期刊
NATURE NEUROSCIENCE
卷 13, 期 5, 页码 622-U140出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nn.2529
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资金
- Canadian Institutes for Health Research (CIHR) [MOP 62738, MOP 81118]
- Ontario Mental Health Foundation
- CisBio
- French government
- CNRS
- INSERM
- Agence Nationale de la Recherche [Blan06-3_135092]
- US National Institutes of Health [R01MH61887, U19MH82441]
- Michael Hooker Distinguished Chair of Pharmacology
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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