The different roles of 5-HT1A/2A receptors in fluoxetine ameliorated pigmentation of C57BL/6 mouse skin in response to stress

Background: 5-HT1A receptor was participated in fluoxetine induced melanogenesis in melanocytes and in normal C57BL/6 mice, but we know little about whether other 5-HT receptors are involved in regulation of fluoxetine promotes pigmentation. Objective: To investigate the role of 5-HT receptors in regulation of fluoxetine ameliorates chronic unpredictable mild stress (CUMS) and chronic restraint stress (CRS) induce hypopigmentation in C57BL/6 mice. Methods: CUMS and CRS were used to induce depigmentation in mice and evaluate the effect of fluoxetine. Western blot, immunohistochemistry and Q-PCR assay were used to determine the levels of protein and mRNA. Masson Fontana staining was used for melanin staining and FITC-Phalloidin staining was used to detect the expression of F-actin. Zebrafish and B16F10 cells were used for the mechanism research. Results: Fluoxetine (2.6 mg/kg, ig) ameliorated hypopigmentation induced by CUMS and CRS in mice, significantly increased the mRNA and protein levels of 5-HT1 A and 5-HT2 A receptors in mice and Bl6F10 cells. The effect of fluoxetine on melanogenesis in B16F10 cells and zebrafish were inhibited by WAY100635 (a selective 5-HT1 A receptor antagonist) and ketanserin (a 5-HT2 A receptor antagonist), respectively. Activation of p38 MAPK signaling pathways was contributed to fluoxetine induced melanogenesis and inhibited by WAY100635, but not ketanserin. However, ketanserin selectively weakened the action of fluoxetine promoted migration and up-regulated Rab27a protein expression in Bl6F10 cells. Conclusions: 5-HT1 A and 2 A receptors contribute to melanogenesis and migration property of fluoxetine. The newly revealed mechanism indicates that fluoxetine and its analogues may be a potential drug for treatment of depigmentation disorders. (C) 2018 Published by Elsevier B.V. on behalf of Japanese Society for Investigative Dermatology.