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Cigarette Smoking Saturates Brain ₄₂ Nicotinic Acetylcholine Receptors

Arthur L. Brody, MD; Mark A. Mandelkern, MD, PhD; Edythe D. London, PhD; Richard E. Olmstead, PhD; Judah Farahi, PhD; David Scheibal, BS; Jennifer Jou, BS; Valerie Allen, BS; Emmanuelle Tiongson, BS; Svetlana I. Chefer, PhD; Andrei O. Koren, PhD; Alexey G. Mukhin, MD, PhD

Arch Gen Psychiatry. 2006;63:907-914.

Context  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 ₄₂* nicotinic acetylcholine receptors (nAChRs) with positron emission tomography (PET) scanning in humans.

Objective  To determine the effect of cigarette smoking on ₄₂* nAChR occupancy in tobacco-dependent smokers.

Design  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 to 3 cigarettes]).

Setting  Academic brain imaging center.

Participants  Eleven tobacco-dependent smokers (paid volunteers).

Main Outcome Measure  Dose-dependent effect of smoking on occupancy of ₄₂* 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 ₄₂* 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 ₄₂* nAChRs.

Conclusions  Cigarette smoking in amounts used by typical daily smokers leads to nearly complete occupancy of ₄₂* nAChRs, indicating that tobacco-dependent smokers maintain ₄₂* nAChR saturation throughout the day. Because prolonged binding of nicotine to ₄₂* 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.

Author Affiliations: Department of Psychiatry and Biobehavioral Sciences (Drs Brody and London, Mr Scheibal, and Mss Jou, Allen, and Tiongson), University of California, Los Angeles; Greater Los Angeles Veterans Affairs Healthcare System Positron Emission Tomography Center (Drs Brody, Mandelkern, London, Olmstead, and Farahi, Mr Scheibal, and Mss Jou, Allen, and Tiongson), Los Angeles; Department of Physics, University of California, Irvine (Dr Mandelkern); Intramural Research Program, Neuroimaging Research Branch, National Institute on Drug Abuse, Rockville, Md (Drs Chefer and Mukhin); and Institute for Neurodegenerative Disorders, New Haven, Conn (Dr Koren).

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