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

© 2010 Nature America, Inc. All rights reserved.

Ana C Magalhaes1, Kevin D Holmes1, Lianne B Dale1, Laetitia Comps-Agrar2, Dennis Lee1, Prem N Yadav3,
Linsay Drysdale1, Michael O Poulter1, Bryan L Roth3, Jean-Philippe Pin2, Hymie Anisman4 & Stephen S G Ferguson1
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-HT 2 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.
Anxiety and major depressive disorder often present as co-morbid disorders and the expression and severity of these disorders are commonly associated with stressful experiences 1. In response to stress,
CRF regulates the activity of hypothalamic-pituitary-adrenal axis and triggers changes in other neurotransmitters systems, such as serotonin
(5-HT)2–6. CRF is also known to influence anxiety responses and
CRFR1 may be particularly important in this regard7–9. 5-HT