Influence of Nicotine Metabolism Ratio on [11C]-(+)-PHNO PET Binding in Tobacco Smokers

Patricia Di Ciano, Rachel F Tyndale, Esmaeil Mansouri, Christian S Hendershot, Alan A Wilson, Dina Lagzdins, Sylvain Houle, Isabelle Boileau, Bernard Le Foll, Patricia Di Ciano, Rachel F Tyndale, Esmaeil Mansouri, Christian S Hendershot, Alan A Wilson, Dina Lagzdins, Sylvain Houle, Isabelle Boileau, Bernard Le Foll

Abstract

Background: Identifying the biological basis of smoking cessation success is of growing interest. The rate of nicotine metabolism, measured by the nicotine metabolite ratio, affects multiple aspects of nicotine dependence. Fast nicotine metabolizers tend to smoke more, experience more withdrawal and craving, and have lower cessation rates compared with slow metabolizers. The nicotine metabolite ratio predicts treatment response, and differences in brain activation between fast metabolizers and slow metabolizers have been reported in fMRI studies. As reinforcing/rewarding effects of tobacco are associated with dopamine transmission, the purpose of the present study was to study the dopaminergic system in human smokers based on their nicotine metabolite ratio.

Methods: The first aim of the study was to explore if there were differences in D2 and D3 receptor binding between fast metabolizers and slow metabolizers during abstinence. The second aim was to explore smoking-induced dopamine release in both groups. Participants underwent 2 [11C]-(+)-PHNO PET scans: one scan during abstinence and the other after smoking a tobacco cigarette. Subjective measures were recorded and blood was drawn for measurement of nicotine and cotinine levels.

Results: During abstinence, slow metabolizers (n = 13) had lower [11C]-(+)-PHNO binding potential than fast metabolizers (n = 15) restricted to the D2 regions of the associative striatum and sensorimotor striatum. After smoking a cigarette, [11C]-(+)-PHNO binding potential was decreased in the limbic striatum and ventral pallidum, suggestive of increases in dopamine, but there were no nicotine metabolite ratio differences.

Conclusions: Further studies are required to delineate if differences in [11C]-(+)-PHNO binding between slow metabolizers and fast metabolizers at abstinence baseline are preexisting traits or induced by prolonged tobacco use.

Figures

Figure 1.
Figure 1.
Binding potential (BPND) measured at abstinence baseline in participants with fast nicotine metabolism ratios (NMRs) (open symbols) or slow NMRs (dark symbols) in regions of interest (ROIs) (presented in order of D3 fraction: SN: substantia nigra; VP: ventral pallidum; GP: globus pallidus; LST: ventral/limbic striatum; AST: associative striatum; SMST: sensorimotor striatum). *P < .05, fast NMR different from slow NMR.
Figure 2.
Figure 2.
Top: Binding potential (BPND) measured at abstinence baseline (open symbols) or after smoking a preferred cigarette (dark symbols) in regions of interest (ROIs). *P < .05, abstinence different from smoking. Bottom: Change in [11C]-(+)-PHNO BPND between abstinence baseline and smoking condition in ROIs. Open symbols are the fast metabolizers (FM) and closed symbols are the slow metabolizers (SM). No differences were found between the FMs and SMs. ROIs are presented in order of D3 fraction: SN: substantia nigra; VP: ventral pallidum; GP: globus pallidus; LST: ventral/limbic striatum; AST: associative striatum; SMST: sensorimotor striatum.
Figure 3.
Figure 3.
Left: Correlation between change in binding potential (BPND) in the ventral/limbic striatum (LST) after smoking and time between smoking and the start of the scan (open symbols) and the number of puffs of the preferred cigarette (dark bars). Right: Correlation between change in BPND in the ventral pallidum (VP) after smoking and inter-puff interval.

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