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Chronic stimulation of corticotropin-releasing factor receptor 1 enhances the anxiogenic response of the cholecystokinin system

Molecular Psychiatry volume 14, pages 291–307 (2009)Cite this article

A Corrigendum to this article was published on 18 November 2009

Abstract

Corticotropin-releasing factor (CRF) and cholecystokinin (CCK), two highly colocalized neuropeptides, have been linked to the etiology of stress-related anxiety disorders. Recent evidence points to the possibility that some of the anxiogenic effects of the central CCK system take place through interplay with the CRF system. The aim of the present study was to examine the effects of chronic, mild activation of CRF receptor 1 (CRF1) on the central CCK system of the C57BL/6J mouse. As shown by in situ hybridization, real-Time PCR and immunohistochemistry, 5 days of intracerebroventricular (i.c.v.) injections of a subeffective dose (2.3 pmol) of cortagine, a CRF1-selective agonist, resulted in an increase in CCK mRNA levels and CCK2 receptor immunoreactivity in several brain regions, such as amygdala and hippocampus, known to be involved in the regulation of anxiety. Mice with elevated endogenous central CCK tone exhibited significantly higher anxiety-like behaviors in the open-field task and elevated plus maze, and enhanced conditioned fear. These behavioral changes were reversed by i.c.v. administration of the CCK2-selective antagonist LY225910, after 5 days of priming with cortagine. Under the same conditions, the intraperitoneal administration of the CRF1 antagonist antalarmin was ineffective. This result indicated that once the CCK system was sensitized by prior CRF1 activation, it exhibited its anxiogenic effects, without influence by CRF1, possibly because of its observed downregulation. In sum, our results provide a novel model for the interaction of the CRF and CCK systems contributing to the development of hypersensitive emotional circuitry.

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Acknowledgements

We thank Dr Martin Rayner for helpful discussion during preparation of the manuscript. This work was supported by Max Planck Society, NIH grant 5U54NS039406-08 and NMRC grant (NMRC/0754/2003).

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  1. T Sherrin and C Todorovic: These authors share equal contribution to this work.

Authors and Affiliations

  1. Specialized Neuroscience Research Program 2, John A Burns School of Medicine, University of Hawaii, Honolulu, HI, USA

    T Sherrin, C Todorovic, T Zeyda & J Spiess

  2. Molecular Neuroendocrinology Laboratory, Max Planck Institute of Experimental Medicine, John A Burns School of Medicine, University of Hawaii, Honolulu, HI, USA

    T Sherrin, C Todorovic, T Zeyda & J Spiess

  3. Department of Pharmacology, Faculty of Medicine, National University of Singapore, Singapore

    T Sherrin, C H Tan, P W T Hon & Y-Z Zhu

  4. Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China

    Y-Z Zhu

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Sherrin, T., Todorovic, C., Zeyda, T. et al. Chronic stimulation of corticotropin-releasing factor receptor 1 enhances the anxiogenic response of the cholecystokinin system. Mol Psychiatry 14, 291–307 (2009). https://doi.org/10.1038/sj.mp.4002121

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