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

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Abstract

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 2–6 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.

Results

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 3–7) 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).

Conclusions

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.

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Acknowledgements

This research was supported in part by a grant from the U.K. Biotechnology and Biological Sciences Research Council. Experimental procedures were in accordance with the UK Animals (Scientific Procedures) Act (1986) and its associated guidelines. We are indebted to two anonymous reviewers for helpful comments on an earlier draft.

Disclosure/conflicts of interest

This research was supported, in part, by a grant from the U.K. Biotechnology and Biological Sciences Research Council. The authors have no financial relationship with the U.K. Biotechnology and Biological Sciences Research Council.

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Authors and Affiliations

  1. School of Psychology, University of Ulster, Coleraine, BT52 1SA, Northern Ireland, UK

    Julian C. Leslie, Kelly Norwood, Michael Begley & David Shaw

  2. Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland

    Paul J. Kennedy

  3. Department of Psychiatry, University College Cork, Cork, Ireland

    Paul J. Kennedy

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  1. Julian C. Leslie
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  2. Kelly Norwood
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  3. Paul J. Kennedy
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  4. Michael Begley
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  5. David Shaw
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Correspondence to Julian C. Leslie.

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Leslie, J.C., Norwood, K., Kennedy, P.J. et al. Facilitation of extinction of operant behaviour in C57Bl/6 mice by chlordiazepoxide and d-cycloserine. Psychopharmacology 223, 223–235 (2012). https://doi.org/10.1007/s00213-012-2710-4

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  • DOI: https://doi.org/10.1007/s00213-012-2710-4

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