Effects of ovarian steroids and raloxifene on proteins that synthesize, transport, and degrade serotonin in the raphe region of macaques

Neuropsychopharmacology. 2004 Nov;29(11):2035-45. doi: 10.1038/sj.npp.1300510.


In the monkey dorsal raphe, we reported that 1-month (mo) of estrogen replacement, with or without progesterone supplementation for 14 days, significantly increased tryptophan hydroxylase-1 (TPH-1) mRNA; decreased serotonin reuptake transporter (SERT) mRNA and decreased monoamine oxidase (MAO)-A mRNA, but had no effect on MAO-B mRNA. Here, we questioned what effect would 1 or 5 mo of ovarian hormones or the selective estrogen receptor modulator (SERM), raloxifene, have on TPH protein and phosphorylation, and on protein expression of SERT, MAO-A or MAO-B? Raloxifene antagonizes estrogen in breast or uterus, but estrogen-like activities in the brain have been reported. Cytoplasmic and membrane extracts of the dorsal raphe region were processed for Western blotting. TPH, phosphoserine, SERT, MAO-A, and MAO-B were detected with specific antibodies. The optical densities of the signals were measured with NIH image and analyzed by ANOVA. Both 1 and 5 mo of estrogen, with or without progesterone, and 5 mo of raloxifene significantly increased TPH protein. Administration for 5 mo of estrogen plus progesterone and raloxifene also increased TPH phosphorylation. Estrogen, with or without progesterone, for 1 mo had no effect on SERT protein. However, 5 mo of estrogen and 5 mo of raloxifene increased SERT protein. Estrogen alone or combined with progesterone for 1 mo caused a significant reduction in MAO-A. Yet, after 5 mo of the same treatments, MAO-A was not different from spayed controls. Estrogen alone had no effect on MAO-B. However, the addition of progesterone significantly increased MAO-B. Raloxifene for 5 mo had no effect on MAO-A or MAO-B. Thus, to various extents, estrogen, progesterone, and raloxifene may increase serotonin production and transport. The expression of the degradative enzymes suggests a complex combination of gene transcription, post-transcriptional processing, and substrate feedback mechanisms.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Estrogens / metabolism
  • Estrogens / pharmacology*
  • Female
  • Macaca mulatta
  • Membrane Glycoproteins / biosynthesis*
  • Membrane Glycoproteins / metabolism
  • Membrane Transport Proteins / biosynthesis*
  • Membrane Transport Proteins / metabolism
  • Nerve Tissue Proteins / biosynthesis*
  • Nerve Tissue Proteins / metabolism
  • Ovary / drug effects
  • Ovary / metabolism
  • Progesterone / metabolism
  • Progesterone / pharmacology*
  • Proteins / metabolism
  • Raloxifene Hydrochloride / pharmacology*
  • Raphe Nuclei / drug effects*
  • Raphe Nuclei / metabolism
  • Serotonin / biosynthesis*
  • Serotonin / metabolism
  • Serotonin Plasma Membrane Transport Proteins


  • Estrogens
  • Membrane Glycoproteins
  • Membrane Transport Proteins
  • Nerve Tissue Proteins
  • Proteins
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin
  • Raloxifene Hydrochloride
  • Progesterone