, Volume 206, Issue 1, pp 109–120 | Cite as

Two modes of intense cocaine bingeing: increased persistence after social defeat stress and increased rate of intake due to extended access conditions in rats

  • Isabel M. H. Quadros
  • Klaus A. Miczek
Original Investigation



Escalated, binge-like patterns of cocaine self-administration are engendered by repeated, intermittent exposure to episodes of social defeat stress, as well as by extended drug access.


The present study investigated if prior exposure to brief episodes of social defeat stress would intensify the escalation of cocaine self-administration associated with extended access conditions. The consequences of both stress sensitization and prolonged access were further assessed with progressive ratio (PR) break points and during a 24-h variable dose “binge”.


Male Long–Evans rats were exposed to four episodes of defeat stress (days 1–4–7–10), and their locomotor response to cocaine was assessed 10 days later. Rats were subsequently implanted with intravenous catheters. After acquisition, stressed and control rats were allowed daily short (1 h/day) or extended (6 h/day) sessions of cocaine self-administration for 14 days (0.75 mg/kg/infusion). In sequence, we determined break points for cocaine on PR tests and assessed drug intake patterns during a 24-h variable dose binge.


Defeat stress induced cross-sensitization to a cocaine challenge, increased break points for cocaine, and produced persistent, escalated cocaine taking during a 24-h binge. Rats with extended access to cocaine—both stressed and controls—similarly escalated their drug intake throughout the 14 days. Extended access conditions accelerated the rate of cocaine self-administration in the first half of the binge, indicated by shorter post-infusion intervals, but failed to amplify the accumulated drug intake in non-stressed controls.


Both social defeat stress and drug access conditions may engender escalated cocaine intake via distinct mechanisms that regulate drug self-administration.


Self-administration Escalation Sensitization Stress Long access Intravenous 



This research was supported by NIDA research grant DA02632 (KAM, PI). We thank Mr. J. Thomas Sopko for outstanding technical assistance, and Jonaton Jang and Fabio C Cruz who assisted with experimental procedures.


