The International Journal of Neuropsychopharmacology

Research Article

Brain nicotinic acetylcholine receptor occupancy: effect of smoking a denicotinized cigarette

Arthur L. Brodya1a2 c1, Mark A. Mandelkerna2a3, Matthew R. Costelloa1a2, Anna L. Abramsa2, David Scheibala2, Judah Farahia2, Edythe D. Londona1a4, Richard E. Olmsteada2, Jed E. Rosea5 and Alexey G. Mukhina5

a1 UCLA Department of Psychiatry and Biobehavioral Sciences, Los Angeles, CA, USA

a2 Greater Los Angeles VA Healthcare System Positron Emission Tomography Center, Los Angeles, CA, USA

a3 UCI Department of Physics, Irvine, CA, USA

a4 UCLA Department of Molecular and Medical Pharmacology, Los Angeles, CA, USA

a5 Duke University School of Medicine, Durham, NC, USA

Abstract

Our group recently reported that smoking a regular cigarette (1.2–1.4 mg nicotine) resulted in 88% occupancy of brain α4β2* nicotinic acetylcholine receptors (nAChRs). However, this study did not determine whether nicotine inhalation or the many other pharmacological and behavioural factors that occur during smoking resulted in this receptor occupancy. If nicotine is solely responsible for α4β2* nAChR occupancy from smoking, then (as estimated from our previous data) smoking a denicotinized (0.05 mg nicotine) or a low-nicotine (0.6 mg nicotine) cigarette (commonly used for research and clinical purposes) would result in substantial 23% and 78% α4β2* nAChR occupancies, respectively, and a plasma nicotine concentration of 0.87 ng/ml would result in 50% α4β2* nAChR occupancy (EC50). Twenty-four positron emission tomography sessions were performed on tobacco-dependent smokers, using 2-[F-18]fluoro-A-85380 (2-FA), a radiotracer that binds to α4β2* nAChRs. 2-FA displacement was determined from before to 3.1 hours after either: no smoking, smoking a denicotinized cigarette, or smoking a low-nicotine cigarette. Analysis of this PET data revealed that smoking a denicotinized and a low-nicotine cigarette resulted in 26% and 79% α4β2* nAChR occupancies, respectively, across three regions of interest. The EC50 determined from this dataset was 0.75 ng/ml. Given the consistency of findings between our previous study with regular cigarettes and the present study, nicotine inhalation during smoking appears to be solely responsible for α4β2* nAChR occupancy, with other factors (if present at all) having either short-lived or very minor effects. Furthermore, smoking a denicotinized cigarette resulted in substantial nAChR occupancy.

(Received March 26 2008)

(Reviewed April 28 2008)

(Revised June 23 2008)

(Accepted July 07 2008)

(Online publication August 18 2008)

Correspondence:

c1 Address for correspondence: A. L. Brody, M.D., UCLA Department of Psychiatry & Biobehavioral Sciences, 300 UCLA Medical Plaza, Suite 2200, Los Angeles, CA 90095, USA. Tel.: 310-268-4778 Fax: 310-206-2802 E-mail: abrody@ucla.edu