CRF receptor 1 regulates anxiety behavior via sensitization of 5-HT2 receptor signaling.
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.
Magalhaes
Ana C
AC
J. Allyn Taylor Centre for Cell Biology, Molecular Brain Research Group, Robarts Research and the Department of Physiology & Pharmacology, The University of Western Ontario, London, Ontario, Canada.
Holmes
Kevin D
KD
Dale
Lianne B
LB
Comps-Agrar
Laetitia
L
Lee
Dennis
D
Yadav
Prem N
PN
Drysdale
Linsay
L
Poulter
Michael O
MO
Roth
Bryan L
BL
Pin
Jean-Philippe
JP
Anisman
Hymie
H
Ferguson
Stephen S G
SS
D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D001007:Anxiety / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D019921:Biotinylation / Q000379:methods; D002478:Cells, Cultured; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D005464:Fluorobenzenes / Q000494:pharmacology; D006728:Hormones / Q000494:pharmacology; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D007476:Ionophores / Q000494:pharmacology; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008985:Monensin / Q000494:pharmacology; D009154:Mutation / Q000235:genetics; D009474:Neurons; D010880:Piperidines / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000166:cytology; D051381:Rats; D011930:Reaction Time / Q000187:drug effects; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics / Q000502:physiology*; D044348:Receptors, Serotonin, 5-HT2 / Q000235:genetics / Q000378:metabolism*; D012701:Serotonin / Q000494:pharmacology; D058826:Serotonin 5-HT2 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D018490:Serotonin Agents / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014162:Transfection; D000099052:CRF Receptor, Type 1
D000662:Amphetamines; D005464:Fluorobenzenes; D006728:Hormones; D007295:Inositol Phosphates; D007476:Ionophores; D010880:Piperidines; D018019:Receptors, Corticotropin-Releasing Hormone; D044348:Receptors, Serotonin, 5-HT2; D058826:Serotonin 5-HT2 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D018490:Serotonin Agents; D012701:Serotonin; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone; D008985:Monensin; D000242:Cyclic AMP; C079049:volinanserin; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine
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