, Volume 184, Issue 3-4, pp 314-327
Date: 02 Jul 2005

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.

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