, Volume 232, Issue 24, pp 4505–4514 | Cite as

Pharmacological and non-pharmacological factors that regulate the acquisition of ketamine self-administration in rats

  • Marco VenniroEmail author
  • Anna Mutti
  • Cristiano Chiamulera
Original Investigation



Recreational ketamine use may be modulated by factors such as ketamine infusion patterns, associated conditioned stimuli and spatial-temporal contexts. Our aim was to study the pharmacological and non-pharmacological factors that regulate the acquisition of ketamine use.


In experiment 1, four groups of male rats were trained to self-administer ketamine during nine 1-h daily sessions, under four reinforcement schedules: i) pre-session ketamine priming (Priming-[KET]), ii) conditioned stimulus (CS) paired to the ketamine infusions ([KET + CS]), iii) neither priming nor CS ([KET]), iv) combination of both (Priming-[KET + CS]). In experiment 2, two groups of male rats were trained to self-administer ketamine during nine 1-h daily or weekly sessions, under the Priming-[KET + CS] schedule. Lever pressing was then extinguished by saline substitution for ketamine infusion. Afterwards, ketamine was made available again upon responding under the same schedule.


The Priming-[KET + CS] schedule of reinforcement showed a significant increase in the number of ketamine reinforcements and a significant discrimination between active vs. inactive levers. The same schedule allowed the establishment of ketamine self-administration on a weekly basis. During the extinction phase, rate of responding significantly dropped in both weekly and daily groups although it was twofold longer in the former, which showed a lack of reacquisition.


Both pre-session ketamine priming and a conditioned stimulus paired to the ketamine infusions are required for the acquisition of ketamine self-administration. The longer extinction and the lack of reacquisition in the weekly group could be due to changes in temporal context that might affect the conditioning process.


Ketamine Priming Conditioned stimulus Self-administration Intermittent Reinforcement Rat 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Ethics approval

All animal procedures were carried out in accordance with the Principles of laboratory animal care (NIH publication No. 85-23, revised 1985), the European Communities Council Directive (2010/63/UE). All efforts were made to minimize animal suffering and to use the least animals.


