Chronic sazetidine-A at behaviorally active doses does not increase nicotinic cholinergic receptors in rodent brain.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Hussmann, GP; Turner, JR; Lomazzo, E; Venkatesh, R; Cousins, V; Xiao, Y; Yasuda, RP; Wolfe, BB; Perry, DC; Rezvani, AH; Levin, ED; Blendy, JA; Kellar, KJ

Published Date

  • November 2012

Published In

Volume / Issue

  • 343 / 2

Start / End Page

  • 441 - 450

PubMed ID

  • 22899752

Pubmed Central ID

  • 22899752

Electronic International Standard Serial Number (EISSN)

  • 1521-0103

Digital Object Identifier (DOI)

  • 10.1124/jpet.112.198085

Language

  • eng

Conference Location

  • United States