Abstract
Background
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.
Methods
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.
Results
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.
Conclusions
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.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Belin-Rauscent A. Belin D. (2012). Animal models of drug addiction. Belin D, (ed). Addictions - from pathophysiology to treatment., InTech, 21-64.
Bouton ME (1986) Slow reacquisition following extinction of conditioned suppression. Learn Motiv 17:1–15
Bouton ME (1993) Context, time, and memory retrieval in the interference paradigms of Pavlovian learning. Psychol Bull 114(1):80–99
Bouton ME, Swartzentruber D (1989) Slow reacquisition following extinction: context, encoding, and retrieval mechanisms. J Exp Psychol Anim Behav Process 15:43–53
Browne CA, Lucki I (2013) Antidepressant effects of ketamine: mechanisms underlying fast-acting novel antidepressants. Front Pharmacol 4:161
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):515–530
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
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):353–366
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.
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):389–395
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
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
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
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
de Wit H (1996) Priming effects with drugs and other reinforcers. Exp Clin Psychopharmacol 4(1):5–10
Dillon P, Copeland J, Jansen K (2003) Patterns of use and harms associated with non-medical ketamine use. Drug Alcohol Depend 69(1):23–28
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
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
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
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
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
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
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
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
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
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
Reid RL (1957) The role of the reinforcer as a stimulus. Br J Psychol 49:192–200
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
Spears JB (1978) Cimetidine and mental confusion. Am J Hosp Pharm 35(9):1035
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
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
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 218:720–727
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
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.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Venniro, M., Mutti, A. & Chiamulera, C. Pharmacological and non-pharmacological factors that regulate the acquisition of ketamine self-administration in rats. Psychopharmacology 232, 4505–4514 (2015). https://doi.org/10.1007/s00213-015-4077-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-015-4077-9