research and treatment. Arch Gen Psychiatry 28:611–616PubMedGoogle Scholar
  196. Willner P (1984) The validity of animal models of depression. Psychopharmacology (Berl) 83:1–16Google Scholar
  197. Willner P (1997) Validity, reliability and utility of the chronic mild stress model of depression: a 10-year review and evaluation. Psychopharmacology (Berl) 134:319–329Google Scholar
  198. Wise RA, Murray A, Bozarth MA (1990) Bromocriptine self-administration and bromocriptine-reinstatement of cocaine-trained and heroin-trained lever pressing in rats. Psychopharmacology (Berl) 100:355–360Google Scholar
  199. Yehuda R, Antelman SM (1993) Criteria for rationally evaluating animal models of posttraumatic stress disorder. Biol Psychiatry 33:479–486PubMedGoogle Scholar
  200. Yonkers KA, Bruce SE, Dyck IR, Keller MB (2003) Chronicity, relapse, and illness—course of panic disorder, social phobia, and generalized anxiety disorder: findings in men and women from 8 years of follow-up. Depress Anxiety 17:173–179PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • David H. Epstein
    • 1
    • 4
  • Kenzie L. Preston
    • 1
  • Jane Stewart
    • 2
  • Yavin Shaham
    • 3
  1. 1.Clinical Pharmacology and Therapeutics Research BranchIRP/NIDA/NIH/DHHSBaltimoreUSA
  2. 2.Center for Studies in Behavioral Neurobiology, Department of PsychologyConcordia UniversityMontrealCanada
  3. 3.Behavioral Neuroscience BranchIRP/NIDA/NIH/DHHSBaltimoreUSA
  4. 4.Treatment Section, Clinical Pharmacology and Therapeutics BranchIRP/NIDA/NIHBaltimoreUSA

Personalised recommendations