%0 Journal Article %A G. Patrick Hussmann %A Jill R. Turner %A Ermelinda Lomazzo %A Rashmi Venkatesh %A Vanessa Cousins %A Yingxian Xiao %A Robert P. Yasuda %A Barry B. Wolfe %A David C. Perry %A Amir H. Rezvani %A Edward D. Levin %A Julie A. Blendy %A Kenneth J. Kellar %T Chronic sazetidine-A at behaviorally active doses does not increase nicotinic cholinergic receptors in rodent brain %D 2012 %R 10.1124/jpet.112.198085 %J Journal of Pharmacology and Experimental Therapeutics %P jpet.112.198085 %X Chronic nicotine administration increases α4β2 neuronal nicotinic acetylcholine receptor (nAChR) density in brain. This up-regulation likely contributes to the development and/or maintenance of nicotine dependence. nAChR up-regulation is believed to be triggered at the ligand binding site, so it is not surprising that other nicotinic ligands also up-regulate nAChRs in brain. These other ligands include varenicline, which is currently used for smoking cessation therapy. Sazetidine-A (saz-A) is a newer nicotinic ligand that binds with high affinity and selectivity at α4β2* nAChRs. In behavioral studies, saz-A decreases nicotine self-administration and increases performance on tasks of attention. We report here that unlike nicotine and varenicline, chronic administration of saz-A at behaviorally active and even higher doses does not up-regulate nAChRs in rodent brains. We used a newly developed method involving radioligand binding to measure the concentrations and nAChR occupancy of saz-A, nicotine and varenicline in brains from chronically treated rats. Our results indicate that saz-A reached concentrations in the brain that were ~150 times its affinity for α4β2* nAChRs and occupied at least 75% of nAChRs. Thus, chronic administration of saz-A did not up-regulate nAChRs despite it reaching brain concentrations that are known to bind and desensitize virtually all α4β2* nAChRs in brain. These findings reinforce a model of nicotine addiction based on desensitization of up-regulated nAChRs and introduce a potential new strategy for smoking cessation therapy in which drugs like saz-A can promote smoking cessation without maintaining nAChR up-regulation, thereby potentially increasing the rate of long-term abstinence from nicotine. %U https://jpet.aspetjournals.org/content/jpet/early/2012/08/16/jpet.112.198085.full.pdf