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

Journal Article (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

  • PMC3477215

Electronic International Standard Serial Number (EISSN)

  • 1521-0103

Digital Object Identifier (DOI)

  • 10.1124/jpet.112.198085

Language

  • eng

Conference Location

  • United States