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 availability (α4β2* subtype) using positron emission tomography (PET) imaging of the radiotracer 2-18F-FA-85380 (2-18F-FA). Methods Twenty four smokers, 12 slow metabolizers (NMR <0.26) and 12 normal metabolizers (NMR ≥0.26), underwent 2-18F-FA-PET brain imaging following overnight nicotine abstinence (18 hours prior to scanning), using a validated bolus plus infusion protocol. Availability of nAChRs was compared between NMR groups in a priori volumes of interest (VOIs), with total distribution volume (VT/fP) being the measure of nAChR availability. Cravings to smoke were assessed prior to and following the scans. Results Thalamic nAChR α4β2* availability was significantly reduced in slow (versus normal) nicotine metabolizers (P=0.04). Slow metabolizers exhibited greater reductions in craving than normal metabolizers from pre- to post-scanning; however, craving was unrelated to availability. Conclusion The rate of nicotine metabolism is associated with thalamic nAChR availability. Additional studies could examine whether altered nAChR availability underlies differences in treatment response between slow and normal metabolizers of nicotine.

Total-Body PET: Maximizing Sensitivity to Create New Opportunities for Clinical Research and Patient Care

“…A second example of multiorgan disease would be the strong link between nonalcoholic fatty liver disease and heart disease, just one of several conditions in which hepatic and cardiac disorders are intertwined (39). In a further example, a clear relationship between the availability of nicotinic acetylcholine receptors in the brain as determined by PET with hepatic nicotine metabolism, and their dependency on smoking, was demonstrated (40). Although these findings lead to an increasing interest in studying and treating disease from a systems perspective, there are few tools and assays that can provide data to support such research.…”

Pharmacogenetic Optimization of Smoking Cessation Treatment

“…Different investigations have selected NMR cut-points based on sensitivity and specificity analyses of smoking cessation outcomes and/or pragmatic reasons (e.g., recruitment goals, statistical power); across different studies slow metabolizers generally represent the lowest 25–40% of the NMR distribution [21, 22]. Slower nicotine metabolizers (determined by CYP2A6 activity group or NMR) have lower cigarette consumption [23], dependence [24, 25], nAChR availability [26], and brain response to smoking (versus control) cues [27, 28], compared to faster nicotine metabolizers. Slower nicotine metabolizers also display higher smoking cessation rates in the absence of pharmacotherapy [29–31].…”

Precision Medicine for Tobacco Dependence: Development and Validation of the Nicotine Metabolite Ratio

“…Because nicotine exerts its effects by binding to nicotinic acetylcholine receptors, Dubroff et al (2015) assessed the relationship between the NMR and α4β2* nAChR availability using PET imaging with 2-(18)F-fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-(18)F-FA). Results showed a reduction of thalamic α4β2* nAChR availability and a greater reduction of craving in slow nicotine metabolizers compared to normal metabolizers after 18 hours of abstinence.…”