, Volume 223, Issue 2, pp 223–235

Facilitation of extinction of operant behaviour in C57Bl/6 mice by chlordiazepoxide and d-cycloserine

  • Julian C. Leslie
  • Kelly Norwood
  • Paul J. Kennedy
  • Michael Begley
  • David Shaw
Original Investigation


Rationale and objective

Effects on the extinction of GABAergic drug, chlordiazepoxide (CDP), and glutamatergic drug, d-cycloserine (DCS), in C57BL/6 mice were compared.

Materials and methods

Following a palatability test (Experiment 1), Experiments 26 involved food-reinforced lever press training followed by extinction sessions at 1- or 4-day intervals. The effects of drugs were examined. Experiment 7 involved a two-lever task.


CDP did not affect food palatability (Experiment 1), but facilitated extinction when administered prior to extinction sessions via intracerebral (Experiment 2) or peripheral administration at 1-day (Experiments 37) or 4-day intervals (Experiment 6). Reducing the amount of training prior to extinction reduced the delay in the effect of CDP typically seen, and CDP had a larger effect in early sessions on mice that had received less training (Experiment 3). There was some evidence that CDP could be blocked by flumazenil (Experiment 4), and CDP withdrawal reversed extinction facilitation (Experiments 5 and 7). With 4-day intervals, DCS administered immediately following extinction sessions, or pre-session CDP, facilitated extinction with 48-trial sessions (experiment 6B). With six-trial sessions, the co-administration of post-session DCS enhanced facilitation produced by pre-session CDP (experiment 6A). Finally, CDP facilitated extinction in a dose-related fashion following training on a two-lever food-reinforced task (Experiment 7).


The findings are consistent with the hypotheses that two neurotransmitter systems have different roles in operant extinction and that glutamatergic systems are involved in extinction learning and GABAergic systems involved in the expression of that learning. This parallels findings with extinction following Pavlovian conditioning, which has been more extensively investigated.


