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-HT(2)R). 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-HT(2)R-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-HT(2)R signaling were dependent on receptor internalization and receptor recycling via rapid recycling endosomes, resulting in increased expression of 5-HT(2)R on the cell surface. Sensitization of 5-HT(2)R 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-HT(2)R signaling.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amphetamines / pharmacology
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Animals
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Anxiety / drug therapy
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Anxiety / metabolism*
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Anxiety / physiopathology
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Behavior, Animal / drug effects
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Behavior, Animal / physiology
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Biotinylation / methods
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Cells, Cultured
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Corticotropin-Releasing Hormone / pharmacology
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Cyclic AMP / metabolism
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Embryo, Mammalian
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Fluorobenzenes / pharmacology
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Hormones / pharmacology
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Humans
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Inositol Phosphates / metabolism
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Ionophores / pharmacology
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Male
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Maze Learning / drug effects
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Maze Learning / physiology
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Mice
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Monensin / pharmacology
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Mutation / genetics
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Neurons
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Piperidines / pharmacology
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Prefrontal Cortex / cytology
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Rats
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Reaction Time / drug effects
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Receptors, Corticotropin-Releasing Hormone / genetics
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Receptors, Corticotropin-Releasing Hormone / physiology*
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Receptors, Serotonin, 5-HT2 / genetics
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Receptors, Serotonin, 5-HT2 / metabolism*
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Serotonin / pharmacology
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Serotonin 5-HT2 Receptor Agonists
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Serotonin 5-HT2 Receptor Antagonists
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Serotonin Agents / pharmacology
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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Transfection
Substances
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Amphetamines
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Fluorobenzenes
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Hormones
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Inositol Phosphates
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Ionophores
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Piperidines
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Receptors, Corticotropin-Releasing Hormone
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Receptors, Serotonin, 5-HT2
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Serotonin 5-HT2 Receptor Agonists
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Serotonin 5-HT2 Receptor Antagonists
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Serotonin Agents
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Serotonin
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CRF receptor type 1
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Corticotropin-Releasing Hormone
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Monensin
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Cyclic AMP
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volinanserin
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4-iodo-2,5-dimethoxyphenylisopropylamine