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

Publication ,  Journal Article
Hussmann, GP; Turner, JR; Lomazzo, E; Venkatesh, R; Cousins, V; Xiao, Y; Yasuda, RP; Wolfe, BB; Perry, DC; Rezvani, AH; Levin, ED; Blendy, JA ...
Published in: J Pharmacol Exp Ther
November 2012

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.

Duke Scholars

Published In

J Pharmacol Exp Ther

DOI

EISSN

1521-0103

Publication Date

November 2012

Volume

343

Issue

2

Start / End Page

441 / 450

Location

United States

Related Subject Headings

  • Varenicline
  • Up-Regulation
  • Self Administration
  • Receptors, Nicotinic
  • Rats, Sprague-Dawley
  • Rats
  • Quinoxalines
  • Pyridines
  • Pregnancy
  • Pharmacology & Pharmacy
 

Citation

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Hussmann, G. P., Turner, J. R., Lomazzo, E., Venkatesh, R., Cousins, V., Xiao, Y., … Kellar, K. J. (2012). Chronic sazetidine-A at behaviorally active doses does not increase nicotinic cholinergic receptors in rodent brain. J Pharmacol Exp Ther, 343(2), 441–450. https://doi.org/10.1124/jpet.112.198085
Hussmann, G Patrick, Jill R. Turner, Ermelinda Lomazzo, Rashmi Venkatesh, Vanessa Cousins, Yingxian Xiao, Robert P. Yasuda, et al. “Chronic sazetidine-A at behaviorally active doses does not increase nicotinic cholinergic receptors in rodent brain.J Pharmacol Exp Ther 343, no. 2 (November 2012): 441–50. https://doi.org/10.1124/jpet.112.198085.
Hussmann GP, Turner JR, Lomazzo E, Venkatesh R, Cousins V, Xiao Y, et al. Chronic sazetidine-A at behaviorally active doses does not increase nicotinic cholinergic receptors in rodent brain. J Pharmacol Exp Ther. 2012 Nov;343(2):441–50.
Hussmann, G. Patrick, et al. “Chronic sazetidine-A at behaviorally active doses does not increase nicotinic cholinergic receptors in rodent brain.J Pharmacol Exp Ther, vol. 343, no. 2, Nov. 2012, pp. 441–50. Pubmed, doi:10.1124/jpet.112.198085.
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. Chronic sazetidine-A at behaviorally active doses does not increase nicotinic cholinergic receptors in rodent brain. J Pharmacol Exp Ther. 2012 Nov;343(2):441–450.
Journal cover image

Published In

J Pharmacol Exp Ther

DOI

EISSN

1521-0103

Publication Date

November 2012

Volume

343

Issue

2

Start / End Page

441 / 450

Location

United States

Related Subject Headings

  • Varenicline
  • Up-Regulation
  • Self Administration
  • Receptors, Nicotinic
  • Rats, Sprague-Dawley
  • Rats
  • Quinoxalines
  • Pyridines
  • Pregnancy
  • Pharmacology & Pharmacy