Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET

User menu

  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
Journal of Pharmacology and Experimental Therapeutics
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET
  • My alerts
  • Log in
  • My Cart
Journal of Pharmacology and Experimental Therapeutics

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Visit jpet on Facebook
  • Follow jpet on Twitter
  • Follow jpet on LinkedIn
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 November 2012, 343 (2) 441-450; DOI: https://doi.org/10.1124/jpet.112.198085
G. Patrick Hussmann
Department of Pharmacology and Physiology, Georgetown University School of Medicine, Washington, District of Columbia (G.P.H., E.L., R.V., Y.X., R.P.Y., B.B.W., K.J.K.); Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania (J.R.T., J.A.B.); Department of Psychiatry and Behavioral Sciences, Duke University, Durham, North Carolina (V.C., A.H.R., E.D.L.); and Department of Pharmacology and Physiology, George Washington University, Washington, District of Columbia (D.C.P.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jill R. Turner
Department of Pharmacology and Physiology, Georgetown University School of Medicine, Washington, District of Columbia (G.P.H., E.L., R.V., Y.X., R.P.Y., B.B.W., K.J.K.); Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania (J.R.T., J.A.B.); Department of Psychiatry and Behavioral Sciences, Duke University, Durham, North Carolina (V.C., A.H.R., E.D.L.); and Department of Pharmacology and Physiology, George Washington University, Washington, District of Columbia (D.C.P.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ermelinda Lomazzo
Department of Pharmacology and Physiology, Georgetown University School of Medicine, Washington, District of Columbia (G.P.H., E.L., R.V., Y.X., R.P.Y., B.B.W., K.J.K.); Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania (J.R.T., J.A.B.); Department of Psychiatry and Behavioral Sciences, Duke University, Durham, North Carolina (V.C., A.H.R., E.D.L.); and Department of Pharmacology and Physiology, George Washington University, Washington, District of Columbia (D.C.P.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Rashmi Venkatesh
Department of Pharmacology and Physiology, Georgetown University School of Medicine, Washington, District of Columbia (G.P.H., E.L., R.V., Y.X., R.P.Y., B.B.W., K.J.K.); Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania (J.R.T., J.A.B.); Department of Psychiatry and Behavioral Sciences, Duke University, Durham, North Carolina (V.C., A.H.R., E.D.L.); and Department of Pharmacology and Physiology, George Washington University, Washington, District of Columbia (D.C.P.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Vanessa Cousins
Department of Pharmacology and Physiology, Georgetown University School of Medicine, Washington, District of Columbia (G.P.H., E.L., R.V., Y.X., R.P.Y., B.B.W., K.J.K.); Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania (J.R.T., J.A.B.); Department of Psychiatry and Behavioral Sciences, Duke University, Durham, North Carolina (V.C., A.H.R., E.D.L.); and Department of Pharmacology and Physiology, George Washington University, Washington, District of Columbia (D.C.P.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yingxian Xiao
Department of Pharmacology and Physiology, Georgetown University School of Medicine, Washington, District of Columbia (G.P.H., E.L., R.V., Y.X., R.P.Y., B.B.W., K.J.K.); Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania (J.R.T., J.A.B.); Department of Psychiatry and Behavioral Sciences, Duke University, Durham, North Carolina (V.C., A.H.R., E.D.L.); and Department of Pharmacology and Physiology, George Washington University, Washington, District of Columbia (D.C.P.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Robert P. Yasuda
Department of Pharmacology and Physiology, Georgetown University School of Medicine, Washington, District of Columbia (G.P.H., E.L., R.V., Y.X., R.P.Y., B.B.W., K.J.K.); Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania (J.R.T., J.A.B.); Department of Psychiatry and Behavioral Sciences, Duke University, Durham, North Carolina (V.C., A.H.R., E.D.L.); and Department of Pharmacology and Physiology, George Washington University, Washington, District of Columbia (D.C.P.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Barry B. Wolfe
Department of Pharmacology and Physiology, Georgetown University School of Medicine, Washington, District of Columbia (G.P.H., E.L., R.V., Y.X., R.P.Y., B.B.W., K.J.K.); Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania (J.R.T., J.A.B.); Department of Psychiatry and Behavioral Sciences, Duke University, Durham, North Carolina (V.C., A.H.R., E.D.L.); and Department of Pharmacology and Physiology, George Washington University, Washington, District of Columbia (D.C.P.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
David C. Perry
Department of Pharmacology and Physiology, Georgetown University School of Medicine, Washington, District of Columbia (G.P.H., E.L., R.V., Y.X., R.P.Y., B.B.W., K.J.K.); Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania (J.R.T., J.A.B.); Department of Psychiatry and Behavioral Sciences, Duke University, Durham, North Carolina (V.C., A.H.R., E.D.L.); and Department of Pharmacology and Physiology, George Washington University, Washington, District of Columbia (D.C.P.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Amir H. Rezvani
Department of Pharmacology and Physiology, Georgetown University School of Medicine, Washington, District of Columbia (G.P.H., E.L., R.V., Y.X., R.P.Y., B.B.W., K.J.K.); Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania (J.R.T., J.A.B.); Department of Psychiatry and Behavioral Sciences, Duke University, Durham, North Carolina (V.C., A.H.R., E.D.L.); and Department of Pharmacology and Physiology, George Washington University, Washington, District of Columbia (D.C.P.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Edward D. Levin
Department of Pharmacology and Physiology, Georgetown University School of Medicine, Washington, District of Columbia (G.P.H., E.L., R.V., Y.X., R.P.Y., B.B.W., K.J.K.); Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania (J.R.T., J.A.B.); Department of Psychiatry and Behavioral Sciences, Duke University, Durham, North Carolina (V.C., A.H.R., E.D.L.); and Department of Pharmacology and Physiology, George Washington University, Washington, District of Columbia (D.C.P.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Julie A. Blendy
Department of Pharmacology and Physiology, Georgetown University School of Medicine, Washington, District of Columbia (G.P.H., E.L., R.V., Y.X., R.P.Y., B.B.W., K.J.K.); Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania (J.R.T., J.A.B.); Department of Psychiatry and Behavioral Sciences, Duke University, Durham, North Carolina (V.C., A.H.R., E.D.L.); and Department of Pharmacology and Physiology, George Washington University, Washington, District of Columbia (D.C.P.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kenneth J. Kellar
Department of Pharmacology and Physiology, Georgetown University School of Medicine, Washington, District of Columbia (G.P.H., E.L., R.V., Y.X., R.P.Y., B.B.W., K.J.K.); Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania (J.R.T., J.A.B.); Department of Psychiatry and Behavioral Sciences, Duke University, Durham, North Carolina (V.C., A.H.R., E.D.L.); and Department of Pharmacology and Physiology, George Washington University, Washington, District of Columbia (D.C.P.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF
Loading

