Cigarette smoking saturates brain alpha 4 beta 2 nicotinic acetylcholine receptors.
BACKGROUND
2-[18F]fluoro-3-(2(S)-azetidinylmethoxy) pyridine (2-F-A-85380, abbreviated as 2-FA) is a recently developed radioligand that allows for visualization of brain alpha 4 beta 2* nicotinic acetylcholine receptors (nAChRs) with positron emission tomography (PET) scanning in humans.


OBJECTIVE
To determine the effect of cigarette smoking on alpha 4 beta 2* nAChR occupancy in tobacco-dependent smokers.


METHODS
Fourteen 2-FA PET scanning sessions were performed. During the PET scanning sessions, subjects smoked 1 of 5 amounts (none, 1 puff, 3 puffs, 1 full cigarette, or to satiety [2(1/2) to 3 cigarettes]).


METHODS
Academic brain imaging center.


METHODS
Eleven tobacco-dependent smokers (paid volunteers). Main Outcome Measure Dose-dependent effect of smoking on occupancy of alpha 4 beta 2* nAChRs, as measured with 2-FA and PET in nAChR-rich brain regions.


RESULTS
Smoking 0.13 (1 to 2 puffs) of a cigarette resulted in 50% occupancy of alpha 4 beta 2* nAChRs for 3.1 hours after smoking. Smoking a full cigarette (or more) resulted in more than 88% receptor occupancy and was accompanied by a reduction in cigarette craving. A venous plasma nicotine concentration of 0.87 ng/mL (roughly 1/25th of the level achieved in typical daily smokers) was associated with 50% occupancy of alpha 4 beta 2* nAChRs.


CONCLUSIONS
Cigarette smoking in amounts used by typical daily smokers leads to nearly complete occupancy of alpha 4 beta 2* nAChRs, indicating that tobacco-dependent smokers maintain alpha 4 beta 2* nAChR saturation throughout the day. Because prolonged binding of nicotine to alpha 4 beta 2* nAChRs is associated with desensitization of these receptors, the extent of receptor occupancy found herein suggests that smoking may lead to withdrawal alleviation by maintaining nAChRs in the desensitized state.
Brody
Arthur L
AL
Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA 90095, USA. abrody@ucla.edu
Mandelkern
Mark A
MA
London
Edythe D
ED
Olmstead
Richard E
RE
Farahi
Judah
J
Scheibal
David
D
Jou
Jennifer
J
Allen
Valerie
V
Tiongson
Emmanuelle
E
Chefer
Svetlana I
SI
Koren
Andrei O
AO
Mukhin
Alexey G
AG
D000328:Adult; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009538:Nicotine / Q000097:blood / Q000378:metabolism; D049268:Positron-Emission Tomography; D011725:Pyridines; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012907:Smoking / Q000097:blood / Q000378:metabolism*; D013375:Substance Withdrawal Syndrome / Q000378:metabolism / Q000517:prevention & control; D014018:Tissue Distribution; D014029:Tobacco Use Disorder / Q000000981:diagnostic imaging / Q000378:metabolism
C499325:2-fluoro-3-(2(S)-azetidinylmethoxy)pyridine; D011725:Pyridines; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D009538:Nicotine