5-HT1A/1B Receptors as Targets for Optimizing Pigmentary Responses in C57BL/6 Mouse Skin to Stress

Abstract

Stress has been reported to induce alterations of skin pigmentary response. Acute stress is associated with increased turnover of serotonin (5-hydroxytryptamine; 5-HT) whereas chronic stress causes a decrease. 5-HT receptors have been detected in pigment cells, indicating their role in skin pigmentation. To ascertain the precise role of 5-HT in stress-induced pigmentary responses, C57BL/6 mice were subjected to chronic restraint stress and chronic unpredictable mild stress (CRS and CUMS, two models of chronic stress) for 21 days, finally resulting in abnormal pigmentary responses. Subsequently, stressed mice were characterized by the absence of a black pigment in dorsal coat. The down-regulation of tyrosinase (TYR) and tyrosinase-related proteins (TRP1 and TRP2) expression in stressed skin was accompanied by reduced levels of 5-HT and decreased expression of 5-HT receptor (5-HTR) system. In both murine B16F10 melanoma cells and normal human melanocytes (NHMCs), 5-HT had a stimulatory effect on melanin production, dendricity and migration. When treated with 5-HT in cultured hair follicles (HFs), the increased expression of melanogenesis-related genes and the activation of 5-HT1A, 1B and 7 receptors also occurred. The serum obtained from stressed mice showed significantly decreased tyrosinase activity in NHMCs compared to that from nonstressed mice. The decrease in tyrosinase activity was further augmented in the presence of 5-HTR1A, 1B and 7 antagonists, WAY100635, SB216641 and SB269970. In vivo, stressed mice received 5-HT precursor 5-hydroxy-l-tryptophan (5-HTP), a member of the class of selective serotonin reuptake inhibitors (fluoxetine; FX) and 5-HTR1A/1B agonists (8-OH-DPAT/CP94253), finally contributing to the normalization of pigmentary responses. Taken together, these data strongly suggest that the serotoninergic system plays an important role in the regulation of stress-induced depigmentation, which can be mediated by 5-HT1A/1B receptors. 5-HT and 5-HTR1A/1B may constitute novel targets for therapy of skin hypopigmentation disorders, especially those worsened with stress.

Effects of two chronic stresses on mental state and hair follicle melanogenesis in mice

“…It has been reported that 5‐HT can induce melanogenesis and mammalian skin can both synthesize and metabolize 5‐HT . LC‐MS assay of 5‐HT in both serum and skin revealed that in mice serum, 5‐HT levels were down‐regulated in both CRS and CUMS groups with no significant differences.…”

“…Six‐ to seven‐week old, male, C57BL/6 mice which are in telogen stage, with profound stress response, were found to be suitable for the study and obtained from Shanghai laboratory animal centre, China. As per standard procedures, all mice were acclimated for a week at a 22±1°C temperature and 50±5% humidity with a 12‐hour light/dark cycle (lights on at 6:00 am and off at 18:00 pm ). During this period, food and water were provided ad libitum.…”

“…To induce anagen, depilation was carried out as per reports . Briefly, after stress exposure for 1 week, wax/rosin mixture (1:1 on weight) was applied to the dorsal skin (from neck to tail) of mice under anaesthesia.…”

Interferon-γ Attenuates 5-Hydroxytryptamine-Induced Melanogenesis in Primary Melanocyte

“…17) It has been reported that interferon-γ (IFN-γ) is highly expressed in the lesions of vitiligo patients. Furthermore, UVB irradiation can induce the secretion of IFN-γ in keratinocytes or macrophages.…”

“…16) Our preliminary study also found that 5-HT 1A receptor took a vital part in 'brain-skin connection' to regulate skin pigmentation. 17) It has been reported that interferon-γ (IFN-γ) is highly expressed in the lesions of vitiligo patients. Furthermore, UVB irradiation can induce the secretion of IFN-γ in keratinocytes or macrophages.…”