Subsets of acetylcholine-stimulated 86Rb+ efflux and [125I]-epibatidine binding sites in C57BL/6 mouse brain are differentially affected by chronic nicotine treatment.
Nicotinic cholinergic receptor (nAChR) sites that bind nicotine with high affinity (likely alpha4beta2-nAChR) increase following chronic nicotine treatment. Effects of chronic treatment on other nAChR binding sites and functional responses of nAChRs are less well studied. Therefore, C57BL/6 mice were intravenously infused for 10 days with saline or nicotine (five doses, 0.25-4.0 mg/kg/h) and nAChR function and three different nicotinic binding sites in 12 brain regions were assessed. Plasma nicotine and cotinine increased linearly with dose. 86Rb+ efflux with higher sensitivity to acetylcholine tended to decrease with increasing dose, whereas efflux with lower sensitivity to acetylcholine tended to increase. As anticipated, likely alpha4beta2-nAChR [125I]-epibatidine binding sites increased with treatment (estimated dosage for one-half maximal increase was 0.44 mg/kg/h, plasma nicotine approximately 20 ng/ml). 86Rb+ efflux with higher sensitivity to acetylcholine and cytisine-sensitive [125I]-epibatidine binding are predominantly alpha4beta2-nAChR. A high correlation between these parameters was observed across brain regions and slopes of these regression lines decreased with treatment dose, suggesting a decrease in function per unit receptor. Likely alpha3beta4-nAChR binding sites were unaffected even at the highest dose (4.0 mg/kg/h, approximately 210 ng/ml). A third set of diverse nAChR binding sites increased in some brain regions, but only after high-dose treatment.
Marks
Michael J
MJ
Institute for Behavioral Genetics, UCB447, University of Colorado, 1480 30th Street, Boulder, CO 80309, USA. marksm@colorado.edu
Rowell
Peter P
PP
Cao
Jian-Zhe
JZ
Grady
Sharon R
SR
McCallum
Sarah E
SE
Collins
Allan C
AC
D000109:Acetylcholine / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007457:Iodine Radioisotopes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009538:Nicotine / Q000008:administration & dosage*; D011725:Pyridines / Q000378:metabolism*; D011950:Receptors, Cholinergic / Q000378:metabolism; D012414:Rubidium Radioisotopes / Q000378:metabolism
D019086:Bridged Bicyclo Compounds, Heterocyclic; D007457:Iodine Radioisotopes; D011725:Pyridines; D011950:Receptors, Cholinergic; D012414:Rubidium Radioisotopes; D009538:Nicotine; C082748:epibatidine; D000109:Acetylcholine