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Deletion of the beta 2 nicotinic acetylcholine receptor subunit alters development of tolerance to nicotine and eliminates receptor upregulation

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Abstract

Rationale

Chronic nicotine exposure induces both tolerance and upregulation of [3H]nicotine binding sites in rodent and human brain. However, the mechanism for chronic tolerance is unclear because a direct relationship between tolerance and receptor upregulation is not consistently observed.

Objectives

In the present experiments, the role of β2* nicotinic acetylcholine receptors (nAChRs) on tolerance development and nAChR upregulation was examined following chronic nicotine treatment of β2 wild-type (+/+), heterozygous (+/−), and null mutant (−/−) mice.

Methods

Saline or nicotine (1, 2, or 4 mg/kg/h) was infused intravenously for 10 days. Locomotor activity and body temperature responses were measured before and after nicotine challenge injection to observe changes in nicotine sensitivity. [3H]Epibatidine binding was then measured in ten brain regions.

Results

β2+/+ mice developed dose-dependent tolerance and upregulation of [3H]epibatidine binding sites. In contrast, β2−/− mice, initially less sensitive to acute nicotine's effects, became more sensitive following treatment with the lowest chronic dose (1 mg/kg/h). β2−/− mice treated with 4.0 mg/kg/h nicotine were no longer supersensitive, indicating that tolerance developed at this higher dose. However, these changes in nicotine sensitivity occurred in the absence of any nAChR changes in either low- or high-affinity [3H]epibatidine sites. Responses of β2+/− mice were intermediate between wild-type and mutant mice.

Conclusions

Upregulation of nAChRs in vivo requires the presence of the β2 subunit. Changes in nicotine sensitivity occurred both in the presence (β2+/+) and absence (β2−/−) of β2* nAChRs and suggest that mechanisms involving both β2* and non-β2* nAChR subtypes modulate adaptation to chronic nicotine exposure.

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Acknowledgements

This work was supported by grants DA-12661 and DA-03194 from the National Institute on Drug Abuse. A.C.C. is supported, in part, by Research Scientist Award DA-00197 from NIDA. S.E.M. was supported by NIDA grant DA-14152.

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Authors and Affiliations

  1. Institute for Behavioral Genetics, University of Colorado, Boulder, CO, 80309, USA

    Sarah E. McCallum, Allan C. Collins & Michael J. Marks

  2. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA

    Richard Paylor

  3. The Parkinson's Institute, 1170 Morse Avenue, Sunnyvale, CA, 94089, USA

    Sarah E. McCallum

Authors
  1. Sarah E. McCallum
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  2. Allan C. Collins
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  3. Richard Paylor
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  4. Michael J. Marks
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Correspondence to Sarah E. McCallum.

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S.E.M. has moved to the Parkinson's Institute, Sunnyvale, CA 94089, USA.

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McCallum, S.E., Collins, A.C., Paylor, R. et al. Deletion of the beta 2 nicotinic acetylcholine receptor subunit alters development of tolerance to nicotine and eliminates receptor upregulation. Psychopharmacology 184, 314–327 (2006). https://doi.org/10.1007/s00213-005-0076-6

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  • DOI: https://doi.org/10.1007/s00213-005-0076-6

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