, Volume 187, Issue 1, pp 60–67

Contributions of prolonged contingent and noncontingent cocaine exposure to enhanced reinstatement of cocaine seeking in rats

Original Investigation



Recent evidence suggests that prolonged cocaine self-administration produces escalation in drug-seeking behavior in rats analogous to the increased intake patterns observed in cocaine-dependent individuals. However, the contributions of prolonged access to cocaine taking vs the pharmacologic effects of the consequent increased cocaine exposure on escalation of drug-seeking behaviors have not been investigated.


The present study assessed the effects of these two factors on maintenance of cocaine self-administration and reinstatement of cocaine seeking.


Male, Sprague–Dawley rats were trained to self-administer cocaine (0.2 mg/i.v. infusion; FR1) for 1 h per day for 10 sessions followed by short access (1 h/day), contingent long access (6 h/day), or noncontingent long access (1 h contingent + 5 h of yoked cocaine infusions/day; i.e., short access + yoked) to cocaine for 14 daily sessions. All rats underwent extinction training and were subsequently tested for the ability of cocaine-paired cues or a cocaine-priming injection (7.5 mg/kg i.p.) to reinstate extinguished cocaine seeking.


Rats in all groups maintained stable responding for cocaine reinforcement and subsequently showed significant reinstatement of cocaine-seeking behavior. Conditioned-cued reinstatement was enhanced after the contingent long access and short access + yoked cocaine exposure relative to short access cocaine exposure. Conversely, cocaine-primed reinstatement was enhanced after contingent long-access cocaine exposure relative to the other two conditions.


Enhanced drug seeking produced by prolonged daily cocaine self-administration is due to a combination of behavioral and pharmacological factors. Specifically, conditioned-cued reinstatement is enhanced by increased cocaine intake and cocaine-primed reinstatement is enhanced by increased cocaine taking.