  1. Belin-Rauscent A. Belin D. (2012). Animal models of drug addiction. Belin D, (ed). Addictions - from pathophysiology to treatment., InTech, 21-64.Google Scholar
  2. Bouton ME (1986) Slow reacquisition following extinction of conditioned suppression. Learn Motiv 17:1–15CrossRefGoogle Scholar
  3. Bouton ME (1993) Context, time, and memory retrieval in the interference paradigms of Pavlovian learning. Psychol Bull 114(1):80–99CrossRefPubMedGoogle Scholar
  4. Bouton ME, Swartzentruber D (1989) Slow reacquisition following extinction: context, encoding, and retrieval mechanisms. J Exp Psychol Anim Behav Process 15:43–53CrossRefGoogle Scholar
  5. Browne CA, Lucki I (2013) Antidepressant effects of ketamine: mechanisms underlying fast-acting novel antidepressants. Front Pharmacol 4:161PubMedCentralCrossRefPubMedGoogle Scholar
  6. Caggiula AR, Donny EC, White AR, Chaudhri N, Booth S, Gharib MA, Hoffman A, Perkins KA, Sved AF (2001) Cue dependency of nicotine self-administration and smoking. Pharmacol Biochem Behav 70(4):515–530CrossRefPubMedGoogle Scholar
  7. Chaudhri N, Caggiula AR, Donny EC, Booth S, Gharib M, Craven L, Palmatier MI, Liu X, Sved AF (2007) Self-administered and noncontingent nicotine enhance reinforced operant responding in rats: impact of nicotine dose and reinforcement schedule. Psychopharmacology (Berlin) 190(3):353–362. doi: 10.1007/s00213-006-0454-8 CrossRefGoogle Scholar
  8. Chaudhri N, Caggiula AR, Donny EC, Palmatier MI, Liu X, Sved AF (2006) Complex interactions between nicotine and nonpharmacological stimuli reveal multiple roles for nicotine in reinforcement. Psychopharmacology (Berlin) 184(3-4):353–366CrossRefGoogle Scholar
  9. Chiamulera C. Venniro M. Cheung DWS. Mutti A. Padovani L. Di Chio M. Fumagalli G. Yew DT (2014). Neuroadaptation induced by acute or chronic ketamine: long term effects of ketamine selfadministration on zif268 expression in rats. Program No. 811.28. 2014 Neuroscience Meeting Planner. Washington, DC: Society for Neuroscience, 2014., Online.Google Scholar
  10. Chiamulera C, Tedesco V, Zangrandi L, Giuliano C, Fumagalli G (2010) Propranolol transiently inhibits reinstatement of nicotine-seeking behaviour in rats. J Psychopharmacol 24(3):389–395CrossRefPubMedGoogle Scholar
  11. Collins GT, Woods JH (2007) Drug and reinforcement history as determinants of the response-maintaining effects of quinpirole in the rat. J Pharmacol Exp Ther 323(2):599–605. doi: 10.1124/jpet.107.123042 CrossRefPubMedGoogle Scholar
  12. Corlett PR, Cambridge V, Gardner JM, Piggot JS, Turner DC, Everitt JC, Arana FS, Morgan HL, Milton AL, Lee JL, Aitken MR, Dickinson A, Everitt BJ, Absalom AR, Adapa R, Subramanian N, Taylor JR, Krystal JH, Fletcher PC (2013) Ketamine effects on memory reconsolidation favor a learning model of delusions. PLoS One 8(6):e65088. doi: 10.1371/journal.pone.0065088 PubMedCentralCrossRefPubMedGoogle Scholar
  13. De Luca MT, Badiani A (2011) Ketamine self-administration in the rat: evidence for a critical role of setting. Psychopharmacology (Berlin) 214(2):549–556. doi: 10.1007/s00213-010-2062-x CrossRefGoogle Scholar
  14. De Luca MT, Meringolo M, Spagnolo PA, Badiani A (2012) The role of setting for ketamine abuse: clinical and preclinical evidence. Rev Neurosci 23(5-6):769–780. doi: 10.1515/revneuro-2012-0078 PubMedGoogle Scholar
  15. de Wit H (1996) Priming effects with drugs and other reinforcers. Exp Clin Psychopharmacol 4(1):5–10CrossRefGoogle Scholar
  16. Dillon P, Copeland J, Jansen K (2003) Patterns of use and harms associated with non-medical ketamine use. Drug Alcohol Depend 69(1):23–28CrossRefPubMedGoogle Scholar
  17. Huang X, Huang K, Zheng W, Beveridge TJ, Yang S, Li X, Li P, Zhou W, Liu Y (2015) The effects of GSK-3beta blockade on ketamine self-administration and relapse to drug-seeking behavior in rats. Drug Alcohol Depend 147:257–265. doi: 10.1016/j.drugalcdep.2014.10.028 CrossRefPubMedGoogle Scholar
  18. Katz JL, Higgins ST (2003) The validity of the reinstatement model of craving and relapse to drug use. Psychopharmacology (Berlin) 168(1-2):21–30. doi: 10.1007/s00213-003-1441-y CrossRefGoogle Scholar