Operant conditioning Extinction Chlordiazepoxide d-cycloserine C57Bl/6 mice 


  1. Amsel A (1962) Frustrative nonreward in partial reinforcement and discrimination learning: some recent history and a theoretical extension. Psychol Rev 69:306–328PubMedCrossRefGoogle Scholar
  2. Balleine BW, Ball J, Dickinson A (1994) Benzodiazepine-induced outcome revaluation and the motivational control in instrumental action in rats. Behav Neurosci 108:573–589PubMedCrossRefGoogle Scholar
  3. Berridge KC, Pecina S (1995) Benzodiazepines, appetite, and taste palatability. Neurosci Biobehav Rev Rev 19:121–131CrossRefGoogle Scholar
  4. Botreau F, Paolone G, Stewart J (2006) d-Cycloserine facilitates extinction of a cocaine-induced conditioned place preference. Behav Brain Res 172:173–178PubMedCrossRefGoogle Scholar
  5. Caldwell ML, Leslie JC (2011). Effects of chlordiazepoxide on drug discrimination training and extinction in C57Bl/6 mice. Paper presented at the Fifth Annual Conference, Division of Behaviour Analysis, Psychological Society of Ireland, Dublin, AprilGoogle Scholar
  6. Cooper SJ (1980) Benzodiazepines as appetite-enhancing compounds. Appetite 1:7–19CrossRefGoogle Scholar
  7. Cooper SJ, Estall LB (1985) Behavioural pharmacology of food, water and salt intake in relation to drug actions at benzodiazepine receptors. Neurosci Biobehav Rev 9:5–19PubMedCrossRefGoogle Scholar
  8. Davis M, Ressler K, Rothbaum BO, Richardson R (2006) Effects of d-cycloserine on extinction: translation from preclinical to clinical work. Biol Psychiatry 60:369–375PubMedCrossRefGoogle Scholar
  9. De Wit H, Stewart J (1981) Reinstatement of cocaine-reinforced responding in the rat. Psychopharmacology 75:134–143PubMedCrossRefGoogle Scholar
  10. Dillon GM, Qu X, Marcus JN, Dodart J-C (2008) Excitotoxic lesions restricted to the dorsal CA1 field of the hippocampus impair spatial memory and extinction learning in C57Bl/6 mice. Neurobiol Learn Mem 90:426–433PubMedCrossRefGoogle Scholar
  11. Emmanouil D, Johnson CH, Quock RM (1994) Nitrous oxide anxiolytic effect in mice in the elevated plus-maze-mediation by benzodiazepine receptors. Psychopharmacology 115:167–172PubMedCrossRefGoogle Scholar
  12. Franklin BJK, Paxinos G (2007) The mouse brain in stereotaxic coordinates. Elsevier, AmsterdamGoogle Scholar
  13. Joel D, Doljansky J (2003) Selective alleviation of compulsive lever-pressing in rats by D-1, but not D-2, blockade: possible implications for the involvement of D-1 receptors in obsessive-compulsive disorder. Neuropsychopharmacology 28:77–85PubMedCrossRefGoogle Scholar
  14. Keller FS, Schoenfeld WN (1950) Principles of psychology. Appleton, New YorkGoogle Scholar
  15. Ledgerwood L, Richardson R, Cranney J (2003) Effects of d-cycloserine on extinction of conditioned freezing. Behav Neurosci 117:341–349PubMedCrossRefGoogle Scholar
  16. Leslie JC, Shaw D, McCabe C, Reynolds DS, Dawson GR (2004) Effects of drugs that potentiate GABA on extinction of positively-reinforced operant behaviour. Neurosci Biobehav Rev 28:229–238PubMedCrossRefGoogle Scholar
  17. Leslie JC, Shaw D, Gregg G, McCormick N, Reynolds DS, Dawson GR (2005) Effects of reinforcement schedule on facilitation of operant extinction by chlordiazepoxide. J Exp Anal Behav 84:327–238PubMedCrossRefGoogle Scholar
  18. Leslie JC, Sharp K, Quigley L, Carson A, McGovern S, Shaw D (2007) Effects of chlordiazepoxide on extinction of operant behaviour in mice vary with time of administration and rate of extinction. Eur J Behav Anal 8:257–266Google Scholar
  19. Mathiasen L, Mizra NR (2005) A comparison of bretazenil, L838,417 and zolpidem in a validated mouse Vogel conflict test. Psychopharmacology 182:475–484PubMedCrossRefGoogle Scholar
  20. McCabe C, Shaw D, Atack JR, Street LJ, Wafford KA, Dawson GR et al (2004) Subtype-selective GABAergic drugs facilitate extinction of mouse operant behavior. Neuropharmacology 46:171–178PubMedCrossRefGoogle Scholar
  21. McKernan RM, Rosahl TW, Reynolds DS, Sur C, Wafford A, Atack JR et al (2000) Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABAA receptor a subtype. Nat Neurosci 3:587–592PubMedCrossRefGoogle Scholar