Cocaine Self-administration Extinction Reinstatement Relapse Access 


  1. Ahmed SH, Cador M (2006) Dissociation of psychomotor sensitization from compulsive cocaine consumption. Neuropsychopharmacology 31:563–571CrossRefPubMedGoogle Scholar
  2. Ahmed SH, Koob GF (1998) Transition from moderate to excessive drug intake: change in hedonic set point. Science 282:298–300CrossRefPubMedGoogle Scholar
  3. Ahmed SH, Koob GF (2005) Transition to drug addiction: a negative reinforcement model based on an allostatic decrease in reward function. Psychopharmacology (Berl) 180:473–490CrossRefGoogle Scholar
  4. 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
  5. Ben-Shahar O, Ahmed SH, Koob GF, Ettenberg A (2004) The transition from controlled to compulsive drug use is associated with a loss of sensitization. Brain Res 995:46–54CrossRefPubMedGoogle Scholar
  6. Ben-Shahar O, Moscarello JM, Jacob B, Roarty MP, Ettenberg A (2005) Prolonged daily exposure to IV cocaine results in tolerance to its stimulant effects. Pharmacol Biochem Behav 82:411–416CrossRefPubMedGoogle Scholar
  7. Dalley JW, Laane K, Pena Y, Theobald DE, Everitt BJ, Robbins TW (2005) Attentional and motivational deficits in rats withdrawn from intravenous self-administration of cocaine or heroin. Psychopharmacology (Berl) 182:579–587CrossRefGoogle Scholar
  8. Ettenberg A (2004) Opponent process properties of self-administered cocaine. Neurosci Biobehav Rev 27:721–728CrossRefPubMedGoogle Scholar
  9. 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 58:751–759CrossRefPubMedGoogle Scholar
  10. Fuchs RA, Evans KA, Parker MP, See RE (2004) Differential involvement of orbitofrontal cortex subregions in conditioned cue-induced and cocaine-primed reinstatement of cocaine seeking in rats. J Neurosci 24:6600–6610CrossRefPubMedGoogle Scholar
  11. Grimm JW, Hope BT, Wise RA, Shaham Y (2001) Neuroadaptation. Incubation of cocaine craving after withdrawal. Nature 412:141–142PubMedCrossRefGoogle Scholar
  12. Koob GF, Le Moal M (2001) Drug addiction, dysregulation of reward, and allostasis. Neuropsychopharmacology 24:97–129CrossRefPubMedGoogle Scholar
  13. Koob GF, Ahmed SH, Boutrel B, Chen SA, Kenny PJ, Markou A, O’Dell LE, Parsons LH, Sanna PP (2004) Neurobiological mechanisms in the transition from drug use to drug dependence. Neurosci Biobehav Rev 27:739–749CrossRefPubMedGoogle Scholar
  14. 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
  15. Lorrain DS, Arnold GM, Vezina P (2000) Previous exposure to amphetamine increases incentive to obtain the drug: long-lasting effects revealed by the progressive ratio schedule. Behav Brain Res 107:9–19CrossRefPubMedGoogle Scholar
  16. Lu L, Grimm JW, Hope BT, Shaham Y (2004) Incubation of cocaine craving after withdrawal: a review of preclinical data. Neuropharmacology 47(Suppl 1):214–226CrossRefPubMedGoogle Scholar
  17. 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
  18. Mendrek A, Blaha CD, Phillips AG (1998) Pre-exposure of rats to amphetamine sensitizes self-administration of this drug under a progressive ratio schedule. Psychopharmacology (Berl) 135:416–422CrossRefGoogle Scholar
  19. Morgan D, Roberts DC, (2004) Sensitization to the reinforcing effects of cocaine following binge-abstinent self-administration Neurosci Biobehav Rev 27:803–812CrossRefPubMedGoogle Scholar
  20. Morgan AD, Campbell UC, Fons RD, Carroll ME (2002a) Effects of agmatine on the escalation of intravenous cocaine and fentanyl self-administration in rats. Pharmacol Biochem Behav 72:380–873CrossRefGoogle Scholar
  21. Morgan D, Brebner K, Lynch WJ, Roberts DC (2002b) Increases in the reinforcing efficacy of cocaine after particular histories of reinforcement. Behav Pharmacol 13:389–396PubMedGoogle Scholar
  22. Mutschler NH, Miczek KA (1998) Withdrawal from a self-administered or non-contingent cocaine binge: differences in ultrasonic distress vocalizations in rats. Psychopharmacology (Berl) 136:402–408CrossRefGoogle Scholar
  23. Paterson NE, Markou A (2003) Increased motivation for self-administered cocaine after escalated cocaine intake. Neuroreport 14:2229–2232CrossRefPubMedGoogle Scholar
  24. 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 78:199–207CrossRefPubMedGoogle Scholar
  25. Suto N, Tanabe LM, Austin JD, Creekmore E, Pham CT, Vezina P (2004) Previous exposure to psychostimulants enhances the reinstatement of cocaine seeking by nucleus accumbens AMPA. Neuropsychopharmacology 29:2149–2159CrossRefPubMedGoogle Scholar
  26. Tran-Nguyen LT, Fuchs RA, Coffey GP, Baker DA, O’Dell LE, Neisewander JL (1998) Time-dependent changes in cocaine-seeking behavior and extracellular dopamine levels in the amygdala during cocaine withdrawal. Neuropsychopharmacology 19:48–59CrossRefPubMedGoogle Scholar
  27. Vanderschuren LJ, Everitt BJ (2004) Drug seeking becomes compulsive after prolonged cocaine self-administration. Science 305:1017–1019CrossRefPubMedGoogle Scholar
  28. Vezina P (2004) Sensitization of midbrain dopamine neuron reactivity and the self-administration of psychomotor stimulant drugs. Neurosci Biobehav Rev 27:827–839CrossRefPubMedGoogle Scholar
  29. Vezina P, Pierre PJ, Lorrain DS (1999) The effect of previous exposure to amphetamine on drug-induced locomotion and self-administration of a low dose of the drug. Psychopharmacology (Berl) 147:125–134CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Tod E. Kippin
    • 1
  • Rita A. Fuchs
    • 1
  • Ronald E. See
    • 1
  1. 1.Department of NeurosciencesMedical University of South CarolinaCharlestonUSA

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