Nicotine metabolism and genetic variation have an impact on nicotine addiction and smoking abstinence; however, further research is required. The nicotine metabolite ratio (NMR) is a robust biomarker of nicotine metabolism used to categorize slow and normal nicotine metabolizers (lower 25th quartile cut off). In two randomized clinical trials of smoking abstinence treatments, we conducted NMR-stratified analyses on smoking abstinence across 13 regions coding for nicotinic acetylcholine receptors and proteins involved in the dopamine reward system. Gene×NMR interaction P-values were adjusted for multiple correlated tests, and we used a Bonferroni-corrected α-level of 0.004 to determine system-wide significance. Three single-nucleotide polymorphisms in DRD1 (rs11746641, rs2168631, and rs11749035) had significant interactions (0.001 ≤ adjusted P-values ≤ 0.004) with increased odds of abstinence within slow metabolizers (odds ratios=3.1-3.5, 95% confidence interval 1.7-6.7). Our findings support the role of DRD1 in nicotine dependence, and identify genetic and nicotine metabolism profiles that may interact to impact nicotine dependence.

Unlabelled

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.