Brain β2*-nicotinic acetylcholine receptor occupancy after use of a nicotine inhaler

Abstract

The Nicotrol® (Pfizer, USA) nicotine inhaler reduces craving by mimicking the behavioural component of cigarettes and delivering controlled doses of nicotine, which binds to the beta-2 subunit-containing nicotinic acetylcholine receptors (β2*-nAChRs). Previous studies examined β2*-nAChR occupancy after administration of regular and low-nicotine cigarettes. Here, we measured occupancy of β2*-nAChRs after administration of nicotine via inhaler, and the relationship between occupancy and changes in craving for tobacco smoking and withdrawal symptoms. Tobacco smokers participated in [123I]5-IA-85380 SPECT studies with either a nicotine inhaler (n=9) or tobacco cigarette (n=4) challenge. [123I]5-IA was administered as a bolus plus constant infusion. After equilibrium was achieved, three 30-min baseline scans were collected, and subjects either used the nicotine inhaler or a regular cigarette, and up to six additional scans were obtained. Receptor occupancy was determined based on the Lassen plot method. Craving for tobacco smoking and withdrawal symptoms were evaluated pre- and post-challenge. Use of the nicotine inhaler produced an average 55.9±6.4% occupancy of β2*-nAChRs 2-5 h post-challenge, whereas use of a cigarette produced significantly higher receptor occupancy (F=10.6, p=0.009) with an average 67.6±14.1% occupancy 1.5-5 h post-challenge. There was a significant decrease in withdrawal symptoms post-nicotine inhaler use (F=6.13, p=0.04). These results demonstrate significant differences in occupancy of β2*-nAChRs by nicotine after use of the inhaler vs. a cigarette and confirm the ability of the nicotine inhaler to relieve withdrawal symptoms.

Fig. 1

SPECT scan day procedures over a 14-h period. Subjects were infused with the radiotracer for the duration of the study. They completed craving and withdrawal assessments post-[¹²³I]5-IA infusion start. At 5.5 h post-infusion STEP scan was obtained, followed by three SPECT emissions at 6–8 h post-infusion start. Then a nicotine challenge (inhaler or cigarette) was administered, subjects again completed questionnaires, and were placed in the camera 10–14 h post-infusion initiation for an additional two sets of three SPECT emissions.

Fig. 2

Time–activity curves before and after Nicotrol nicotine inhaler (left : 30-yr-old Hispanic man, 276.8 MBq injected total) and regular cigarette use (right : 22-yr-old Asian woman, 301.6 MBq injected total) abstinent for 1 wk prior to scan and imaged using [¹²³I]5-IA SPECT. Equilibrium, defined as <5% change per hour, was reached prior to challenge. Three equilibrium scans were obtained, the nicotine inhaler or cigarette were administered, and the subject then participated in up to six post-inhaler scans starting 2 h after administration of nicotine inhaler.

Fig. 3

β₂^*-nAChR occupancy in each subject over the 4 h of scan time after the nicotine challenge. Subjects were placed in the camera on average 108.2 (±22.1) min post-initiation of nicotine inhaler challenge (–◆–) and 91.8 (±20.3) min post-initiation of cigarette challenge (–●–). Average receptor occupancy across subjects and scans was 56.7±6.7% for nicotine inhaler, which is less than after smoking one regular cigarette (66.4±5.7 %).

Fig. 4

Subjects with a greater desire to smoke a cigarette after use of the nicotine inhaler had higher β₂^*-nAChR occupancy by nicotine. Individual subject data are shown in the scatter plot and the regression line represents correlation results for scan 1 (ρ=0.92, p=0.001).