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

Abstract

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. 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. 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. 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. 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.