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


CONCLUSIONS
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.
Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania jacob.dubroff@uphs.upenn.edu.
Jacob G
JG
Dubroff
Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania.
Robert K
RK
Doot
Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania.
Mary
M
Falcone
Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania.
Robert A
RA
Schnoll
Global Medical Affairs, GlaxoSmithKline, Brussels, Belgium.
Riju
R
Ray
Department of Pharmacology and Toxicology, and Department of Psychiatry, CAMH, University of Toronto, Toronto, Canada.
Rachel F
RF
Tyndale
Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, California; and Department of Psychiatry, Veterans Administration Greater Los Angeles Healthcare System, Los Angeles, California.
Arthur L
AL
Brody
Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania.
Catherine
C
Hou
Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania.
Alexander
A
Schmitz
Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania.
Caryn
C
Lerman
D000328:Adult; D001384:Azetidines; D001682:Biological Availability; D001921:Brain / Q000378:metabolism; D066249:Craving; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008875:Middle Aged; D009538:Nicotine / Q000378:metabolism* / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D011725:Pyridines; D019275:Radiopharmaceuticals; D011978:Receptors, Nicotinic / Q000378:metabolism*; D015203:Reproducibility of Results; D012907:Smoking / Q000378:metabolism* / Q000523:psychology; D013788:Thalamus / Q000000981:diagnostic imaging; D014029:Tobacco Use Disorder / Q000378:metabolism / Q000523:psychology; D055815:Young Adult
C119803:2-fluoro-3-(2-azetidinylmethoxy)pyridine; D001384:Azetidines; D011725:Pyridines; D019275:Radiopharmaceuticals; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D009538:Nicotine
2-18F-FA-85380; PET; addiction; nicotine; nicotine metabolite ratio; α4β2* nAChR