  1. Ahmed SH, Cador M (2006) Dissociation of psychomotor sensitization from compulsive cocaine consumption. Neuropsychopharmacology 31:563–571PubMedCrossRefGoogle Scholar
  2. Ahmed SH, Koob GF (1998) Transition from moderate to excessive drug intake: change in hedonic set point. Science 282:298–300PubMedCrossRefGoogle Scholar
  3. Ahmed SH, Koob GF (1999) Long-lasting increase in the set point for cocaine self-administration after escalation in rats. Psychopharmacology 146:303–312PubMedCrossRefGoogle Scholar
  4. Ahmed SH, Walker JR, Koob GF (2000) Persistent increase in the motivation to take heroin in rats with a history of drug escalation. Neuropsychopharmacology 22:413–421PubMedCrossRefGoogle Scholar
  5. Ahmed SH, Kenny PJ, Koob GF, Markou A (2002) Neurobiological evidence for hedonic allostasis associated with escalating cocaine use. Nat Neurosci 5:625–626PubMedGoogle Scholar
  6. Cabib S, Orsini C, Le Moal M, Piazza PV (2000) Abolition and reversal of strain differences in behavioral responses to drugs of abuse after a brief experience. Science 289:463–465PubMedCrossRefGoogle Scholar
  7. Covington HE III, Miczek KA (2001) Repeated social-defeat stress, cocaine or morphine. Effects on behavioral sensitization and intravenous cocaine self-administration “binges”. Psychopharmacology (Berl) 158:388–398CrossRefGoogle Scholar
  8. Covington HE III, Miczek KA (2005) Intense cocaine self-administration after episodic social defeat stress, but not after aggressive behavior: dissociation from corticosterone activation. Psychopharmacology (Berl) 183:331–340CrossRefGoogle Scholar
  9. Covington HE III, Tropea TF, Rajadhyaksha AM, Kosofsky BE, Miczek KA (2008) NMDA receptors in the rat VTA: a critical site for social stress to intensify cocaine taking. Psychopharmacology (Berl) 197:203–216CrossRefGoogle Scholar
  10. Deroche V, Marinelli M, Maccari S, Lemoal M, Simon H, Piazza PV (1995) Stress-induced sensitization and glucocorticoids. 1. Sensitization of dopamine-dependent locomotor effects of amphetamine and morphine depends on stress-induced corticosterone secretion. J Neurosci 15:7181–7188PubMedGoogle Scholar
  11. Ferrario CR, Robinson TE (2007) Amphetamine pretreatment accelerates the subsequent escalation of cocaine self-administration behavior. Eur Neuropsychopharmacol 17:352–357PubMedCrossRefGoogle Scholar
  12. Ferrario CR, Gorny G, Crombag HS, Li Y, Kolb B, Robinson TE (2005) Neural and behavioral plasticity associated with the transition from controlled to escalated cocaine use. Biol Psychiatry 58:751–759PubMedCrossRefGoogle Scholar
  13. Fish EW, Faccidomo S, Miczek KA (1999) Aggression heightened by alcohol or social instigation in mice: reduction by the 5-HT1B receptor agonist CP-94, 253. Psychopharmacology 146:391–399PubMedCrossRefGoogle Scholar
  14. Gawin FH (1991) Cocaine addiction: psychology and neurophysiology. Science 251(5001):1580–6PubMedCrossRefGoogle Scholar
  15. Gawin FH, Kleber HD (1988) Evolving conceptualizations of cocaine dependence. Yale J Biol Med 61(2):123–136PubMedGoogle Scholar
  16. Gerber GJ, Wise RA (1989) Pharmacological regulation of intravenous cocaine and heroin self-administration in rats: a variable dose paradigm. Pharmacol Biochem Behav 32:527–531PubMedCrossRefGoogle Scholar
  17. Goeders NE (2002) The HPA axis and cocaine reinforcement. Psychoneuroendocrinology 27:13–33PubMedCrossRefGoogle Scholar
  18. Goeders NE (2003) The impact of stress on addiction. Eur Neuropsychopharmacol 13(6):435–41PubMedCrossRefGoogle Scholar
  19. Grimm JW, Hope BT, Wise RA, Shaham Y (2001) Neuroadaptation. Incubation of cocaine craving after withdrawal. Nature 412(6843):141–142PubMedCrossRefGoogle Scholar
  20. Hodos W (1961) Progressive ratio as a measure of reward strength. Science 134:943–944PubMedCrossRefGoogle Scholar