  19. Lankenau SE, Bloom JJ, Shin C (2010) Longitudinal trajectories of ketamine use among young injection drug users. Int J Drug Policy 21(4):306–314. doi: 10.1016/j.drugpo.2010.01.007 PubMedCentralCrossRefPubMedGoogle Scholar
  20. Lankenau SE, Sanders B (2007) Patterns of ketamine use among young injection drug users. J Psychoactive Drugs 39(1):21–29. doi: 10.1080/02791072.2007.10399861 PubMedCentralCrossRefPubMedGoogle Scholar
  21. Markou A, Chiamulera C, Geyer MA, Tricklebank M, Steckler T (2009) Removing obstacles in neuroscience drug discovery: the future path for animal models. Neuropsychopharmacology 34(1):74–89. doi: 10.1038/npp.2008.173 PubMedCentralCrossRefPubMedGoogle Scholar
  22. Morgan CJ, Curran HV, Independent Scientific Committee on Drugs (2012) Ketamine use: a review. Addiction 107(1):27–38. doi: 10.1111/j.1360-0443.2011.03576.x CrossRefPubMedGoogle Scholar
  23. Morgan CJ, Muetzelfeldt L, Curran HV (2009) Ketamine use, cognition and psychological wellbeing: a comparison of frequent, infrequent and ex-users with polydrug and non-using controls. Addiction 104(1):77–87. doi: 10.1111/j.1360-0443.2008.02394.x CrossRefPubMedGoogle Scholar
  24. Morgan CJ, Muetzelfeldt L, Curran HV (2010) Consequences of chronic ketamine self-administration upon neurocognitive function and psychological wellbeing: a 1-year longitudinal study. Addiction 105(1):121–133. doi: 10.1111/j.1360-0443.2009.02761.x CrossRefPubMedGoogle Scholar
  25. Palmatier MI, Bevins RA (2007) Facilitation by drug states does not depend on acquired excitatory strength. Behav Brain Res 176(2):292–301. doi: 10.1016/j.bbr.2006.10.015 PubMedCentralCrossRefPubMedGoogle Scholar
  26. Palmatier MI, Evans-Martin FF, Hoffman A, Caggiula AR, Chaudhri N, Donny EC, Liu X, Booth S, Gharib M, Craven L, Sved AF (2006) Dissociating the primary reinforcing and reinforcement-enhancing effects of nicotine using a rat self-administration paradigm with concurrently available drug and environmental reinforcers. Psychopharmacology (Berlin) 184(3-4):391–400. doi: 10.1007/s00213-005-0183-4 CrossRefGoogle Scholar
  27. Reid RL (1957) The role of the reinforcer as a stimulus. Br J Psychol 49:192–200Google Scholar
  28. Schifano F, Corkery J, Oyefeso A, Tonia T, Ghodse AH (2008) Trapped in the “K-hole”: overview of deaths associated with ketamine misuse in the UK (1993-2006). J Clin Psychopharmacol 28(1):114–116. doi: 10.1097/JCP.0b013e3181612cdc CrossRefPubMedGoogle Scholar
  29. Spears JB (1978) Cimetidine and mental confusion. Am J Hosp Pharm 35(9):1035PubMedGoogle Scholar
  30. Tedesco V, Ravagnani C, Bertoglio D, Chiamulera C (2013) Acute ketamine-induced neuroplasticity: ribosomal protein S6 phosphorylation expression in drug addiction-related rat brain areas. Neuroreport 24(7):388–393. doi: 10.1097/WNR.0b013e32836131ad CrossRefPubMedGoogle Scholar
  31. Trujillo KA, Zamora JJ, Warmoth KP (2008) Increased response to ketamine following treatment at long intervals: implications for intermittent use. Biol Psychiatry 63(2):178–183. doi: 10.1016/j.biopsych.2007.02.014 CrossRefPubMedGoogle Scholar
  32. Young AM, Woods JH (1981) Maintenance of behavior by ketamine and related compounds in rhesus monkeys with different self-administration histories. J Pharmacol Exp Ther 218:720–727PubMedGoogle Scholar
  33. van der Kam EL, De Vry J, Tzschentke TM (2009) 2-Methyl-6-(phenylethynyl)-pyridine (MPEP) potentiates ketamine and heroin reward as assessed by acquisition, extinction, and reinstatement of conditioned place preference in the rat. Eur J Pharmacol 606(1-3):94–101. doi: 10.1016/j.ejphar.2008.12.042 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Marco Venniro
    • 1
    Email author
  • Anna Mutti
    • 1
  • Cristiano Chiamulera
    • 1
  1. 1.Neuropsychopharmacology Laboratory, Section of Pharmacology, Department of Public Health and Community MedicineUniversity of VeronaVeronaItaly

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