Decreased Nicotinic Receptor Availability in Smokers with Slow Rates of Nicotine Metabolism

Abstract

The nicotine metabolite ratio (NMR), a stable measure of hepatic nicotine metabolism via the CYP2A6 pathway and total nicotine clearance, is a predictive biomarker of response to nicotine replacement therapy, with increased quit rates in slower metabolizers. Nicotine binds directly to nicotinic acetylcholine receptors (nAChRs) to exert its psychoactive effects. This study examined the relationship between NMR and nAChR (α4β2* subtype) availability using PET imaging of the radiotracer 2-(18)F-fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-(18)F-FA-85380, or 2-(18)F-FA).

Methods: Twenty-four smokers-12 slow metabolizers (NMR < 0.26) and 12 normal metabolizers (NMR ≥ 0.26)-underwent 2-(18)F-FA-PET brain imaging after overnight nicotine abstinence (18 h before scanning), using a validated bolus-plus-infusion protocol. Availability of nAChRs was compared between NMR groups in a priori volumes of interest, with total distribution volume (VT/fP) being the measure of nAChR availability. Cravings to smoke were assessed before and after the scans.

Results: Thalamic nAChR α4β2* availability was significantly reduced in slow nicotine metabolizers (P = 0.04). Slow metabolizers exhibited greater reductions in cravings after scanning than normal metabolizers; however, craving was unrelated to nAChR availability.

Conclusion: The rate of nicotine metabolism is associated with thalamic nAChR availability. Additional studies could examine whether altered nAChR availability underlies the differences in treatment response between slow and normal metabolizers of nicotine.

Keywords: 2-18F-FA-85380; PET; addiction; nicotine; nicotine metabolite ratio; α4β2* nAChR.

© 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Figures

Figure 1. 2-[18F]FA VT/fP by region

Partial volume corrected VT/fP values by NMR group: Smokers with slower nicotine metabolism (NMR <0.26) demonstrated decreased VT/fP in brain compared to those with normal metabolism including in the thalamus (p=0.037), the region of greatest nAChR density within the CNS. This relationship persisted and approached significance when comparing VT/fP between slow (bottom quartile) and normal NMR groups for the entire brain (p=0.07). P values were calculated using one-way ANOVA. “*” indicates P < 0.05. Error bars show standard error of the mean. For whole brain, frontal lobe, thalamus and temporal lobe, P=0.07, 0.1, 0.04 and 0.1, respectively).

Figure 2. Mean 2-[18F]FA VT/fP Images

Mean positron emission tomographic (PET) images demonstrating lower 2-[18F]FA binding in subgroup with slower hepatic metabolism of nicotine. Mean PET images for normal metabolizer cohort (left) and cohort with slower rates of hepatic nicotine metabolism (right) were spatially normalized to the same template. VT/fP indicates the total volume of distribution.