Abstract
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.
Footnotes
This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grants DA012976, DA015767, DA027990, F32-DA026236]; and the National Institutes of Health National Cancer Institute [Grant CA143187].
Sazetidine-A was developed by K.J.K., Y.X., and Georgetown University. Georgetown University currently holds the patent on sazetidine-A.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS:
- nAChR
- neuronal nicotinic acetylcholine receptor
- [3H]EB
- [3H]epibatidine
- [125I]EB
- [125I]epibatidine
- Nic
- nicotine
- saz-A
- sazetidine-A
- Var
- varenicline
- MK801
- (5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine.
- Received July 3, 2012.
- Accepted August 15, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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