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Research ArticleNEUROPHARMACOLOGY

Chronic Administration of the Selective Corticotropin-Releasing Factor 1 Receptor Antagonist CP-154,526: Behavioral, Endocrine and Neurochemical Effects in the Rat

Lotta Arborelius, Kelly H. Skelton, Karacheri V. Thrivikraman, Paul M. Plotsky, David W. Schulz and Michael J. Owens
Journal of Pharmacology and Experimental Therapeutics August 2000, 294 (2) 588-597;
Lotta Arborelius
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Kelly H. Skelton
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Karacheri V. Thrivikraman
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Paul M. Plotsky
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David W. Schulz
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Michael J. Owens
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Abstract

Corticotropin-releasing factor 1 (CRF1) receptor antagonists may represent a novel group of drugs for the pharmacotherapy of depression and/or anxiety disorders. We have investigated the behavioral, endocrine, and neurochemical effects of chronic administration of a selective CRF1 receptor antagonist, CP-154,526. After 9 to 10 days of treatment with CP-154,526 (3.2 mg/kg/day), defensive withdrawal behavior was significantly decreased suggesting anxiolytic activity. In animals treated for 14 days with the low dose of CP-154,526, serum corticosterone concentrations returned to baseline levels faster after application of an airpuff startle. Using in situ hybridization, no changes in CRF1 receptor mRNA expression were detected in parietal cortex, basolateral amygdala, or cerebellum after chronic treatment with CP-154,526. A dose-dependent decrease in CRF mRNA expression was observed in the hypothalamic paraventricular nucleus (PVN) and the Barrington's nucleus, an effect that was significant at the high but not the low dose of CP-154,526. CP-154,526 did not alter central CRF2A receptor binding or mRNA expression, or urocortin mRNA expression. The present findings suggest that chronic administration of CP-154,526 produces anxiolytic-like effects but no evidence of adrenal insufficiency. Previous postmortem studies revealed increased CRF peptide and mRNA levels in the PVN of depressed patients, which may mediate the hyperactivity of the hypothalamic-pituitary-adrenal axis observed in such patients. In view of a possible use for CRF1 receptor antagonists in the treatment of depression, the present finding that CP-154,526 decreases CRF synthesis in the PVN is of considerable interest.

Footnotes

  • Send reprint requests to: Michael J. Owens, Ph.D., Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, 1639 Pierce Dr., Ste. 4000, Atlanta, GA 30322. E-mail: mowens{at}emory.edu

  • ↵1 Supported by a grant from Pfizer Incorporated, the Swedish Medical Research Council, and the Svenska Institutet.

  • Abbreviations:
    CRF
    corticotropin-releasing factor
    PVN
    paraventricular nucleus of the hypothalamus
    HPA
    hypothalamic-pituitary-adrenal
    LS
    lateral septum
    VMH
    ventromedial hypothalamus
    DRN
    dorsal raphe nucleus
    RIA
    radioimmunoassay
    ME
    median eminence
    DTT
    dithiothreitol
    SSC
    standard saline citrate
    LC
    locus ceruleus
    CeA
    central nucleus of amygdala
    BNST
    bed nucleus of stria terminalis
    bp
    base pairs
    • Received March 15, 2000.
    • Accepted May 3, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 294 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 294, Issue 2
1 Aug 2000
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Research ArticleNEUROPHARMACOLOGY

Chronic Administration of the Selective Corticotropin-Releasing Factor 1 Receptor Antagonist CP-154,526: Behavioral, Endocrine and Neurochemical Effects in the Rat

Lotta Arborelius, Kelly H. Skelton, Karacheri V. Thrivikraman, Paul M. Plotsky, David W. Schulz and Michael J. Owens
Journal of Pharmacology and Experimental Therapeutics August 1, 2000, 294 (2) 588-597;

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Research ArticleNEUROPHARMACOLOGY

Chronic Administration of the Selective Corticotropin-Releasing Factor 1 Receptor Antagonist CP-154,526: Behavioral, Endocrine and Neurochemical Effects in the Rat

Lotta Arborelius, Kelly H. Skelton, Karacheri V. Thrivikraman, Paul M. Plotsky, David W. Schulz and Michael J. Owens
Journal of Pharmacology and Experimental Therapeutics August 1, 2000, 294 (2) 588-597;
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