Effect of hepatic nicotine metabolism on nicotinic acetylcholine receptor availability and craving

Objectives Smokers who metabolize nicotine more slowly (measured by the nicotine metabolite ratio (NMR); 3'-hydroxycotinine/cotinine) have a higher likelihood of successful smoking cessation (1) and may experience less nicotine reward and less severe withdrawal (2,3). 2-[18F]FA-PET imaging, specific for nicotinic acetylcholine receptor (nAChR) α4β2 subunit, has demonstrated increased nAChR density in smokers compared to nonsmokers with density decreasing after quitting (4,5). Our goal was to determine the relationship of nAChR availability using 2-[18F]FA-PET brain imaging with NMR in abstaining smokers and examine its association with craving symptoms.

Methods Smokers (n=8 slow and n=12 normal metabolizers) were recruited as part of larger treatment study (Pharmacogenetics Research Network Grant). After overnight nicotine abstinence, participants underwent bolus plus infusion 2-[18F] FA-PET imaging from 6 to 7.5 hours after injection (6). Before and following 2-[18F]FA infusion, participants’ smoking urges were measured using the Questionnaire of Smoking Urgency (7). Participants’ plasma NMR levels were determined and compared to distribution volumes (VT) calculated from the ratio of partial volume corrected 2-[18F] FA-PET uptake in co-registered PET and T1-weighted MRI images and non-metabolized 2-[18F]FA in plasma (1,6).

Results Smokers with slower nicotine metabolism (NMR <0.26) demonstrated decreased VT in thalamus (p=0.03) compared to those with normal metabolism. Pre and post smoking craving decreased in only smokers with slower NMRs (p=0.018).

Conclusions These preliminary results suggest that underlying changes in nAChR availability in smokers are conferred by individual differences in the hepatic metabolism of nicotine and may drive nicotine craving.

Research Support Pharmacogenetics Research Network Grant (NIDA/NCI/NHGRI/NIGMS), Abramson Cancer Center at the University of Pennsylvania, ITMAT UPENN (NIH), McCabe Pilot Award (UPENN)