  21. Kabbaj M, Norton CS, Kollack-Walker S, Watson SJ, Robinson TE, Akil H (2001) Social defeat alters the acquisition of cocaine self-administration in rats: role of individual differences in cocaine-taking behavior. Psychopharmacology (Berl) 158:382–387CrossRefGoogle Scholar
  22. Knackstedt LA, Kalivas PW (2007) Extended access to cocaine self-administration enhances drug-primed reinstatement but not behavioral sensitization. J Pharmacol Exp Ther 322:1103–1109PubMedCrossRefGoogle Scholar
  23. Koob G, Kreek MJ (2007) Stress, dysregulation of drug reward pathways, and the transition to drug dependence. Am J Psychiatry 164:1149–1159PubMedCrossRefGoogle Scholar
  24. Koob GF, Le Moal M (1997) Drug abuse: hedonic homeostatic dysregulation. Science 278:52–59PubMedCrossRefGoogle Scholar
  25. Lenoir M, Ahmed SH (2007) Heroin-induced reinstatement is specific to compulsive heroin use and dissociable from heroin reward and sensitization. Neuropsychopharmacology 32:616–624PubMedCrossRefGoogle Scholar
  26. Liu Y, Roberts DC, Morgan D (2005) Effects of extended-access self-administration and deprivation on breakpoints maintained by cocaine in rats. Psychopharmacology (Berl) 179:644–651CrossRefGoogle Scholar
  27. Lu L, Grimm JW, Hope BT, Shaham Y (2004) Incubation of cocaine craving after withdrawal: a review of preclinical data. Neuropharmacology 47(S1):214–226PubMedCrossRefGoogle Scholar
  28. Mantsch JR, Katz ES (2007) Elevation of glucocorticoids is necessary but not sufficient for the escalation of cocaine self-administration by chronic electric footshock stress in rats. Neuropsychopharmacology 32:367–376PubMedCrossRefGoogle Scholar
  29. Mantsch JR, Yuferov V, Mathieu-Kia AM, Ho A, Kreek MJ (2004) Effects of extended access to high versus low cocaine doses on self-administration, cocaine-induced reinstatement and brain mRNA levels in rats. Psychopharmacology (Berl) 175:26–36CrossRefGoogle Scholar
  30. Mantsch JR, Baker DA, Serge JP, Hoks MA, Francis DM, Katz ES (2008) Surgical adrenalectomy with diurnal corticosterone replacement slows escalation and prevents the augmentation of cocaine-induced reinstatement in rats self-administering cocaine under long-access conditions. Neuropsychopharmacology 33:814–826PubMedCrossRefGoogle Scholar
  31. Marinelli M, Piazza PV (2002) Interaction between glucocorticoid hormones, stress and psychostimulant drugs. Eur J NeuroSci 16:387–394PubMedCrossRefGoogle Scholar
  32. Miczek KA, Mutschler NH (1996) Activational effects of social stress on IV cocaine self-administration in rats. Psychopharmacology 128:256–264PubMedCrossRefGoogle Scholar
  33. Miczek KA, Covington HE, Nikulina EA, Hammer RP (2004) Aggression and defeat: persistent effects on cocaine self-administration and gene expression in peptidergic and aminergic mesocorticolimbic circuits. Neurosci Biobehav Rev 27:787–802PubMedCrossRefGoogle Scholar
  34. Miczek KA, Yap JJ, Covington HE III (2008) Social stress, therapeutics and drug abuse: preclinical models of escalated and depressed intake. Pharmacol Ther 120:102–128PubMedCrossRefGoogle Scholar
  35. Moffett MC, Vicentic A, Kozel M, Plotsky P, Francis DD, Kuhar MJ (2007) Maternal separation alters drug intake patterns in adulthood in rats. Biochem Pharmacol 73:321–330PubMedCrossRefGoogle Scholar
  36. Morgan D, Roberts DCS (2004) Sensitization to the reinforcing effects of cocaine following binge-abstinent self-administration. Neurosci Biobehav Rev 27:803–812PubMedCrossRefGoogle Scholar
  37. National Research Council (1996) Guide for the care and use of laboratory animals. National Academy Press, Washington DCGoogle Scholar
  38. Nikulina EM, Covington HE III, Ganschow L, Hammer RP Jr, Miczek KA (2004) Long-term behavioral and neuronal cross-sensitization to amphetamine induced by repeated brief social defeat stress: Fos in the ventral tegmental area and amygdala. Neuroscience 123:857–865PubMedCrossRefGoogle Scholar
