PT  - JOURNAL ARTICLE
AU  - G. Patrick Hussmann
AU  - Jill R. Turner
AU  - Ermelinda Lomazzo
AU  - Rashmi Venkatesh
AU  - Vanessa Cousins
AU  - Yingxian Xiao
AU  - Robert P. Yasuda
AU  - Barry B. Wolfe
AU  - David C. Perry
AU  - Amir H. Rezvani
AU  - Edward D. Levin
AU  - Julie A. Blendy
AU  - Kenneth J. Kellar
TI  - Chronic Sazetidine-A at Behaviorally Active Doses Does Not Increase Nicotinic Cholinergic Receptors in Rodent Brain
AID  - 10.1124/jpet.112.198085
DP  - 2012 Nov 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 441--450
VI  - 343
IP  - 2
4099  - http://jpet.aspetjournals.org/content/343/2/441.short
4100  - http://jpet.aspetjournals.org/content/343/2/441.full
SO  - J Pharmacol Exp Ther2012 Nov 01; 343
AB  - Chronic nicotine administration increases α4β2 neuronal nicotinic acetylcholine receptor (nAChR) density in brain. This up-regulation probably 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 the 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 such as saz-A can promote smoking cessation without maintaining nAChR up-regulation, thereby potentially increasing the rate of long-term abstinence from nicotine.