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

作者：Dubroff Jacob G^*; Doot Robert K; Falcone Mary; Schnoll Robert A; Ray Riju; Tyndale Rachel F; Brody Arthur L; Hou Catherine; Schmitz Alexander; Lerman Caryn

来源：Journal of Nuclear Medicine, 2015, 56(11): 1724-1729.

DOI：10.2967/jnumed.115.155002

• PET
• nicotine
• addiction
• 2-F-18-FA-85380
• nicotine metabolite ratio
• alpha 4 beta 2*nAChR

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 (alpha 4 beta 2* subtype) availability using PET imaging of the radiotracer 2-F-18-fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-F-18-FA-85380, or 2-F-18-FA). Methods: Twenty-four smokers-12 slow metabolizers (NMR < 0.26) and 12 normal metabolizers (NMR >= 0.26) underwent 2-F-18-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 (V-T/f(P)) being the measure of nAChR availability. Cravings to smoke were assessed before and after the scans. Results: Thalamic nAChR alpha 4 beta 2* 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.

• 出版日期2015-11