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CRF receptor 1 regulates anxiety behavior via sensitization of 5-HT2 receptor signaling

Nature Neuroscience volume 13, pages 622–629 (2010)Cite this article

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Abstract

Stress and anxiety disorders are risk factors for depression and these behaviors are modulated by corticotrophin-releasing factor receptor 1 (CRFR1) and serotonin receptor (5-HT2R). However, the potential behavioral and cellular interaction between these two receptors is unclear. We found that pre-administration of corticotrophin-releasing factor (CRF) into the prefrontal cortex of mice enhanced 5-HT2R–mediated anxiety behaviors in response to 2,5-dimethoxy-4-iodoamphetamine. In both heterologous cell cultures and mouse cortical neurons, activation of CRFR1 also enhanced 5-HT2 receptor–mediated inositol phosphate formation. CRFR1-mediated increases in 5-HT2R signaling were dependent on receptor internalization and receptor recycling via rapid recycling endosomes, resulting in increased expression of 5-HT2R on the cell surface. Sensitization of 5-HT2R signaling by CRFR1 required intact PDZ domain–binding motifs at the end of the C-terminal tails of both receptor types. These data suggest a mechanism by which CRF, a peptide known to be released by stress, enhances anxiety-related behavior via sensitization of 5-HT2R signaling.

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Figure 1: Effect of CRFR1 activation on 5-HT2R signaling.
Figure 2: Effect of CRFR1 activation on 5-HT2R signaling in neurons.
Figure 3: Role of endocytosis in CRFR1-dependent augmentation of 5-HT2R signaling.
Figure 4: Role of receptor recycling in CRF-modulated 5-HT2R signaling.
Figure 5: Receptor determinants of CRF-dependent increases in 5-HT2R signaling.
Figure 6: Analysis of CRF pretreatment on 5-HT2R–mediated anxiety-related behaviors.
Figure 7: Analysis of CRF pretreatment on 5-HT2R–mediated anxiety-related behaviors following M100907 treatment.

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Acknowledgements

A.C.M. and D.L. received Canadian Institutes for Health Research (CIHR) fellowships. K.D.H. received a fellowship from the Ontario Mental Health Foundation. L.C.-A. was supported by a Conventions Industrielles de Formation par la Recherche fellowship from CisBio and the French government. J.-P.P. was supported by CNRS, INSERM, the Agence Nationale de la Recherche grant Blan06-3_135092 and CisBio. S.S.G.F. and H.A. hold Tier I Canada Research Chairs, and S.S.G.F. is a Heart and Stroke Foundation of Ontario Career Investigator. This research was funded by CIHR grant MOP 62738 to S.S.G.F., CIHR grant MOP 81118 to H.A., US National Institutes of Health grants R01MH61887 and U19MH82441 and the Michael Hooker Distinguished Chair of Pharmacology to B.L.R.

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Authors and Affiliations

  1. Robarts Research and the Department of Physiology & Pharmacology, J. Allyn Taylor Centre for Cell Biology, Molecular Brain Research Group, The University of Western Ontario, London, Ontario, Canada

    Ana C Magalhaes, Kevin D Holmes, Lianne B Dale, Dennis Lee, Linsay Drysdale, Michael O Poulter & Stephen S G Ferguson

  2. Institut de Génomique Fonctionnelle, Départment de Pharmacologie Moléculaire, UMR 5203 CNRS, U 661 INSERM, University of Montpellier I & II, Montpellier, France

    Laetitia Comps-Agrar & Jean-Philippe Pin

  3. Department of Pharmacology, University of North Carolina Chapel Hill, Chapel Hill, North Carolina, USA

    Prem N Yadav & Bryan L Roth

  4. Institute of Neurosciences, Centre for Research on Stress, Coping & Well-being, Life Sciences Research Centre, Carleton University, Ottawa, Ontario, Canada

    Hymie Anisman

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Contributions

M.O.P., K.D.H., A.C.M., H.A. and S.S.G.F. conceived the experiments. H.A. carried out the behavioral experiments. A.C.M., K.D.H., L.B.D., L.C.-A., J.-P.P., L.D., P.N.Y. and D.L. performed the rest of the experiments. S.S.G.F., A.C.M., B.L.R. and H.A. analyzed the data and wrote the manuscript.

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Correspondence to Stephen S G Ferguson.

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Magalhaes, A., Holmes, K., Dale, L. et al. CRF receptor 1 regulates anxiety behavior via sensitization of 5-HT2 receptor signaling. Nat Neurosci 13, 622–629 (2010). https://doi.org/10.1038/nn.2529

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