title: A single administration of low-dose varenicline saturates α4β2* nicotinic acetylcholine receptors in the human brain.
abstract: The primary objective of this project was to determine the α4β2(*) nicotinic acetylcholine receptor (nAChR) occupancy in human brain of a single low dose of varenicline (0.5 mg), and to explore the relationship between receptor occupancy by varenicline and tobacco withdrawal symptoms ((*)denoting other putative nAChR subunits). Otherwise healthy smokers (n=9) underwent two positron emission tomography (PET) sessions with the selective α4β2(*) radioligand 2-FA. For the PET sessions, participants received either a low dose of varenicline (0.5 mg) or matching placebo pill (double-blind, random order) before imaging. For both sessions, participants received bolus plus continuous infusions of 2-FA, were scanned for 1 h after allowing the radiotracer to reach a steady state, smoked to satiety, and were scanned for 2 more hours. We estimated the fractional receptor occupancy by a single dose of varenicline (0.5 mg) and the corresponding varenicline dissociation constant (K(V)), along with the effect of low-dose varenicline, pill placebo, and smoking-to-satiety on withdrawal rating scales. The data are compatible with 100% occupancy of α4β2(*) nAChRs by a single dose of varenicline, with a 90% lower confidence limit of 89% occupancy for the thalamus and brainstem. The corresponding 90% upper limit on effective K(V) with respect to plasma varenicline was 0.49 nM. Smoking to satiety, but not low-dose varenicline, significantly reduced withdrawal symptoms. Our findings demonstrate that low-dose varenicline results in saturation of α4β2(*) nAChRs in the thalamus and brainstem without reducing withdrawal symptoms.
authors.affiliation: Hatos Center for Neuropharmacology, Semel Institute, University of California, Los Angeles, CA, USA. shahrdad@ucla.edu
authors.forename: Shahrdad
authors.initials: S
authors.lastname: Lotfipour
authors.forename: Mark
authors.initials: M
authors.lastname: Mandelkern
authors.forename: Miguel
authors.initials: M
authors.lastname: Alvarez-Estrada
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Brody
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001552:Benzazepines / Q000494:pharmacology*; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism; D003367:Cotinine / Q000097:blood; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018722:Nicotinic Agonists / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology*; D011877:Radionuclide Imaging; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012907:Smoking / Q000097:blood; D000068580:Varenicline
chemical_list: D001552:Benzazepines; D018722:Nicotinic Agonists; D011810:Quinoxalines; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D003367:Cotinine; D000068580:Varenicline