Estradiol reduced 5-HT reuptake by downregulating the gene expression of Plasma Membrane Monoamine Transporter (PMAT, Slc29a4) through estrogen receptor β and the MAPK/ERK signaling pathway

Estrogen deficiency-induced female depression is closely related to 5-hydroxytriptamine (5-HT) deficiency. Estradiol (17β-estradiol, E2) regulates the monoamine transporters and acts as an antidepressant by affecting 5-HT clearance through estrogen receptors and related signaling pathways at the genomic level, although the specific mechanisms require further exploration. The brain expresses higher levels of plasma membrane monoamine transporter (PMAT, involved in 5-HT reuptake of the uptake 2 system) than other uptake transporters. In this study, we found that estrogen-deficient ovariectomized (OVX) rats had high PMAT mRNA and protein expression levels in the hippocampus and estradiol significantly reduced these levels. Furthermore, estradiol inhibited PMAT expression and reduced 5-HT reuptake in neurons and astrocytes and estradiol regulated the PMAT expression mainly by affecting estrogen receptor β (ERβ) at the genomic level in astrocytes. Further experiments showed that estradiol also regulated PMAT expression through the MAPK/ERK signaling pathway and not through the PI3K/AKT signaling pathway. In conclusion, estradiol inhibited 5-HT reuptake by regulating PMAT expression at the genomic level through ERβ and the MAPK/ERK signaling pathway, highlighting the importance of PMAT in the antidepressant effects of estradiol through 5-HT clearance reduction.