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Ligands selective for α4β2 but not α3β4 or α7 nicotinic receptors generalise to the nicotine discriminative stimulus in the rat

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Abstract

Rationale

Nicotine produces behavioural effects that are potentially related to its interaction with diverse nicotinic acetylcholine receptor populations. Evidence from gene deletion studies suggests that the interoceptive stimulus properties of nicotine are mediated by heteromeric high-affinity receptors containing α4β2 subunits. Mice lacking β2 subunits do not discriminate nicotine (Shoaib et al., Neuropharmacology, 42:530–539, 2002), and nicotine does not elicit dopamine release in these animals (Grady et al., J Neurochem, 76:258–268, 2001). The stimulus properties of nicotine can be detected in rats using a two-lever operant drug discrimination paradigm, allowing them to be classified pharmacologically using ligands with selectivity for receptors containing α4β2, α3β4 or α7 subunits.

Materials and methods

Rats trained to discriminate 0.4 mg/kg nicotine from vehicle were given the nicotinic receptor agonists, cytisine, varenicline, TC2559, ABT-594, A-85380 (all having high affinity but varying selectivity for α4β2-containing receptors), and WO 03/062224 and WO 01/60821A1 (selective for β4- and α7-containing receptors, respectively). In separate studies, WO 03/062224 was used as the training stimulus.

Results

Nicotine, TC-2559, A-85380 and ABT-594 showed dose-dependent and complete stimulus substitution, whilst WO 03/062224 and WO 01/60821A1 were completely without effect. Cytisine and varenicline showed partial generalisation, consistent with their partial agonist activity at nicotinic receptors eliciting dopamine release in rat striatal slices. After almost 50 training sessions with WO 03/062224, there was no clear evidence that an α3β4 receptor agonist could sustain a discriminable stimulus.

Conclusion

Substitution to the nicotine discriminative stimulus required high-affinity and high intrinsic activity at β2 but not at β4- or at α7-containing nicotinic receptors.

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Acknowledgements

This work would not have been made possible without the technical assistance of Louise Wallace, Anne-Helene Clugery, Daniel Kumpik, Kimberley Smith, Ellen Colvin and John Boot.

All experiments conducted within this paper comply with the current laws of the country in which they were performed.

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Authors and Affiliations

  1. Eli Lilly & Co. Ltd., Lilly Research Centre, Sunninghill Road, Windlesham, Surrey, GU20 6PH, UK

    Janice W. Smith, Adrian Mogg, Elisiana Tafi, Eleanor Peacey, Ian A. Pullar, Philip Szekeres & Mark Tricklebank

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  1. Janice W. Smith
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  2. Adrian Mogg
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  3. Elisiana Tafi
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Correspondence to Janice W. Smith.

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Smith, J.W., Mogg, A., Tafi, E. et al. Ligands selective for α4β2 but not α3β4 or α7 nicotinic receptors generalise to the nicotine discriminative stimulus in the rat. Psychopharmacology 190, 157–170 (2007). https://doi.org/10.1007/s00213-006-0596-8

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  • DOI: https://doi.org/10.1007/s00213-006-0596-8

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