Cigarette smoking saturates brain α4β2 nicotinic acetylcholine receptors

Context: 2-[F-18]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 alpha(4)beta(2)* nicotinic acetylcholine receptors (nAChRs) with positron emission tomography (PET) scanning in humans. Objective: To determine the effect of cigarette smoking on alpha(4)beta(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(2)/(1) 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 alpha(4)beta(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 alpha(4)beta(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 (25)/(1)th of the level achieved in typical daily smokers) was associated with 50% occupancy of alpha(4)beta(2)* nAChRs. Conclusions: Cigarette smoking in amounts used by typical daily smokers leads to nearly complete occupancy of alpha(4)beta(2)* nAChRs, indicating that tobacco-dependent smokers maintain alpha(4)beta(2)* nAChR saturation throughout the day. Because prolonged binding of nicotine to alpha(4)beta(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.