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.

    http://dx.doi.org/10.1124/jpet.112.198085.

  • 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
View Full Text

JPET articles become freely available 12 months after publication, and remain freely available for 5 years. 

Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page. 

 

  • Click here for information on institutional subscriptions.
  • Click here for information on individual ASPET membership.

 

Log in using your username and password

Forgot your user name or password?

Purchase access

You may purchase access to this article. This will require you to create an account if you don't already have one.
PreviousNext
Back to top

In this issue

Journal of Pharmacology and Experimental Therapeutics: 343 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 343, Issue 2
1 Nov 2012
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Editorial Board (PDF)
  • Front Matter (PDF)
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Journal of Pharmacology and Experimental Therapeutics article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Chronic Sazetidine-A at Behaviorally Active Doses Does Not Increase Nicotinic Cholinergic Receptors in Rodent Brain
(Your Name) has forwarded a page to you from Journal of Pharmacology and Experimental Therapeutics
(Your Name) thought you would be interested in this article in Journal of Pharmacology and Experimental Therapeutics.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticleNeuropharmacology

Saz-A Does Not Up-Regulate nAChRs in 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 November 1, 2012, 343 (2) 441-450; DOI: https://doi.org/10.1124/jpet.112.198085

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero

Share
Research ArticleNeuropharmacology

Saz-A Does Not Up-Regulate nAChRs in 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 November 1, 2012, 343 (2) 441-450; DOI: https://doi.org/10.1124/jpet.112.198085
Reddit logo Twitter logo Facebook logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Introduction
    • Materials and Methods
    • Results
    • Discussion
    • Authorship Contributions
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Combination therapy against cholinergic-induced SE
  • Sex Differences in Benzodiazepine Refractory Status Epilepticus
  • Biodistribution of Agmatine to Brain and Spinal Cord
Show more Neuropharmacology

Similar Articles

Advertisement
  • Home
  • Alerts
Facebook   Twitter   LinkedIn   RSS

Navigate

  • Current Issue
  • Fast Forward by date
  • Fast Forward by section
  • Latest Articles
  • Archive
  • Search for Articles
  • Feedback
  • ASPET

More Information

  • About JPET
  • Editorial Board
  • Instructions to Authors
  • Submit a Manuscript
  • Customized Alerts
  • RSS Feeds
  • Subscriptions
  • Permissions
  • Terms & Conditions of Use

ASPET's Other Journals

  • Drug Metabolism and Disposition
  • Molecular Pharmacology
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-0103 (Online)

Copyright © 2023 by the American Society for Pharmacology and Experimental Therapeutics