Endogenous Serotonin and Milk Production Regulation in the Mammary Gland

Abstract

Intrinsic serotonin (5-hydroxytryptamine; 5-HT) synthesized within the mammary epithelium has an important physiological role in milk volume homeostasis in many species including mice, cows, and humans. During lactation, mammary epithelial cells activate 5-HT synthesis by tryptophan hydroxylase 1 (TPH1). TPH1 catalyzes the rate-limiting step in 5-HT biosynthesis within mammary glands. 5-HT synthesized in mammary glands is released into both the apical (milk) and basolateral spaces by a vesicular monoamine transporter. 5-HT released into milk is incorporated by the apical membrane-expressed serotonin reuptake transporter and degraded by the monoamine oxidase A enzyme. Suckling maintains 5-HT at low levels in milk. When the mammary gland becomes filled with milk, 5-HT provides a negative feedback signal that suppresses further milk synthesis in the mammary epithelium. Our research, using human mammary epithelial MCF-12A cells, shows that the expression of β-casein, a differentiation marker, is suppressed via 5-HT-mediated inhibition of signal transducer and activator of transcription 5. Additionally, our results show that reduced β-casein expression in MCF-12A cells is associated with 5-HT receptor expression. Furthermore, we show that 5-HT receptor-mediated suppression of β-casein expression is involved in the activation of protein kinase A and protein-tyrosine phosphatase 1B. Thus, this mechanism might be associated with the feedback signals by 5-HT within the mammary epithelium. Hence, further research that builds on our findings should include the elucidation of the physiological roles of 5-HT present in milk synthesized by mammary epithelial cells in vivo and its effects on nursing infants.

Morphological, hormonal, and molecular changes in different maternal tissues during lactation and post-lactation

“…Suckling is an important mechanism that regulates and maintains low levels of serotonin in milk. When the mammary gland is filled with milk, serotonin provides a negative feedback that inhibits milk synthesis in the mammary epithelium [37]. The expression of β-casein is suppressed in the mammary epithelial MCF-12A cells and is associated with the serotonin-7 receptor (5HT/) expression [37].…”

“…When the mammary gland is filled with milk, serotonin provides a negative feedback that inhibits milk synthesis in the mammary epithelium [37]. The expression of β-casein is suppressed in the mammary epithelial MCF-12A cells and is associated with the serotonin-7 receptor (5HT/) expression [37]. Furthermore, during lactation, serotonin has a negative control over the β-casein expression in the mammary gland through the serotonin-7 receptor (5HT7) expression [37], and increased mRNA abundance of calcium transporters Ncx1, Serca2, Spca2, Pmca2, and Sglt1, but not the calcium-sensing receptor expression in the mammary gland [35], and increased osteoclasts and resorption of bone [35].…”

Tryptophan metabolism is dysregulated in individuals with Fanconi anemia

“…It is possible that skin tissue damage from the transplant preparative regimen releases a surge of serotonin, explaining the increases in circulating serotonin we measured. However, with multiple peripheral sites in the body capable of intrinsic serotonin production in addition to the skin, including the lungs, pancreas, adipocytes, and mammary epithelium, 16,23,49,50 additional investigation surrounding contributing sites of production is warranted.…”

Exploring the Efficacy of Comprehensive Management of Breast Abscesses in Restoring Milk Volume

“…In this study, the onset time for breast abscess was the lactation maintenance stage. At this stage, the milk volume is influenced by hormonal and local control mechanisms, and the latter regulate the development of mammary gland epithelial cells (acini) and milk secretion from them (Chiba et al, 2018) to meet the physiological needs of infants. In our study, with the increase in the frequency of milk expression, the milk volume from both the healthy breasts and breasts with abscesses increased.…”