  22. Myers KM, Davis M (2002) Behavioral and neural analysis of extinction. Neuron 36:567–584PubMedCrossRefGoogle Scholar
  23. Nevin JA, Mandell C, Atak JR (1983) The analysis of behavioral momentum. J Exp Anal Behav 39:49–59PubMedCrossRefGoogle Scholar
  24. Norwood K, McGovern SFJ, Kennedy PJ, Shaw D, Leslie JC (2011) Effects of chlordiazepoxide on runway behaviours of C57Bl/6 mice under continuous or partial reinforcement. Behav Pharmacol 22:167–172PubMedCrossRefGoogle Scholar
  25. Paolone G, Botreau F, Stewart J (2009) The facilitative effects of d-cycloserine on extinction of a cocaine-induced conditioned place preference can be long lasting and resistant to reinstatement. Psychopharmacology 202:403–409PubMedCrossRefGoogle Scholar
  26. Parnas AS, Weber M, Richardson R (2005) Effects of multiple exposures to d-cycloserine on extinction of conditioned fear in rats. Neurobiol Learn Mem 83:224–231PubMedCrossRefGoogle Scholar
  27. Pitman RK (1989) Animal models of compulsive behavior. Biol Psychiatry 26:189–198PubMedCrossRefGoogle Scholar
  28. Poling A, Byrne T, Christian L, Lesage MG (2000) Effects of cocaine and morphine under mixed-ratio schedules of food delivery: support for a behavioral momentum analysis. Pharmacol Biochem Behav 66:313–321PubMedCrossRefGoogle Scholar
  29. Quartermain D, Mower J, Rafferty MF, Herting RL, Lanthorn TH (1994) Acute but not chronic activation of the NMDA-coupled glycine receptor with d-cycloserine facilitates learning and retention. Eur J Pharmacol 257:7–12PubMedCrossRefGoogle Scholar
  30. Quirk GJ, Mueller D (2008) Neural mechanisms of extinction learning and retrieval. Neuropsychopharmacology 33:56–72PubMedCrossRefGoogle Scholar
  31. Shaw D, Dawson GR, Reynolds DS, McCabe C, Leslie JC (2004) Effects of chlordiazepoxide on extinction and re-acquisition of operant behavior in mice. Behav Pharmacol 15:225–232PubMedGoogle Scholar
  32. Shaw D, Norwood K, Sharp K, Quigley L, McGovern S, Leslie JC (2009) Facilitation of extinction of operant behaviour in mice by d-cycloserine. Psychopharmacology 202:397–402PubMedCrossRefGoogle Scholar
  33. Sidman M (1960) Tactics of scientific research. Basic Books, New YorkGoogle Scholar
  34. Skinner BF (1938) The behavior of organisms. Apple-Century-Crofts, New YorkGoogle Scholar
  35. Stephens DN, Elliman TD, Dunworth SJ (2000) State-dependent behavioural sensitization: evidence from a chlordiazepoxide state. Behav Pharmacol 11:161–167PubMedCrossRefGoogle Scholar
  36. Thanos PK, Subrize M, Lui W, Puca Z, Ananth M, Michaelides M, Wang GJ, Volkow ND (2011) d-Cycloserine facilitates extinction of cocaine self-administration in c57 mice. Synapse 65:1099–1105PubMedCrossRefGoogle Scholar
  37. Walker DL, Ressler KJ, Lu KT, Davis M (2002) Facilitation of conditioned fear extinction by systemic administration or intra-amygdala infusions of d-cycloserine as assessed with fear-potentiated startle in rats. J Neurosci 22:2343–2351PubMedGoogle Scholar
  38. Williams JH, Gray JA, Sinden J, Buckland C, Rawlins JNP (1990) Effects of GABAergic drugs, fornicotomy, hippocampectomy and septal lesions on the extinction of a discrete-trial fixed ratio 5 lever-press response. Behav Brain Res 41:129–150PubMedCrossRefGoogle Scholar
  39. Willner PJ, Crowe R (1977) Effect of chlordiazepoxide on the partial reinforcement extinction effect. Pharmacol Biochem Behav 7:479–482PubMedCrossRefGoogle Scholar
  40. Wise RA, Dawson V (1974) Diazepam-induced eating and lever pressing for food in sated rats. J Comp Physiol Psychol 86:930–941PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Julian C. Leslie
    • 1
  • Kelly Norwood
    • 1
  • Paul J. Kennedy
    • 2
    • 3
  • Michael Begley
    • 1
  • David Shaw
    • 1
  1. 1.School of PsychologyUniversity of UlsterColeraineUK
  2. 2.Alimentary Pharmabiotic CentreUniversity College CorkCorkIreland
  3. 3.Department of PsychiatryUniversity College CorkCorkIreland

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