Subsets of acetylcholine-stimulated 86Rb+ efflux and [125I]-epibatidine binding sites in C57BL/6 mouse brain are differentially affected by chronic nicotine treatment

Neuropharmacology. 2004 Jun;46(8):1141-57. doi: 10.1016/j.neuropharm.2004.02.009.


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.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetylcholine / pharmacology*
  • Animals
  • Binding Sites / drug effects
  • Binding Sites / physiology
  • Brain / drug effects
  • Brain / metabolism*
  • Bridged Bicyclo Compounds, Heterocyclic / metabolism*
  • Dose-Response Relationship, Drug
  • Female
  • Iodine Radioisotopes / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Nicotine / administration & dosage*
  • Pyridines / metabolism*
  • Receptors, Cholinergic / metabolism
  • Rubidium Radioisotopes / metabolism


  • Bridged Bicyclo Compounds, Heterocyclic
  • Iodine Radioisotopes
  • Pyridines
  • Receptors, Cholinergic
  • Rubidium Radioisotopes
  • Nicotine
  • epibatidine
  • Acetylcholine