Cigarette Smoking Saturates Brain α4β2 Nicotinic Acetylcholine Receptors

Context 2-[18F]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 α4β2* nicotinic acetylcholine receptors (nAChRs) with positron emission tomography (PET) scanning in humans. Objective To determine the effect of cigarette smoking on α4β2* 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 [2½ 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 α4β2* 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 α4β2* 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 α4β2* nAChRs. Conclusions Cigarette smoking in amounts used by typical daily smokers leads to nearly complete occupancy of α4β2* nAChRs, indicating that tobacco-dependent smokers maintain α4β2* nAChR saturation throughout the day. Because prolonged binding of nicotine to α4β2* 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.