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Author Notes:

Correspondence: David A. Gutman, MD PhD, Center for Comprehensive Informatics, Emory University, 36 Eagle Row Room 572, Suite 4000, Atlanta, GA 30322; Email: dgutman@emory.edu

Acknowledgments: We would like to thank Dr. Kelly Skelton and Susan Plott for their technical assistance.

Disclosures: Dr. Gutman and Dr. Thrivikraman have no financial disclosures.

Michael J. Owens, Ph.D. consults for H. Lundbeck A/S, Takeda; Receives honorarium from Eli Lilly; holds a patent for 'Method of assessing antidepressant drug therapy via transport inhibition of monoamine neurotransmitters' (US 7,148,027 B2).

Charles B. Nemeroff, M.D. Ph.D. serves on the Scientific Advisory Board of AFSP, AstraZeneca, Forest Laboratories, NARSAD, Quintiles, Janssen/Ortho-McNeil, PharmaNeuroboost and Mt. Cook Pharma, Inc; is a stockholder/holds equity at Corcept, Revaax, NovaDel Pharma, CeNeRx and PharmaNeuroboost; serves on the board of directors of American Foundation for Suicide Prevention (AFSP), George West Mental Health Foundation and NovaDel Pharma, Mt. Cook Pharma, Inc; holds patents for 'Method and devices for transdermal delivery of lithium' (US 6,375,990 B1) and 'Method of assessing antidepressant drug therapy via transport inhibition of monoamine neurotransmitters' (US 7,148,027 B2).

Subjects:

Research Funding:

This work was supported by NIH MH 42088 and MH-58299.

Michael J. Owens, Ph.D. receives research grants from NIH, Eli Lilly, Pfizer, GlaxoSmithKline, Lundbeck, Cyberonics, Ortho-McNeil Janssen, AstraZeneca, Dainippon Sumitomo Pharma and SK Life Sciences.

Charles B. Nemeroff, M.D. Ph.D receives research grants from NIH

Keywords:

  • CRF
  • CRH
  • R121919
  • NBI-30775
  • CRF Antagonist
  • animal models

Persistent anxiolytic affects after chronic administration of the CRF1 receptor antagonist R121919 in rats

Tools:

Journal Title:

Neuropharmacology

Volume:

Volume 60, Number 7-8

Publisher:

, Pages 1135-1141

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Corticotropin-releasing factor (CRF) functions as one of the major mediators of the mammalian stress response and appears to play a key role in the pathophysiology of mood and anxiety disorders. Small molecule CRF1 receptor antagonists may represent a novel form of pharmacotherapy for these disorders. The therapeutic success of CRF1 receptor antagonists will depend, in part, upon whether tolerance develops to the actions of these compounds and whether appropriate patterns of HPA axis function is maintained. This study evaluated the effects of long term (~4 week) treatment with the CRF1 receptor antagonist R121919, on CRF receptor function, HPA axis activity, behavioral measures, adrenal gland size, and body weight gain. Animals treated with 20 mg/kg/day of R121919 spent significantly more time in the open field in a defensive withdrawal test (138±36 seconds for R121919 vs 52±12 seconds for vehicle, p=0.01). No significant effect of chronic CRF1 receptor blockade on basal ACTH or corticosterone concentrations were detected, nor were significant changes detected in an elevated plus maze test. Both vehicle- and R121919- treated rats showed increases in AUC and peak ACTH and corticosterone concentrations following air puff startle stress, without any overall group differences, although a clear but non-significant attenuation in HPA axis response was observable in R121919 treated animals. Chronic CRF1 receptor blockade increased CRF peptide mRNA expression in the PVN and decreased CRF peptide mRNA expression in the central nucleus of the amygdala. Overall our results suggest that anxiolytic effects of chronic CRF1 receptor antagonism persist following chronic administration without significant attenuation of the HPA axis’s ability to mount a stress response.

Copyright information:

© 2010 Elsevier Ltd. All rights reserved.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported License (http://creativecommons.org/licenses/by-nc-nd/3.0/).

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