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Research ArticleArticle

Long-Term Regulation of Locus Ceruleus Sensitivity to Corticotropin-Releasing Factor by Swim Stress

Andre L. Curtis, Luis A. Pavcovich and Rita J. Valentino
Journal of Pharmacology and Experimental Therapeutics June 1999, 289 (3) 1211-1219;
Andre L. Curtis
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Luis A. Pavcovich
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Rita J. Valentino
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Abstract

Corticotropin-releasing factor (CRF) acts as a putative neurotransmitter in the locus ceruleus (LC) to mediate its activation by certain stressors. In this study, we quantified LC sensitivity to CRF 24 h after swim stress, at a time when behavioral depression that is sensitive to antidepressants is apparent. Rats were placed in a tank with 30 cm (swim stress) or 4 cm water and 24 h later, either behavior was monitored in a forced swim test or LC discharge was recorded. Swim stress rats were more immobile than control animals in the swim test. LC neurons of swim stress rats were sensitized to low doses of CRF (0.1–0.3 μg i.c.v.) that were ineffective in control animals and were desensitized to higher doses. Swim stress selectively altered LC sensitivity to CRF because neither LC spontaneous discharge nor responses to other agents (e.g., carbachol, vasoactive intestinal peptide) were altered. Finally, the mechanism for sensitization was localized to the LC because neuronal activation by low doses of CRF was prevented by the intracerulear administration of a CRF antagonist. CRF dose-response curves were consistent with a two-site model with similar dissociation constants under control conditions but divergent dissociation constants after swim stress. The results suggest that swim stress (and perhaps other stressors) functionally alters CRF receptors that have an impact on LC activity. Stress-induced regulation of LC sensitivity to CRF may underlie behavioral aspects of stress-related psychiatric disorders.

Footnotes

  • Send reprint requests to: Dr. Rita J. Valentino, Department of Psychiatry, MS 403, Medical College of Pennsylvania and Hahnemann University, Broad and Vine St., Philadelphia, PA 19102-1192. E-mail:valentinor{at}auhs.edu

  • ↵1 This work was supported by U.S. Public Health Service Grants MH42796, MH40008, and MH00840 (an RSDA award to R.J.V.) and an NARSAD Young Investigator Award (to L.A.P.).

  • Abbreviations:
    CRF
    corticotropin-releasing factor
    aCSF
    artificial cerebrospinal fluid
    DPheCRF12–41
    [d-Phe12,Nle21,38,CαMeLeu37]r /hCRF(12–41)
    LC
    locus ceruleus
    PSB
    pontamine sky blue
    VIP
    vasoactive intestinal peptide
    • Received November 5, 1998.
    • Accepted January 22, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 289 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 289, Issue 3
1 Jun 1999
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Research ArticleArticle

Long-Term Regulation of Locus Ceruleus Sensitivity to Corticotropin-Releasing Factor by Swim Stress

Andre L. Curtis, Luis A. Pavcovich and Rita J. Valentino
Journal of Pharmacology and Experimental Therapeutics June 1, 1999, 289 (3) 1211-1219;

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Research ArticleArticle

Long-Term Regulation of Locus Ceruleus Sensitivity to Corticotropin-Releasing Factor by Swim Stress

Andre L. Curtis, Luis A. Pavcovich and Rita J. Valentino
Journal of Pharmacology and Experimental Therapeutics June 1, 1999, 289 (3) 1211-1219;
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