Cigarette Smoking Saturates Brain α4β2 Nicotinic Acetylcholine Receptors

Context: 2-[ 18 F]fluoro-3-(2(S)-azetidinylmethoxy) pyridine (2-F-A-85380, abbreviated as 2-FA) is a recently developed radioligand that allows for visualization of brain ␣ 4 ␤ 2 * nicotinic acetylcholine receptors (nAChRs) with positron emission tomography (PET) scanning in humans.Objective: To determine the effect of cigarette smoking on ␣ 4 ␤ 2 * nAChR occupancy in tobacco-dependent smokers.Design: Fourteen 2-FA PET scanning sessions were performed.During the PET scanning sessions, subjects smoked 1 of 5 amounts (none, 1 puff, 3 puffs, 1 full cigarette, or to satiety [2 1 ⁄2 to 3 cigarettes]).Setting: Academic brain imaging center.Participants: Eleven tobacco-dependent smokers (paid volunteers).Main Outcome Measure: Dose-dependent effect of smoking on occupancy of ␣ 4 ␤ 2 * nAChRs, as measured with 2-FA and PET in nAChR-rich brain regions.Results: Smoking 0.13 (1 to 2 puffs) of a cigarette resulted in 50% occupancy of ␣ 4 ␤ 2 * nAChRs for 3.1 hours after smoking.Smoking a full cigarette (or more) resulted in more than 88% receptor occupancy and was accompanied by a reduction in cigarette craving.A venous plasma nicotine concentration of 0.87 ng/mL (roughly 1 ⁄25th of the level achieved in typical daily smokers) was associated with 50% occupancy of ␣ 4 ␤ 2 * nAChRs.Conclusions: Cigarette smoking in amounts used by typical daily smokers leads to nearly complete occupancy of ␣ 4 ␤ 2 * nAChRs, indicating that tobacco-dependent smokers maintain ␣ 4 ␤ 2 * nAChR saturation throughout the day.Because prolonged binding of nicotine to ␣ 4 ␤ 2 * nAChRs is associated with desensitization of these receptors, the extent of receptor occupancy found herein suggests that smoking may lead to withdrawal alleviation by maintaining nAChRs in the desensitized state.