期刊
PSYCHOPHARMACOLOGY
卷 184, 期 3-4, 页码 314-327出版社
SPRINGER
DOI: 10.1007/s00213-005-0076-6
关键词
nicotine; beta 2 null mutant mouse; tolerance; sensitivity; receptor upregulation; [H-3]epibatidine
资金
- NIDA NIH HHS [DA-14152, DA-12661, DA-03194, DA-00197] Funding Source: Medline
Rationale: Chronic nicotine exposure induces both tolerance and upregulation of [H-3]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 beta 2* nicotinic acetylcholine receptors (nAChRs) on tolerance development and nAChR upregulation was examined following chronic nicotine treatment of beta 2 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. [H-3]Epibatidine binding was then measured in ten brain regions. Results: beta 2+/+ mice developed dose-dependent tolerance and upregulation of [H-3]epibatidine binding sites. In contrast, beta 2-/- mice, initially less sensitive to acute nicotine's effects, became more sensitive following treatment with the lowest chronic dose (1 mg/kg/h). beta 2-/- 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 [H-3]epibatidine sites. Responses of beta 2+/- mice were intermediate between wild-type and mutant mice. Conclusion: Upregulation of nAChRs in vivo requires the presence of the beta 2 subunit. Changes in nicotine sensitivity occurred both in the presence (beta 2+/+) and absence (beta 2-/-) of beta 2* nAChRs and suggest that mechanisms involving both beta 2* and non-beta 2* nAChR subtypes modulate adaptation to chronic nicotine exposure.
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