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Research ArticleNeuropharmacology

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

G. Patrick Hussmann, Jill R. Turner, Ermelinda Lomazzo, Rashmi Venkatesh, Vanessa Cousins, Yingxian Xiao, Robert P. Yasuda, Barry B. Wolfe, David C. Perry, Amir H. Rezvani, Edward D. Levin, Julie A. Blendy and Kenneth J. Kellar
Journal of Pharmacology and Experimental Therapeutics August 16, 2012, jpet.112.198085; DOI: https://doi.org/10.1124/jpet.112.198085
G. Patrick Hussmann
1 Georgetown University;
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Jill R. Turner
2 University of Pennsylvania;
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Ermelinda Lomazzo
1 Georgetown University;
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Rashmi Venkatesh
1 Georgetown University;
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Vanessa Cousins
3 Duke University;
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Yingxian Xiao
1 Georgetown University;
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Robert P. Yasuda
1 Georgetown University;
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Barry B. Wolfe
1 Georgetown University;
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David C. Perry
4 George Washington University
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Amir H. Rezvani
3 Duke University;
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Edward D. Levin
3 Duke University;
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Julie A. Blendy
2 University of Pennsylvania;
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Kenneth J. Kellar
1 Georgetown University;
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Abstract

Chronic nicotine administration increases α4β2 neuronal nicotinic acetylcholine receptor (nAChR) density in brain. This up-regulation likely 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 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 like saz-A can promote smoking cessation without maintaining nAChR up-regulation, thereby potentially increasing the rate of long-term abstinence from nicotine.

  • acetylcholine receptors
  • nicotine
  • nicotinic acetylcholine receptors
  • receptor-up regulation
  • Received July 3, 2012.
  • Revision received August 14, 2012.
  • Accepted August 15, 2012.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 385 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 385, Issue 3
1 Jun 2023
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Research ArticleNeuropharmacology

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

G. Patrick Hussmann, Jill R. Turner, Ermelinda Lomazzo, Rashmi Venkatesh, Vanessa Cousins, Yingxian Xiao, Robert P. Yasuda, Barry B. Wolfe, David C. Perry, Amir H. Rezvani, Edward D. Levin, Julie A. Blendy and Kenneth J. Kellar
Journal of Pharmacology and Experimental Therapeutics August 16, 2012, jpet.112.198085; DOI: https://doi.org/10.1124/jpet.112.198085

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Research ArticleNeuropharmacology

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

G. Patrick Hussmann, Jill R. Turner, Ermelinda Lomazzo, Rashmi Venkatesh, Vanessa Cousins, Yingxian Xiao, Robert P. Yasuda, Barry B. Wolfe, David C. Perry, Amir H. Rezvani, Edward D. Levin, Julie A. Blendy and Kenneth J. Kellar
Journal of Pharmacology and Experimental Therapeutics August 16, 2012, jpet.112.198085; DOI: https://doi.org/10.1124/jpet.112.198085
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