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An examination of NMDA receptor contribution to conditioned responding evoked by the conditional stimulus effects of nicotine

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Abstract

Rationale

Research using a drug discriminated goal-tracking (DGT) task showed that the N-methyl-d-aspartate (NMDA) channel blocker MK-801 (dizocilpine) reduced the nicotine-evoked conditioned response (CR).

Objectives

Given the unknown mechanism of the effect, Experiment 1 replicated the MK-801 results and included tests with NMDA receptor ligands. Experiments 2a and 2b tested whether MK-801 pretreatment blocked DGT via a state-dependency effect.

Methods

In Experiment 1, adult male Sprague–Dawley rats received intermittent access to liquid sucrose following nicotine (0.4 mg base/kg); no sucrose was delivered on intermixed saline sessions. Conditioning was indicated by increased anticipatory dipper entries (goal-tracking) on nicotine compared to saline sessions. Antagonism and/or substitution tests were conducted with MK-801, phencyclidine, CGP 39551, d-CPPene (SDZ EAA 494), Ro 25,6981, L-701,324, ACPC, and NMDA. In Experiment 2a, rats received nicotine and sucrose on every session—no intermixed saline sessions without sucrose. Tests combined MK-801 or the non-competitive nicotinic acetylcholine receptor antagonist, mecamylamine with either nicotine or saline. Experiment 2b had sucrose delivered on saline sessions and no sucrose on intermixed nicotine sessions followed by MK-801 antagonism tests of the saline CS.

Results

MK-801 and phencyclidine dose-dependently attenuated the CR in Experiment 1. Ro-25,6981 enhanced the CR, but did not substitute for nicotine. Other ligands showed inconsistent effects. In Experiment 2a, MK-801 pretreatment reduced goal-tracking when given before nicotine and saline test sessions; mecamylamine pretreatment had no effect. In Experiment 2b, MK-801 dose-dependently attenuated the saline-evoked CR.

Conclusions

Combined, the results suggest that MK-801 blocks discriminated goal-tracking by virtue of state-changing properties.

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Acknowledgments

We are grateful for the excellent laboratory assistance of George D. Lyford and Jacob M. Williams. We thank Gonzalo Urcelay for his insightful comments on an earlier version of the report and the National Institute on Drug Abuse Drug Supply Program for providing the phencyclidine. The research and R.A. Bevins were supported by United States Public Health Service grant DA018114. J.E. Murray was supported by NIDA F31 DA025399 and MRC 9536855 (to B.J. Everitt) during the preparation of this manuscript. None of these organizations had any role in the study design, the data collection, analysis, or interpretation, or in the writing of the manuscript or the decision to submit the paper for publication. All MED-PC programs used in the present article are available upon request to R.A. Bevins, rbevins1@unl.edu. Correspondence related to this article should be addressed to Jennifer E. Murray, Department of Experimental Psychology, Downing Street, Cambridge, UK, CB2 3EB, or e-mail jem98@cam.ac.uk.

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  1. Department of Psychology, University of Nebraska—Lincoln, Lincoln, NE, 68588-0308, USA

    Jennifer E. Murray, Andrew W. Walker, Robert J. Polewan & Rick A. Bevins

  2. Department of Experimental Psychology, University of Cambridge, Cambridge, CB2 3EB, UK

    Jennifer E. Murray

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  1. Jennifer E. Murray
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Murray, J.E., Walker, A.W., Polewan, R.J. et al. An examination of NMDA receptor contribution to conditioned responding evoked by the conditional stimulus effects of nicotine. Psychopharmacology 213, 131–141 (2011). https://doi.org/10.1007/s00213-010-2022-5

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  • DOI: https://doi.org/10.1007/s00213-010-2022-5

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