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 ArticleArticle

Sustained Desensitization of Hypothalamic 5-Hydroxytryptamine1A Receptors after Discontinuation of Fluoxetine: Inhibited Neuroendocrine Responses to 8-Hydroxy-2-(Dipropylamino)Tetralin in the Absence of Changes in Gi/o/z Proteins

D. K. Raap, F. Garcia, N. A. Muma, W. A. Wolf, G. Battaglia and L. D. van de Kar
Journal of Pharmacology and Experimental Therapeutics February 1999, 288 (2) 561-567;
D. K. Raap
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
F. Garcia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
N. A. Muma
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
W. A. Wolf
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
G. Battaglia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
L. D. van de Kar
  • 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

Long-term exposure to fluoxetine produces a desensitization of hypothalamic postsynaptic 5-hydroxytryptamine (5-HT)1Areceptors, indicated by a substantial inhibition of the 5-HT1A receptor-mediated stimulation of oxytocin and adrenocorticotropic hormone (ACTH) secretion. The present study investigated the time course and mechanism of this desensitization after discontinuation of fluoxetine administration. Male rats were injected with saline or fluoxetine (10 mg/kg/day, i.p.) for 14 days and were challenged with a 5-HT1A agonist, [8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT) 50 μg/kg, s.c.] 2, 4, 7, 14, 28, or 60 days post-treatment. In control animals, 8-OH-DPAT significantly increased (approximately 15-fold) plasma levels of oxytocin and ACTH. At 2 days post-treatment, oxytocin and ACTH responses to 8-OH-DPAT were reduced by 74% and 68%, respectively. During further withdrawal from fluoxetine, there was a gradual increase in the oxytocin response toward control levels. However, even 60 days after discontinuation of fluoxetine, the oxytocin response was still significantly reduced by 26% compared with controls. In contrast, the suppressed ACTH response to 8-OH-DPAT (a less-sensitive indicator of desensitization) gradually returned to control levels by day 14 of withdrawal from fluoxetine. Interestingly, the sustained reductions in the hormone responses occurred in the absence of reductions in Gz or Gi protein levels in the hypothalamus. Furthermore, this desensitization was sustained in the absence of detectable levels of fluoxetine and norfluoxetine in plasma and brain tissue. These findings suggest that the sustained desensitization of hypothalamic 5-HT1Areceptor systems, observed during fluoxetine withdrawal, may be due to altered interactions among the protein components of the 5-HT1A receptor system, rather than their absolute levels.

Footnotes

  • Send reprint requests to: Louis D. Van de Kar, Department of Pharmacology, Stritch School of Medicine, Loyola University of Chicago, 2160 S. First Ave., Maywood IL 60153.E-mail:lvandek{at}luc.edu

  • ↵1 This study was supported in part by U.S. Public Health Service Grant NS34153 (to L.D.V.dK.). A portion of this study was presented as a poster at the Society for Neuroscience meeting (Soc Neurosci Abstr 23, 385.5, 1997).

  • ↵2 Current address: Biological Psychiatry and Research Service, Hines Veterans Administration Medical Center, Hines, IL 60141.

  • Abbreviations:
    5-HT
    5-hydroxytryptamine (serotonin)
    8-OH-DPAT
    8-hydroxy-2-(dipropylamino)tetralin
    ACTH
    adrenocorticotropic hormone
    ANOVA
    analysis of variance
    CRH
    corticotrophin-releasing hormone
    HPLC
    high-pressure liquid chromatography
    IOD
    integrated optical density
    SSRI
    selective serotonin reuptake inhibitor
    • Received May 1, 1998.
    • Accepted September 1, 1998.
  • 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: 288 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 288, Issue 2
1 Feb 1999
  • Table of Contents
  • About the Cover
  • Index by author
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.
Sustained Desensitization of Hypothalamic 5-Hydroxytryptamine1A Receptors after Discontinuation of Fluoxetine: Inhibited Neuroendocrine Responses to 8-Hydroxy-2-(Dipropylamino)Tetralin in the Absence of Changes in Gi/o/z Proteins
(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 ArticleArticle

Sustained Desensitization of Hypothalamic 5-Hydroxytryptamine1A Receptors after Discontinuation of Fluoxetine: Inhibited Neuroendocrine Responses to 8-Hydroxy-2-(Dipropylamino)Tetralin in the Absence of Changes in Gi/o/z Proteins

D. K. Raap, F. Garcia, N. A. Muma, W. A. Wolf, G. Battaglia and L. D. van de Kar
Journal of Pharmacology and Experimental Therapeutics February 1, 1999, 288 (2) 561-567;

Citation Manager Formats

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

Share
Research ArticleArticle

Sustained Desensitization of Hypothalamic 5-Hydroxytryptamine1A Receptors after Discontinuation of Fluoxetine: Inhibited Neuroendocrine Responses to 8-Hydroxy-2-(Dipropylamino)Tetralin in the Absence of Changes in Gi/o/z Proteins

D. K. Raap, F. Garcia, N. A. Muma, W. A. Wolf, G. Battaglia and L. D. van de Kar
Journal of Pharmacology and Experimental Therapeutics February 1, 1999, 288 (2) 561-567;
del.icio.us logo Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

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

Related Articles

Cited By...

More in this TOC Section

  • PST3093 Stimulates SERCA2a and Improves Cardiac Function
  • CRV431 Decreases Liver Fibrosis and Tumor Development
  • Discriminative Stimulus Effects of Zolpidem in Squirrel Monkeys: Comparison with Conventional Benzodiazepines and Sedative-Hypnotics
Show more Article

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