monensin and 4-iodo-2-5-dimethoxyphenylisopropylamine

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.

Topics: Amphetamines; Animals; Anxiety; Behavior, Animal; Biotinylation; Cells, Cultured; Corticotropin-Releasing Hormone; Cyclic AMP; Disease Models, Animal; Dose-Response Relationship, Drug; Embryo, Mammalian; Fluorobenzenes; Hormones; Humans; Inositol Phosphates; Ionophores; Male; Maze Learning; Mice; Monensin; Mutation; Neurons; Piperidines; Prefrontal Cortex; Rats; Reaction Time; Receptors, Corticotropin-Releasing Hormone; Receptors, Serotonin, 5-HT2; Serotonin; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Serotonin Agents; Signal Transduction; Transfection