Cigarette smoking saturates brain alpha 4 beta 2 nicotinic acetylcholine receptors

Abstract

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 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(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 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 1/25th 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.

Figure 1

Time-activity curves (mean±SEM) for the 2 subjects undergoing full (8 hours) scanning with no smoking. The graphs demonstrate that 3 to 4 hours from the beginning of radioligand infusion are needed to reach a near steady state in the primary regions of interest for the bolus/infusion paradigm used herein. The average increase in radioactivity starting 3.5 hours after initiation of 2-[¹⁸F]fluoro-3-(2(S)-azetidinylmethoxy) pyridine (2-F-A-85380) administration was 3.2%, 3.2%, and 2.6% per hour for the thalamus, brainstem, and cerebellum, respectively.

Figure 2

Time-activity curves for the 5 smoking levels for the primary regions of interest. A, Thalamus. B, Brainstem. C, Cerebellum. Radioactivity is expressed as percentage of baseline value (mean radioactivity for the hour before the smoking break±standard errors of the mean between subjects). 1 indicates 0 cigarettes; 2 indicates 1 puff; 3 indicates 3 puffs; 4 indicates 1 full cigarette; and 5 indicates satiety (2.8 cigarettes). Dotted lines indicate the time of the smoking break. D, Displacement of radioactivity in the whole brain and regions of interest in a subject who smoked to satiety (2.5 cigarettes) during the break (mean±SE in volume of interest).

Figure 3

2-[¹⁸F]fluoro-3-(2(S)-azetidinylmethoxy) pyridine (2-F-A-85380) positron emission tomography (PET) images before (top row) and 3.1 hours after (bottom row) cigarette smoking. Images were obtained by averaging the six 10-minute frames over the 1 hour prior to the smoking break and by averaging the seven 10-minute scans from a mean of 3.1 hours after smoking the cigarette amount listed. The far right column shows a magnetic resonance image (MRI) of the brain and a PET image of nondisplaceable radioactivity distribution (calculated). All PET images were aligned to the level shown on the MRI.

Figure 4

Effects of variable smoking (number of cigarettes) and venous plasma nicotine levels on radiotracer displacement. A, Percentage of displacement of total radioactivity (C_t) in regions of interest for the range of smoking levels from 0 to 2.8 cigarettes, based on the ratio of displaced C_t by each cigarette dose to prebreak C_t, without correction for the imperfect steady state of the radiotracer found in control scans. B and C, Displacement of specific binding (SB) (a measure that takes into account nondisplaceable radioactivity derived from the asymptotic portion of the saturation curve in part A) by the varying smoking levels without and with correction for the imperfect steady state, respectively. D, Specific binding displacement as a function of venous plasma nicotine levels, corrected.