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


OBJECTIVE
In the present experiments, the role of beta2* nicotinic acetylcholine receptors (nAChRs) on tolerance development and nAChR upregulation was examined following chronic nicotine treatment of beta2 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
Beta2+/+ mice developed dose-dependent tolerance and upregulation of [3H]epibatidine binding sites. In contrast, beta2-/- mice, initially less sensitive to acute nicotine's effects, became more sensitive following treatment with the lowest chronic dose (1 mg/kg/h). Beta2-/- 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 beta2+/- mice were intermediate between wild-type and mutant mice.


CONCLUSIONS
Upregulation of nAChRs in vivo requires the presence of the beta2 subunit. Changes in nicotine sensitivity occurred both in the presence (beta2+/+) and absence (beta2-/-) of beta2* nAChRs and suggest that mechanisms involving both beta2* and non-beta2* nAChR subtypes modulate adaptation to chronic nicotine exposure.
Institute for Behavioral Genetics, University of Colorado, Boulder, CO 80309, USA. smccallum@thepi.org
Sarah E
SE
McCallum
Allan C
AC
Collins
Richard
R
Paylor
Michael J
MJ
Marks
D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000187:drug effects*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000493:pharmacokinetics; D002872:Chromosome Deletion; D005838:Genotype; D006579:Heterozygote; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009154:Mutation; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000493:pharmacokinetics; D011725:Pyridines / Q000493:pharmacokinetics; D011978:Receptors, Nicotinic / Q000235:genetics*; D014029:Tobacco Use Disorder / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics
D019086:Bridged Bicyclo Compounds, Heterocyclic; D009538:Nicotine; D018722:Nicotinic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; C082748:epibatidine