  39. Oleson EB, Roberts DC (2009) Behavioral economic assessment of price and cocaine consumption following self-administration histories that produce escalation of either final ratios or intake. Neuropsychopharmacology 34(3):796–804PubMedCrossRefGoogle Scholar
  40. Oleson EB, Talluri S, Childers SR, Smith JE, Roberts DC, Bonin KD, Budygin EA (2009) Dopamine uptake changes associated with cocaine self-administration. Neuropsychopharmacology 34(5):1174–84PubMedCrossRefGoogle Scholar
  41. Pacchioni AM, Gioino G, Assis A, Cancela LM (2002) A single exposure to restraint stress induces behavioral and neurochemical sensitization to stimulating effects of amphetamine: involvement of NMDA receptors. Ann N Y Acad Sci 965:233–246PubMedCrossRefGoogle Scholar
  42. Paterson NE, Markou A (2003) Increased motivation for self-administered cocaine after escalated cocaine intake. NeuroReport 14:2229–2232PubMedCrossRefGoogle Scholar
  43. Richardson NR, Roberts DCS (1996) Progressive ratio schedules in drug self-administration studies in rats: a method to evaluate reinforcing efficacy. J Neurosci Methods 66:1–11PubMedCrossRefGoogle Scholar
  44. Roberts DC, Morgan D, Liu Y (2007) How to make a rat addicted to cocaine. Prog Neuropsychopharmacol Biol Psychiatry 31:1614–1624PubMedCrossRefGoogle Scholar
  45. Robinson TE, Berridge KC (1993) The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Brain Res Rev 18:247–291PubMedCrossRefGoogle Scholar
  46. Robinson TE, Berridge KC (2000) The psychology and neurobiology of addiction: an incentive-sensitization view. Addiction 95:S91–S117PubMedGoogle Scholar
  47. Roth ME, Carroll ME (2004) Sex differences in the escalation of intravenous cocaine intake following long- or short-access to cocaine self-administration. Pharmacol Biochem Behav 78:199–207PubMedCrossRefGoogle Scholar
  48. Rouge-Pont F, Marinelli M, Le Moal M, Simon H, Piazza PV (1995) Stress-induced sensitization and glucocorticoids. 2. Sensitization of the increase in extracellular dopamine induced by cocaine depends on stress-induced corticosterone secretion. J Neurosci 15:7189–7195PubMedGoogle Scholar
  49. Sinha R (2001) How does stress increase risk of drug abuse and relapse? Psychopharmacology (Berl) 158(4):343–359Google Scholar
  50. Sinha R (2008) Chronic stress, drug use, and vulnerability to addiction. Ann N Y Acad Sci 1141:105–130Google Scholar
  51. Sorge RE, Stewart J (2005) The contribution of drug history and time since termination of drug taking to footshock stress-induced cocaine seeking in rats. Psychopharmacology (Berl) 183(2):210–217CrossRefGoogle Scholar
  52. Tidey JW, Miczek KA (1997) Acquisition of cocaine self-administration after social stress: role of accumbens dopamine. Psychopharmacology (Berl) 130:203–212CrossRefGoogle Scholar
  53. Tornatzky W, Miczek KA (1993) Long-term impairment of autonomic circadian rhythms after brief intermittent social stress. Physiol Behav 53:983–993PubMedCrossRefGoogle Scholar
  54. Tornatzky W, Miczek KA (2000) Cocaine self-administration “binges”: transition from behavioral and autonomic regulation toward homeostatic dysregulation in rats. Psychopharmacology 148:289–298PubMedCrossRefGoogle Scholar
  55. Vezina P (2004) Sensitization of midbrain dopamine neuron reactivity and the self-administration of psychomotor stimulant drugs. Neurosci Biobehav Rev 27:827–839PubMedCrossRefGoogle Scholar
  56. Wee S, Mandyam CD, Lekic DM, Koob GF (2008) Alpha 1-noradrenergic system role in increased motivation for cocaine intake in rats with prolonged access. Eur Neuropsychopharmacol 18:303–311PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  1. 1.Department of PsychologyTufts UniversityMedfordUSA
  2. 2.Center for Neuroscience Research, Department of Neuroscience, Tufts UniversityBostonUSA
  3. 3.Department of NeuroscienceTufts UniversityBostonUSA
  4. 4.Department of PsychiatryTufts UniversityBostonUSA
  5. 5.Department of Pharmacology and Experimental TherapeuticsTufts UniversityBostonUSA

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